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[ "The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK55___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .", "[ Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin - converting enzyme inhibitor in patients with chronic glomerulonephritis ] . P30556 blocker ( ARB ) and angiotensin - converting enzyme inhibitor ( ACEI ) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis . Recently , an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy , but the mechanism responsible for the effect has not yet been determined . In this study , we examined additive effect of these two drugs in chronic glomerulonephritis patients . Ten patients with biopsy - proven primary glomerulonephritis ( eight IgA nephropathy patients , two membranous nephropathy patients ) , non - nephrotic proteinuria ( protein , 0 . 5 to 3 . 5 g / day ) received candesartan cilexetil ( 2 or 4 mg ) for 8 weeks . After the 8 weeks , a combination of perindopril erbumine ( 1 or 2 mg ) and candesartan cilexetil was administered to the patients . DB00790 was stopped after the 8 - week administration of the two drugs . DB00796 alone reduced proteinuria by 13 % . Combination of these two drugs induced a more remarkable reduction of proteinuria ( 48 % ; p < 0 . 05 vs other periods ) . The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria . The combination of drugs also reduced the amount of urinary type - IV collagen excretion . An additive effect of ACEI and ARB on proteinuria and urinary type - IV collagen excretion was recognized in patients with chronic glomerulonephritis .", "[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .", "Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .", "Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK45___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK45___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK45___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK45___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK45___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK45___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK45___ .", "The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK5___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .", "___MASK23___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK23___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .", "Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK75___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK75___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK75___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .", "Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .", "[ Association study of renin - angiotensin system genes and hemostasis system genes with ischemic stroke among Russians of Central Russia ] . The analysis of alleles and genotypes frequencies of 14 SNP in genes of rennin - angiotensin system ( REN , AGT , P30556 , P50052 , P30411 , P07550 ) and hemostasis system ( P02675 , F2 , P12259 , P08709 , P05106 , P05121 , P42898 ) , as well as P12821 insertion - deletion polymorphism in patients with stroke comparing to healthy controls matched by age , sex and ethnicity has been carried out . The genotyping procedure included the amplification of selected gene sequences following by hybridization of fluorescently labeled fragments with SNP - specific DNA probes . The analysis of allele frequencies of each gene separately revealed no statistically significant differences between groups of patients with stroke and healthy donors . Also the complex study has been performed to estimate the contribution of rennin - angiotensin system and hemostasis system genes to the genetic susceptibility to ischemic stroke among Russians from Central Russia using method MDR ( Multifactor Dimensionality Reduction ) . The combination with increased risk for development of ischemic stroke was presented by complex genotype P02675 G /- x P12821 I /- x P42898 C /- x P05121 5G / 5G ( p = 0 . 03 , OR = 2 . 4 , 95 % CI 1 . 1 - 5 . 3 ) , which frequency was statistically significant higher in patients with stroke compared to healthy control .", "[ The role of glycogen synthase kinase - 3 beta in the pathogenesis of liver ischemia reperfusion injury ] . OBJECTIVE : To investigate the role of the key intracellular signaling molecule glycogen synthase kinase - 3 beta in the mechanism of liver ischemia reperfusion ( IR ) . METHODS : C57BL / 6 mice were subjected to 90 min warm liver cephalad lobe ischemia , followed by various length of reperfusion . Experiment groups included sham control group , liver IRI model group and glycogen synthase kinase - 3 beta inhibitor - treated group ( SB216763 in DB01093 , 25 g / kg , i . p , 2 hour prior to the onset of liver ischemia ) . The expression of glycogen synthase kinase - 3 beta protein was analysed by Western blotting . The serum ALT levels were determined to reflect the function of liver . The affected liver lobes were harvested for histology analysis . The inflammatory gene expression was detected by Quantitative PCR . RESULTS : By western blot analysis , we found that ischemia itself activated glycogen synthase kinase - 3 beta by a significant decrease of its phosphorylation . P49841 inhibitor SB216763 - pretreatment ameliorated the liver damages significantly as compared to the controls ( sALT : 2046 +/- 513 U / L vs 5809 +/- 1689 U / L , P = 0 . 0153 ) , and suppressed the gene expressions of IL - 12 , TNFa , IL - 1b and P05231 . CONCLUSIONS : This study demonstrated that the ischemia process modulated liver innate immune activation via a GSK - 3 - dependent mechanism which favored the development of a pro - inflammation response and lead to liver tissue damages . GSK - 3b may be a new therapeutic target to ameliorate liver IRI in transplant patients .", "Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .", "Cooperative regulation of extracellular signal - regulated kinase activation and cell shape change by filamin A and beta - arrestins . beta - Arrestins ( betaarr ) are multifunctional adaptor proteins that can act as scaffolds for G protein - coupled receptor activation of mitogen - activated protein kinases ( MAPK ) . Here , we identify the actin - binding and scaffolding protein filamin A ( P21333 ) as a betaarr - binding partner using Son of sevenless recruitment system screening , a classical yeast two - hybrid system , coimmunoprecipitation analyses , and direct binding in vitro . In P21333 , the betaarr - binding site involves tandem repeat 22 in the carboxyl terminus . betaarr binds P21333 through both its N - and C - terminal domains , indicating the presence of multiple binding sites . We demonstrate that betaarr and P21333 act cooperatively to activate the MAPK extracellular signal - regulated kinase ( P29323 ) downstream of activated muscarinic M1 ( M1MR ) and angiotensin II type 1a ( P30556 ) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of betaarr - P28482 complex formation by P21333 . In Hep2 cells , stimulation of M1MR or P30556 results in the colocalization of receptor , betaarr , P21333 , and active P29323 in membrane ruffles . Reduction of endogenous levels of betaarr or P21333 and a catalytically inactive dominant negative Q02750 , which prevents P29323 activation , inhibit membrane ruffle formation , indicating the functional requirement for betaarr , P21333 , and active P29323 in this process . Our results indicate that betaarr and P21333 cooperate to regulate P29323 activation and actin cytoskeleton reorganization .", "___MASK88___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .", "Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome . The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease ( CKD ) in Japanese individuals with metabolic syndrome . The study population comprised 2150 Japanese individuals with metabolic syndrome , including 411 subjects with CKD [ estimated glomerular filtration rate ( eGFR ) < 50 mL / min / 1 . 73m ( 2 ) ] and 1739 controls ( eGFR >/= 60 mL / min / 1 . 73m ( 2 ) ) . The genotypes for 100 polymorphisms of 80 candidate genes were determined . The chi - square test , multivariable logistic regression analysis with adjustment for covariates , as well as a stepwise forward selection procedure revealed that nine polymorphisms of P02649 , O95477 , P23219 , P01375 , Q96IY4 , P30556 , Q8NGZ3 , and P16520 were associated ( P < 0 . 05 ) with the prevalence of CKD . Among these polymorphisms , the - 219G --> T polymorphism of P02649 ( rs405509 ) was most significantly associated with CKD in Japanese individuals with metabolic syndrome .", "___MASK79___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK79___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK79___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .", "A - type natriuretic peptide level in angiotensin II type 1a receptor knockout mice . A - type ( atrial ) natriuretic peptide ( P01160 ) levels in the heart and plasma were examined by immunohistochemistry , electron microscopy , and radioimmunoassay ( RIA ) in angiotensin II type 1a receptor knockout ( Agtr1a KO ) mice . Additionally , the P01160 mRNA level in the heart was measured using a real - time polymerase chain reaction ( PCR ) assay . The blood pressure in Agtr1a KO mice was significantly lower than that in wild - type ( WT ) mice . The number of P01160 granules and P01160 immunoreactivity in the auricular cardiocytes were significantly lower in Agtr1a KO mice than in WT mice . Ultrastructurally , the ventricular cardiocytes in Agtr1a KO mice occasionally had P01160 - like granules , which were not present in WT mice . The plasma , auricular , and ventricular P01160 and plasma cyclic guanosine monophosphate ( cGMP ) concentrations were significantly higher in Agtr1a KO mice than in WT mice . The P01160 mRNA levels of the auricular and ventricular cardiocytes in the Agtr1a KO mice were almost twice as large as those in WT mice . The present data suggest that a notable increase in the P01160 biosynthesis and release in the heart of Agtr1a KO mice may account for the reduction in blood pressure together with the lack of an P30556 receptor in this model .", "DB00796 inhibits Toll - like receptor expression and activity both in vitro and in vivo . INTRODUCTION : Toll - like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis , atherosclerosis , and arthritis . O60603 and O00206 expression is upregulated in the inflammatory diseases . Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT ( 1 ) R . P30556 blocker ( ARB ) , widely used as an antihypertensive drug , has been reported to also have anti - inflammatory effects . Thus , we investigated whether an ARB exerts anti - inflammatory effects via inhibiting O60603 and O00206 expression . METHODS AND RESULTS : Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan . Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced O60603 and O00206 expression of both mRNA and protein levels ( P < 0 . 05 vs . control ) along with decrease in the activity of NF - kappaB and the expression of IL - 1beta , P05231 , P01375 , and P13500 . Furthermore , candesartan treated mice show decreased O60603 and O00206 expression compared to vehicle control mice . CONCLUSION : Pam3CSK4 and LPS induced O60603 and O00206 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo . Thus , we define a novel pathway by which candesartan could induce anti - inflammatory effects .", "[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK1___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .", "___MASK87___ unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . ___MASK87___ ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .", "Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .", "DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "___MASK75___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation ." ]

[ "___MASK1___", "___MASK23___", "___MASK45___", "___MASK55___", "___MASK5___", "___MASK75___", "___MASK79___", "___MASK87___", "___MASK88___" ]

[ "DB00197 inhibits vascular endothelial growth factor - induced angiogenic signaling via suppression of reactive oxygen species production and extracellular signal - regulated kinase phosphorylation in endothelial cells . Thiazolidinediones , peroxisome proliferators - activated receptor gamma ( PPARgamma ) ligands , have been recognized as a potential therapeutic agents for the treatment of pathological neovascularization . In the present study , we examined the molecular mechanism by which troglitazone ( TROG ) , a PPARgamma agonist , exerts its inhibitory action in vascular endothelial growth factor ( P15692 ) - induced angiogenesis signaling . In an in vitro angiogenesis model using human umbilical vein endothelial cells , TROG ( 20 muM ) significantly suppressed P15692 - induced cell proliferation and invasion of the cells into the Matrigel basement membrane , which was not reversed by treatment with Q07869 antagonists , GW9662 ( 10 muM ) and bisphenol A diglycidyl ether ( 10 muM ) . TROG also blocked P15692 - induced reactive oxygen species ( ROS ) production and its downstream extracellular signal - regulated kinase ( P29323 ) phosphorylation , and this inhibitory effect was not reversed by GW9662 ( 10 muM ) . The antiangiogenic activity of TROG correlated with suppression of P15692 - induced matrix metalloproteinase ( MMP ) - 2 and membrane type 1 ( MT1 ) - MMP expression . In addition , the effects of TROG on P15692 - induced P08253 and P50281 expression were comparable to those of the NADPH oxidase inhibitor diphenylene iodium ( 10 muM ) and P29323 inhibitor PD98056 ( 10 muM ) . Furthermore , in an in vivo angiogenesis system using a chick chorioallantoic membrane model , TROG dose - dependently inhibited P15692 - induced angiogenesis , which was similar to the inhibitory effect of DB06151 on P15692 - induced angiogenesis . The results suggest that the inhibitory effects of TROG on P15692 - induced angiogenesis were mediated through the suppression of P15692 - induced ROS production and P29323 phosphorylation .", "Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK35___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .", "Mediator subunit Gal11p / Q96RN5 is required for fatty acid - dependent gene activation by yeast transcription factor Oaf1p . The yeast zinc cluster transcription factor Oaf1p activates transcription of target genes in response to direct binding of fatty acids in a manner analogous to the vertebrate nuclear receptor peroxisome proliferator - activated receptoralpha ( PPARalpha ) . PPARs and other metazoan nuclear receptors productively engage several distinct LXXLL motif - containing co - activators , including P52701 family members and the Q15648 / MED1 subunit of the Mediator co - activator , to promote ligand - dependent gene activation . Yeast , however , does not appear to harbor LXXLL motif co - activators , and the mechanism of fatty acid - dependent gene activation by the yeast PPARalpha analog Oaf1p is unknown . Here we show that the yeast Mediator subunit Gal11p / Q96RN5 and its activator - targeted KIX domain plays a critical role in fatty acid - dependent transcriptional regulation of fatty acid beta - oxidation and peroxisomal genes by Oaf1p and for the ability of yeast to utilize fatty acids as a sole carbon source . Moreover , structural studies by NMR spectroscopy reveal that the Oaf1p activation domain interacts with the Gal11p / Q96RN5 KIX domain in a manner similar to the yeast zinc cluster family member and xenobiotic receptor Pdr1p , revealing that the Gal11p / Q96RN5 KIX domain is a key target of several ligand - dependent transcription factors in yeast . Together with previous work showing that the Caenorhabditis elegans Gal11p / Q96RN5 homolog MDT - 15 plays a critical role in regulation of fatty acid metabolism by the nematode Q07869 - like nuclear receptor NHR - 49 , the findings presented here provide evidence for an ancient and essential role of a Mediator co - activator subunit in regulation of fatty acid metabolism by nuclear receptor - like transcription factors in eukaryotes .", "Chronic myeloid leukemic cells trigger poly ( ADP - ribose ) polymerase - dependent inactivation and cell death in lymphocytes . NK cells and T cells are commonly dysfunctional in CML , and their status may determine the course of disease . We aimed to define the molecular mechanisms of leukemia - induced immunosuppression with focus on the role of ROS and the P09874 pathway of cell death . Malignant granulocytes from patients with P11274 - P00519 - positive CML expressed the oxygen radical - producing enzyme NOX , produced large amounts of ROS , and triggered extensive cell death in NK cells . Inhibition of P09874 maintained NK cell viability in cocultures with suppressive leukemic cells . Under conditions of oxidative stress , P09874 inhibition upheld the capacity of NK cells to kill myeloid leukemic cells , in addition to restoring the proliferation and cytokine production of NK cells and cytotoxic T cells . Our findings are suggestive of a novel pathway of relevance to immunosuppression in CML .", "DB09341 transporter - 2 ( P11168 ) promoter mediated transgenic insulin production reduces hyperglycemia in diabetic mice . P01308 production afforded by hepatic gene therapy ( HGT ) retains promise as a potential treatment for type 1 diabetes , but successful approaches have been limited . We employed a novel and previously untested promoter for this purpose , glucose transporter - 2 ( P11168 ) to drive insulin production via delivery by recombinant adeno - associated virus ( rAAV ) . In vitro , the P11168 promoter was capable of robust glucose - responsive expression in transduced HepG2 human hepatoma cells . Therefore , rAAV constructs were designed to express the furin - cleavable human preproinsulin B10 gene , under the control of the murine P11168 promoter and packaged for delivery with rAAV expressing the type 5 capsid . DB00428 - induced diabetic mice were subjected to hepatic portal vein injection immediately followed by implantation of a sustained - release insulin pellet to allow time for transgenic expression . All mice injected with the rAAV5 - P11168 - fHPIB10 virus remained euglycemic for up to 35 days post - injection , with 50 % euglycemic after 77 days post - injection . In contrast , mock - injected mice became hyperglycemic within 15 days post - injection following dissolution of the insulin pellet . Serum levels of both human insulin and C - peptide further confirmed successful transgenic delivery by the rAAV5 - P11168 - fHPIB10 virus . These findings indicate that the P11168 promoter may be a potential candidate for regulating transgenic insulin production for hepatic insulin gene therapy in the treatment of type I diabetes .", "Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( ___MASK51___ ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of ___MASK51___ - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves ___MASK51___ - induced steatotic phenotype in the liver . In wild - type mice ___MASK51___ induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , ___MASK51___ did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes ___MASK51___ - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .", "Aging and age - related diseases -- from endocrine therapy to target therapy . Aging represents an important health issue not only for the individual , but also for society in general . Burdens associated with aging are expanding as longevity increases . This has led to an enhanced focus on issues related to aging and age - related diseases . Until recently , anti - aging endocrine - therapy has been largely limited to hormone - replacement therapy ( HRT ) that is associated with multiple side effects , including an increased risk of cancer . This has greatly limited the application of HRT in anti - aging therapy . Recently , the focus of anti - aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks . In this regard , the P01286 - GH - DB01277 / P01308 , TOR - P23443 , NAD (+)- Sirtuin , P04637 , Q9UEF7 and P02649 pathways have been linked to processes associated with age - related diseases , including cancer , cardiovascular disease , diabetes , osteoporosis , and neurodegenerative diseases , all of which directly influence health in aging , and represent key targets in anti - aging therapy .", "Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .", "Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK15___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .", "Novel roles of Akt and P42345 in suppressing TGF - beta / P36897 - mediated P84022 activation . P01308 - like growth factor - I inhibits transforming growth factor - beta ( TGF - beta ) signaling by blocking activation of P84022 ( S3 ) , via a phosphatidylinositol 3 - kinase ( PI3K ) / Akt - dependent pathway . Here we provide the first report that the kinase activity of Akt is necessary for its ability to suppress many TGF - beta responses , including S3 activation and induction of apoptosis . Wild - type and myristoylated Akts ( Akt ( WT ) and Akt ( Myr ) ) suppress TGF - beta - induced phospho - activation of S3 but not Q15796 ( S2 ) , whereas kinase - dead Akt1 ( Akt1K179M ) or dominant - negative PI3K enhances TGF - beta - induced phospho - activation of both S2 and S3 . Using siRNA , rapamycin ( Rap ) , and adenoviral expression for P62942 - resistant and constitutively active P36897 ( P36897 ) , we demonstrate that mammalian target of Rap ( P42345 ) mediates Akt1 suppression of phospho - activation of S3 . These and further data on Akt1 - S3 binding do not support a recently proposed model that Akt blocks S3 activation through physical interaction and sequestration of S3 from TGF - beta receptors . We propose a novel model whereby Akt suppresses activation of S3 in an Akt kinase - dependent manner through P42345 , a likely route for loss of tumor suppression by TGF - beta in cancers .", "DB00428 - nicotinamide - induced diabetes in the rat . Characteristics of the experimental model . Administration of both streptozotocin ( Q11206 ) and nicotinamide ( NA ) has been proposed to induce experimental diabetes in the rat . Q11206 is well known to cause pancreatic B - cell damage , whereas NA is administered to rats to partially protect insulin - secreting cells against Q11206 . Q11206 is transported into B - cells via the glucose transporter P11168 and causes DNA damage leading to increased activity of poly ( ADP - ribose ) polymerase ( P09874 ) to repair DNA . However , exaggerated activity of this enzyme results in depletion of intracellular NAD (+) and DB00171 , and the insulin - secreting cells undergo necrosis . The protective action of NA is due to the inhibition of P09874 activity . NA inhibits this enzyme , preventing depletion of NAD (+) and DB00171 in cells exposed to Q11206 . Moreover , NA serves as a precursor of NAD (+) and thereby additionally increases intracellular NAD (+) levels . The severity of diabetes in experimental rats strongly depends on the doses of Q11206 and NA given to these animals . Therefore , in diabetic rats , blood glucose may be changed in a broad range -- from slight hyperglycemia to substantial hyperglycemia compared with control animals . Similarly , blood insulin may be only slightly decreased or substantial hypoinsulinemia may be induced . In vitro studies demonstrated that the insulin - secretory response to glucose is attenuated in Q11206 - NA - induced diabetic rats compared with control animals . This is due to reduced B - cell mass as well as metabolic defects in the insulin - secreting cells . Results of numerous experiments have demonstrated that this model of diabetes is useful in studies of different aspects of diabetes .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK70___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "Single daily dose corticosteroid treatment . Thirteen patients with rheumatoid or psoriatic arthritis who had not previously received corticosteroids were treated with prednisolone in a single - dose each morning . P01308 - hypoglycaemia tests were performed before starting steroids in each patient , and again at the conclusion of the study in twelve of the thirteen ( duration of steroid treatment 8 - 40 m ) . There was no difference in the mean basal or peak levels of corticosteroids , or the mean peak of growth hormone ( GH ) in the tests done before or during treatment , although one patient lost GH responsiveness . There was thus no evidence of hypothalamo - pituitary - adrenal ( Q9Y251 ) suppression in any of the twelve patients , and there was a good therapeutic response in twelve out of thirteen . One patient was dropped from the trial because treatment failed . In contrast , of seven patients who had received a similar total dose of prednisolone twice daily , three showed Q9Y251 suppression and two had lost GH responsiveness .", "A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK98___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK98___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .", "Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK51___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .", "Nuclear factor kappa B inhibition improves conductance artery function in type 2 diabetic mice . BACKGROUND : We previously reported that enhanced nuclear factor kappa B ( NFκB ) activity is responsible for resistance arteries dysfunction in type 2 diabetic mice . METHODS : In this study , we aimed to determine whether augmented NFκB activity also impairs conductance artery ( thoracic aorta ) function in type 2 diabetic mice . We treated type 2 diabetic ( db (-) / db (-) ) and control ( db (-) / db (+) ) mice with two NFκB inhibitors ( dehydroxymethylepoxyquinomicin , 6 mg / kg , twice a week and IKK - NBD peptide , 500 µg / kg / day ) for 4 weeks . RESULTS : As expected , the NFκB inhibition did not affect blood glucose level and body weight . Thoracic aorta vascular endothelium - dependent relaxation ( EDR ) , determined by the wire myograph , was impaired in diabetic mice compared with control and was significantly improved after NFκB inhibition . Interestingly , thoracic EDR was also rescued in db (-) / db (- p50NFκB -/-) and db (-) / db (- P09874 -/-) double knockout mice compared with db (-) / db (-) mice . Similarly , the acute in vitro down regulation of NFκB - p65 using p65 shRNA lentiviral particles in arteries from db (-) / db (-) mice also improved thoracic aorta EDR . Western blot analysis showed that the p65NFκB phosphorylation , cleaved P09874 and P35354 expression were increased in thoracic aorta from diabetic mice , which were restored after NFκB inhibition and in db (-) / db (- p - 50NFκB -/-) and db (-) / db (- P09874 -/-) mice . CONCLUSIONS : The present results indicate that in male type 2 diabetic mice , the augmented NFκB activity also impairs conductance artery function through P09874 and P35354 - dependent mechanisms .", "Serum concentrations of growth factors in women with and without endometriosis : the action of anti - endometriosis medicines . Endometriosis is a common gynecologic syndrome of unknown etiology and pathogenesis . Growth factors and inflammatory mediators produced by peritoneal leukocytes have recently been postulated to participate in the pathogenesis of endometriosis . Angiogenic factors released from peritoneal macrophages may also play a role in the development of this disease . In the present study , we investigate the soluble levels of vascular endothelial growth factor ( P15692 ) , epidermal growth factor - receptor ( P01133 - R ) , granulocyte / macrophage - colony stimulating factor ( GM - P04141 ) , P01308 - like growth factor - 1 ( DB01277 ) and interferon - gamma ( P01579 ) in the serum of 28 women with and 20 without endometriosis . We also compared these levels before , during and after treatment with danazol and leuprorelin acetate depot , the two therapeutic regiments of choice concerning this disease . We found that only sVEGF levels were higher in women with endometriosis in comparison to controls ( P < 0 . 001 ) while sEGF - R is not present . GM - P04141 , DB01277 and P01579 soluble levels are not affected in either healthy or endometriotic subjects . The 6 - month treatment with danazol decreased sVEGF levels ( P < 0 . 02 ) and increased sEGF - R levels ( P < 0 . 001 ) . These observations support the view that P15692 may be associated with the disease process and that danazol may bring sVEGF levels to a normal threshold . However , future studies will be focused on the anti - angiogenic control of the action of P15692 in patients with endometriosis .", "Antihyperglycemic Activity of Houttuynia cordata Thunb . in DB00428 - Induced Diabetic Rats . Present study is an attempt to investigate plausible mechanism involved behind antidiabetic activity of standardized Houttuynia cordata Thunb . extract in streptozotocin - induced diabetic rats . The plant is used as a medicinal salad for lowering blood sugar level in North - Eastern parts of India . Oral administration of extract at 200 and 400 mg / kg dose level daily for 21 days showed a significant ( P < 0 . 05 ) decrease in fasting plasma glucose and also elevated insulin level in streptozotocin - induced diabetic rats . It also significantly reversed all the alterations in biochemical parameters , that is , total lipid profile , blood urea , creatinine , protein , and antioxidant enzymes in liver , pancreas , and adipose tissue of diabetic rats . Furthermore , we have demonstrated that the extract significantly reversed the expression patterns of various glucose homeostatic enzyme genes like P11168 , P14672 , and caspase - 3 levels but did not show any significant effect on Q07869 - γ protein expressions . Additionally , the extract positively regulated mitochondrial membrane potential and succinate dehydrogenase ( SDH ) activity in diabetic rats . The findings justified the antidiabetic effect of H . cordata which is attributed to an upregulation of P14672 and potential antioxidant activity , which may play beneficial role in resolving complication associated with diabetes .", "[ ___MASK88___ : A new drug of B - cell malignancies ] . ___MASK88___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK88___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK88___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .", "___MASK33___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK33___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK90___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .", "aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK82___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .", "DB00428 diabetes and the expression of P11166 at the brush border and basolateral membranes of intestinal enterocytes . Changes in membrane expression of sodium - dependent glucose transporter ( P13866 ) and glucose transporter isoform ( P11168 ) protein have been implicated in the increased intestinal glucose transport in streptozotocin - diabetes . The possible involvement of P11166 in the transport response , however , has not previously been studied . Using confocal microscopy on tissue sections and Western blotting of purified brush border membrane ( BBM ) and basolateral membrane ( BLM ) , we have examined enterocyte expression of P11166 in untreated and in 1 and 21 day streptozotocin diabetic rats . In control enterocytes , P11166 was absent at the BBM and detected at low levels at the BLM . Diabetes resulted in a 4 - to 5 - fold increased expression of P11166 at the BLM and the protein could also be readily detected at the BBM . P01308 treatment of diabetic rats increased P11166 level at the BBM but was without effect on expression of the protein at the BLM ." ]

[ "___MASK15___", "___MASK33___", "___MASK35___", "___MASK51___", "___MASK70___", "___MASK82___", "___MASK88___", "___MASK90___", "___MASK98___" ]

[ "Polymorphism identification in the P11310 , P01008 , P22301 , P15173 and P01222 genes of cattle .", "Two thyroid hormone regulated genes , the beta - subunits of nerve growth factor ( P01138 ) and thyroid stimulating hormone ( P01222 ) , are located less than 310 kb apart in both human and mouse genomes . Two thyroid hormone regulated genes , the beta - subunits of nerve growth factor ( P01138 ) and thyroid stimulating hormone ( P01222 ) , have been assigned to mouse chromosome 3 and human chromosome 1p22 . We have used the techniques of linkage analysis and pulsed field gel electrophoresis to determine the proximity of these two antithetically regulated genes in this conserved linkage group . Four novel restriction fragment length polymorphisms were identified at the human P01222 gene . Two - point linkage analysis between P01222 and P01138 in 46 families , including the Centre d ' Etude du Polymorphisme Humain ( CEPH ) reference panel , demonstrated no recombination ( theta = 0 . 00 , Z = 42 . 8 ) . Analysis of this region by pulsed field gel electrophoresis showed that the genes for P01222 and P01138 are located less than 310 kb apart in man and 220 kb in the mouse .", "Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .", "Q9NR12 - 420 , a small molecular inhibitor of P01375 - α , prolongs islet allograft survival by induction of suppressor of cytokine signaling - 1 : synergistic effect with cyclosporin - A . Inflammatory insults following islet transplantation ( ITx ) hinders engraftment and long - term function of the transplanted ( Tx ) islets . Using a murine model of ITx , we determined the role of Q9NR12 - 420 , a novel P01375 - α inhibitor , both individually and in combination with the immunosuppressant cyclosporine A ( Q13216 ) in islet engraftment and survival . Diabetic C57BL / 6 mice were Tx with 500 BALB / c islets under the kidney capsule . Four cohorts were used : Q9NR12 - 420 only , Q13216 only , combination of Q9NR12 - 420 and Q13216 ( Q9NR12 + Q13216 ) , and control ( n = 12 per cohort ) . Serial monitoring of blood glucose levels revealed that Q9NR12 + Q13216 ( 35 ± 5 days ) prolonged stable blood insulin levels compared to control ( 6 ± 4 days ) . Immunohistology demonstrated that coadministration ( Q9NR12 + Q13216 ) results in a significant decrease in CD8 (+) T - cell infiltration ( Q9NR12 + Q13216 : 31 ± 18 vs . control : 224 ± 51 cells , p < 0 . 001 ) . Serum cytokine analysis revealed that Q9NR12 - 420 administration resulted in an increase in the anti - inflammatory cytokine P22301 ( 2 . 5 - fold ) , and a decrease in P01375 - α ( threefold ) with no change in P60568 . However , coadministration resulted in a marked decrease in both P60568 and P01375 - α ( threefold ) along with increase in P22301 ( threefold ) . Coadministration also demonstrated increase of antiapoptotic O15524 and Mn - SOD expression and significant reduction of donor - specific antibodies ( p < 0 . 005 ) . In conclusion , Q9NR12 - 420 administration with Q13216 results in the upregulation of anti - inflammatory and antiapoptotic mechanisms which facilitate islet allograft engraftment and survival .", "[ New pharmacological approaches to the treatment of schizophrenia ] . Schizophrenia is a serious mental disorder with a challenging rational pharmacotherapy . Neurochemical transmission in the dopaminergic system , especially via D2 receptors , and related changes in postsynaptic signal transduction are very important in both the formation of schizophrenia and current pharmacotherapeutic treatment with antipsychotic drugs . Blocking the serotonergic 5 - Q13049 and P28335 receptors is growing growing importance with regard to the action mechanisms of new generation antipsychotic medications . Recent preclinical and clinical data show that dysfunction of central neurotrophins , such as nerve growth factor ( P01138 ) , brain - derived neurotrophic factor ( P23560 ) , and neurophin - 3 ( P20783 ) might contribute to impaired brain development and neuroplasticity , leading to schizophrenia . In addition , some recent studies suggest that there is an important relationship between alcohol and substance addiction , and schizophrenia . There is also some preclinical data indicating that the central nitrergic system and agmatine ( 3 / 4 ) a biologically active agent produced after decarboxylation of arginine ( 3 / 4 ) might be interesting and important targets for understanding the etiopathogenesis of schizophrenia and for development of new drugs . Selective dopamine D3 receptor antagonists , specific agonists for metabotropic and DB01221 receptors of the glutamatergic system , and nicotinic alpha - 7 receptor agonists were reported in preclinical and a limited number of clinical studies as potential new targets for schizophrenia treatment . In this review , new advances in the pharmacotherapy of schizophrenia and possible new targets are discussed in the light of the current literature .", "Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 - binding cassette transporters ( ABCs ) in one of the most drug - resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical - pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real - time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high - resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical - pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up - regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up - regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down - regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC .", "The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK11___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK11___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK11___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK11___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .", "Changes of thyroid hormone levels and related gene expression in zebrafish on early life stage exposure to triadimefon . In this study , zebrafish was exposed to triadimefon . Thyroid hormones levels and the expression of related genes in the hypothalamic - pituitary - thyroid ( Q9HD23 ) axis , including thyroid - stimulating hormone ( P01222 ) , deiodinases ( dio1 and dio2 ) and the thyroid hormone receptor ( thraa and thrb ) were evaluated . After triadimefon exposure , increased DB00451 can be explained by increased thyroid - stimulating hormone ( P01222 ) . The conversion of DB00451 to DB00279 ( deiodinase type I - dio1 ) was decreased , which reduced the DB00279 level . P10828 ( thrb ) mRNA levels were significantly down - regulated , possibly as a response to the decreased DB00279 levels . The overall results indicated that triadimefon exposure could alter gene expression in the Q9HD23 axis and that mechanisms of disruption of thyroid status by triadimefon could occur at several steps in the synthesis , regulation , and action of thyroid hormones .", "Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK50___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .", "DB00024 : an endogenous regulator of the in vitro immune response . We have previously shown that thyrotropin ( DB00024 ) , which is produced by lymphocytes in response to the T cell mitogen staphylococcal enterotoxin A , enhances in vitro antibody production to T cell - dependent and independent Ag ( SRBC and trinitrophenylated Brucella abortus [ BA - O15533 ] , respectively ) as determined by a direct plaque - forming cell assay . As a result of these studies , experiments were designed to examine the possible immunoregulatory function of thyrotropin - releasing hormone ( TRH ) on the in vitro antibody response to the T cell - independent Ag BA - TNP . Our studies demonstrate that TRH at very low concentrations ( pM ) enhances the in vitro plaque - forming cell response to BA - TNP and also induces splenocyte production of DB00024 . Other hypothalamic - releasing factors were without effect . This enhancement effect by TRH was specifically blocked by rabbit antisera to the P01222 subunit , whereas addition of normal rabbit sera had no effect . These data suggest that TRH specifically enhances the in vitro antibody response via production of immunoreactive DB00024 .", "___MASK35___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .", "___MASK41___ overcomes gefitinib resistance in human non - small cell lung cancer cells with K - Ras mutations . ___MASK41___ is a 3 - hydroxy - 3 - methylglutaryl - coenzyme A ( HMG - DB01992 ) reductase inhibitor . Its inhibitory action on P04035 leads to depletion of isoprenoids , which inhibits post - translational modification of DB01367 . In this study , we investigated the effect of combining lovastatin with gefitinib on gefitinib - resistant human non - small cell lung cancer ( NSCLC ) cell lines with K - Ras mutations . Antitumor effects were measured by growth inhibition and 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide assay . Effects on apoptosis were determined by flow cytometry , DNA fragmentation , and immunoblots . Protein levels of DB01367 , AKT / pAKT , and RAF / P27361 / 2 in cancer cells were analyzed by immunoblot . Compared with gefitinib alone , a combination of gefitinib with lovastatin showed significantly enhanced cell growth inhibition and cytotoxicity in gefitinib - resistant A549 and NCI - H460 human NSCLC cells . In addition , lovastatin combination treatment significantly increased gefitinib - related apoptosis , as determined by fluorescence microscopy and flow cytometric analysis . These effects correlated with up - regulation of cleaved caspase - 3 , poly ( ADP - ribose ) polymerase ( PARP ) , and Bax and down - regulation of Bcl - 2 . The combination of lovastatin and gefitinib effectively down - regulated DB01367 protein and suppressed the phosphorylation of RAF , P27361 / 2 , AKT , and P00533 in both cell lines . Taken together , these results suggest lovastatin can overcome gefitinib resistance , in NSCLC cells with K - Ras mutations , by down regulation of DB01367 protein , which leads to inhibition of both RAF / P29323 and AKT pathways .", "Gene expression profiling of human kidneys undergoing laparoscopic donor nephrectomy . BACKGROUND AND OBJECTIVES : The objective was to compare gene expression profiles of 6 kidneys from open donor nephrectomy with 6 kidneys removed after laparoscopic donor nephrectomy and several hours of carbon dioxide pneumoperitoneum with DNA microarrays and identify small - molecule drugs . METHODS : The gene expression profile GSE3297 was downloaded from the Gene Expression Omnibus database , and the differentially expressed genes were identified by a bioinformatics approach . First , Osprey software was used to construct a differentially expressed gene associated network . Then , DAVID ( Database for Annotation , Visualization , and Integrated Discovery ) and FuncAssociate were used to perform functional analyses . Finally , the Connectivity Map was used to screen for small - molecule drugs . RESULTS : A total of 285 differentially expressed genes were identified , including 148 down - regulated genes and 137 up - regulated genes . In addition , the differentially expressed genes in the most significant Gene Ontology term were P55212 , P01116 , O15524 , P03372 , P01222 , P02452 , and P50281 . Furthermore , several differentially expressed genes , including P42224 , P42226 , Q07890 , and O15524 , participated in the most remarkable Janus kinase - signal transducer and activator of transcription signaling pathway . Finally , luteolin -- with the highest score ( 0 . 887 ) -- was identified as the small - molecule drug . CONCLUSIONS : Our data show an altered renal transcriptome induced by several hours of carbon dioxide pneumoperitoneum and laparoscopic surgery characterized by up - regulation of genes associated with acute inflammation , apoptosis , and immune injury , which could potentially result in renal injury and an enhanced immune response in the recipient after transplant .", "cDNA microarray reveals signaling pathways involved in hormones expression of human pituitary . Pituitary , a master gland of neuroendocrine system , secretes hormones that orchestrate many physiological processes , under the regulation of multiple signaling pathways . To investigate the genes involved in hormones expression of human pituitary , homemade cDNA microarray containing 14 , 800 human genes / ESTs were used to profile the gene expression in both fetal and adult pituitaries . Seven hundred and twelve known genes changed over 2 - fold between the both tissues . Of which , 23 genes were changed with hormones expression in aging were confirmed by RT - PCR , not only the known regulators such as Pit1 , P43694 , P11474 , GABA - A , and EMK , but also LOC55884 , P51452 , Q9H307 , and O43598 , which had not been reported to be involved in the hormones expression . Correspondingly , the mRNAs of GH , PRL , P01189 , P01222 , DB00094 - beta , and LH - beta , was increased as much as 6 - to 20 - fold in adult pituitary than those in fetal pituitary , by real - time quantitative RT - PCR assay . In addition , the mRNAs of signaling pathways , such as DB02527 - PKA - CREB , PI3K - Akt , and PKA - P29323 were further investigated . Of them , it was only DB02527 - PKA - CREB pathway , but not PI3K - Akt and PKA - P29323 have the same expressing pattern as hormones . It suggested that cDNA microarray is highly advantages to profile the differential expressed genes that were involved in hormones expression of human pituitary , but it might ignore some responding proteins regulated posttranscriptionally .", "___MASK29___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK29___ , in the USA in 2003 .", "The bone morphogenetic protein signaling pathway is upregulated in a mouse model of total parenteral nutrition . Total parenteral nutrition ( O15533 ) results in intestinal mucosal atrophic changes due to an absence of enteral nutrition ; however , the mechanisms responsible for this are not fully understood . It has been shown that bone morphogenetic protein ( BMP ) activation inhibits intestinal epithelial cell ( EC ) proliferation . Therefore , we hypothesized that the BMP pathway could be upregulated by O15533 . To address this , we randomly assigned mice to receive O15533 or to be enterally fed ( control ) for 7 d . Mucosal EC isolates were harvested from the entire length of small intestine for RNA and protein measurements . Q8N1N2 - thickness , mid - small bowel was processed for histological examination . O15533 increased the abundance of P12643 , P12644 , and Q13873 at the RNA and protein levels . Phosphorylation of Q15797 , Q99717 , and Smad8 also was greater in the O15533 group than in the control , which helped to confirm activation of this pathway . Interestingly , the O15533 and control groups did not differ in the mRNA expression of the extracellular soluble bmp antagonists , noggin , gremlin , chordin , or follistatin . Compared to the control group , the expression of c - Myc ( cellular myelocytomatosis ) mRNA was lower , whereas the level of P38936 ( P38936 / CIP1 ) was greater , in the O15533 group . Because the BMP family may function through suppression of Wnt - beta - catenin signaling , this pathway was also examined . mRNA expression of Wnt 3 , Wnt5a , and the Wnt receptor Lrp5 were lower in the O15533 group compared to controls . The results suggest that the BMP signaling pathway may be involved in the development of intestinal mucosal atrophy due to O15533 administration .", "DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .", "Disruption of Src function potentiates Chk1 - inhibitor - induced apoptosis in human multiple myeloma cells in vitro and in vivo . Ras / MEK / P29323 pathway activation represents an important compensatory response of human multiple myeloma ( MM ) cells to checkpoint kinase 1 ( Chk1 ) inhibitors . To investigate the functional roles of Src in this event and potential therapeutic significance , interactions between Src and Chk1 inhibitors ( eg , P55089 - 01 or Chk1i ) were examined in vitro and in vivo . The dual Src / Abl inhibitors BMS354825 and ___MASK16___ blocked Chk1 - inhibitor - induced extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) activation , markedly increasing apoptosis in association with BimEL up - regulation , p34 ( cdc2 ) activation , and DNA damage in MM cell lines and primary CD138 (+) MM samples . Loss - of - function Src mutants ( K297R , K296R / Y528F ) or shRNA knock - down of Src prevented the P27361 / 2 activation induced by Chk1 inhibitors and increased apoptosis . Conversely , constitutively active Ras or mitogen - activated protein kinase / P29323 kinase 1 ( Q02750 ) significantly diminished the ability of Src inhibitors to potentiate Chk1 - inhibitor lethality . Moreover , Src / Chk1 - inhibitor cotreatment attenuated MM - cell production of vascular endothelial growth factor and other angiogenic factors ( eg , P03950 [ angiogenin ] , P01033 / 2 [ tissue inhibitor of metalloproteinases 1 / 2 ] , and RANTES [ regulated on activation normal T - cell expressed and secreted ] ) , and inhibited in vitro angiogenesis . Finally , coadministration of BMS354825 and P55089 - 01 suppressed human MM tumor growth in a murine xenograft model , increased apoptosis , and diminished angiogenesis . These findings suggest that Src kinase is required for Chk1 - inhibitor - mediated Ras → P27361 / 2 signaling activation , and that disruption of this event sharply potentiates the anti - MM activity of Chk1 inhi - bitors in vitro and in vivo .", "Expression of recombinant human Q9Y6W8 and in vitro characterization of its bioactivity on B lymphocytes . Inducible costimulator ( Q9Y6W8 ) is a novel costimulatory molecule expressed in activated T cell and has critical regulation effect on special immune response . In this study , the cDNA encoding human Q9Y6W8 was cloned from activated tonsil cells via RT - PCR , and was expressed in E . coli on pET28 expression vector . The recombinant Q9Y6W8 protein expressed from E . coli showed a molecular weight of 14 kD on SDS - polyacrylamide gel electrophoresis and was further confirmed by Western blot . In presence of P22301 , the purified rhICOS significantly increased in vitro B cell growth stimulated by pokeweed mitogen ( PWM ) , and enhanced the secretion of IgG from B cells .", "___MASK37___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .", "Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK68___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .", "Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK63___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together ." ]

[ "___MASK11___", "___MASK16___", "___MASK29___", "___MASK35___", "___MASK37___", "___MASK41___", "___MASK50___", "___MASK63___", "___MASK68___" ]

[ "Induction of autophagy is an early response to gefitinib and a potential therapeutic target in breast cancer . Gefitinib ( ___MASK83___ (®) , ZD1839 ) is a small molecule inhibitor of the epidermal growth factor receptor ( P00533 ) tyrosine kinase . We report on an early cellular response to gefitinib that involves induction of functional autophagic flux in phenotypically diverse breast cancer cells that were sensitive ( BT474 and SKBR3 ) or insensitive ( MCF7 - GFPLC3 and JIMT - 1 ) to gefitinib . Our data show that elevation of autophagy in gefitinib - treated breast cancer cells correlated with downregulation of AKT and P27361 / 2 signaling early in the course of treatment . Inhibition of autophagosome formation by BECLIN - 1 or O95352 siRNA in combination with gefitinib reduced the abundance of autophagic organelles and sensitized SKBR3 but not MCF7 - GFPLC3 cells to cell death . However , inhibition of the late stage of gefitinib - induced autophagy with hydroxychloroquine ( HCQ ) or bafilomycin A1 significantly increased ( p < 0 . 05 ) cell death in gefitinib - sensitive SKBR3 and BT474 cells , as well as in gefitinib - insensitive JIMT - 1 and MCF7 - GFPLC3 cells , relative to the effects observed with the respective single agents . Treatment with the combination of gefitinib and HCQ was more effective ( p < 0 . 05 ) in delaying tumor growth than either monotherapy ( p > 0 . 05 ) , when compared to vehicle - treated controls . Our results also show that elevated autophagosome content following short - term treatment with gefitinib is a reversible response that ceases upon removal of the drug . In aggregate , these data demonstrate that elevated autophagic flux is an early response to gefitinib and that targeting P00533 and autophagy should be considered when developing new therapeutic strategies for P00533 expressing breast cancers .", "Stress - induced alterations in P08908 receptor transcriptional modulators O75398 and Q6P1N0 . The effect of stress on the mRNA and protein level of the P08908 receptor and two of its key transcriptional modulators , O75398 and Q6P1N0 , was examined in the prefrontal cortex ( P27918 ) and hippocampus ( Hp ) using rodent models : olfactory bulbectomy ( OB ) and prenatal stress ( PS ) in male and female rats ; chronic mild stress in male rats ( CMS ) and pregnancy stress . In P27918 , CMS induced the most widespread changes , with significant reduction in both mRNA and protein levels of O75398 , P08908 receptor and in Q6P1N0 mRNA ; while in Hp P08908 receptor and Q6P1N0 protein levels were also decreased . In male , but not female OB rats P27918 Q6P1N0 and P08908 receptor protein levels were reduced , while in Hp P08908 receptor , Q6P1N0 and O75398 mRNA ' s but not protein were reduced . In PS rats P27918 P08908 receptor protein was reduced more in females than males ; while in Hp Q6P1N0 protein was increased in females . In pregnancy stress , P27918 O75398 , Q6P1N0 and P08908 protein receptor levels were reduced , and in HP P08908 receptor protein levels were also reduced ; in HP only O75398 and Q6P1N0 mRNA levels were reduced . Overall , CMS and stress during pregnancy produced the most salient changes in P08908 receptor and transcription factor expression , suggesting a primary role for altered transcription factor expression in chronic regulation of P08908 receptor expression . By contrast , OB ( in males ) and PS ( in females ) produced gender - specific reductions in P27918 P08908 receptor protein levels , suggesting a role for post - transcriptional regulation . These and previous data suggest that chronic stress might be a key regulator of O75398 / Q6P1N0 gene expression .", "Macrophages may promote cancer growth via a GM - P04141 / HB - P01133 paracrine loop that is enhanced by P48061 . BACKGROUND : Increased numbers of tumour - associated macrophages correlate with shortened survival in some cancers . The molecular bases of this correlation are not thoroughly understood . Events triggered by P48061 may play a part , as P48061 drives the migration of both P61073 - positive cancer cells and macrophages and may promote a molecular crosstalk between them . RESULTS : Samples of P00533 - positive colon cancer metastases in liver , a tissue with high expression of P48061 , were analysed by immunohistochemistry . In all of the patient biopsies , P34810 - positive tumour - associated macrophages presented a mixed P02778 ( M1 ) / Q86VB7 ( M2 ) pattern , expressed P61073 , GM - P04141 and HB - P01133 , and some stained positive for P48061 . Cancer cells stained positive for P61073 , P48061 , P00533 , Q15303 and GM - P04141 . Regulatory interactions among these proteins were validated via experiments in vitro involving crosstalk between human mononuclear phagocytes and the cell lines DLD - 1 ( human colon adenocarcinoma ) and HeLa ( human cervical carcinoma ) , which express the above - mentioned ligand / receptor repertoire . P48061 induced mononuclear phagocytes to release HB - P01133 , which activated P00533 and triggered anti - apoptotic and proliferative signals in cancer cells . The cancer cells then proliferated and released GM - P04141 , which in turn activated mononuclear phagocytes and induced them to release more HB - P01133 . Blockade of GM - P04141 with neutralising antibodies or siRNA suppressed this loop . CONCLUSIONS : P48061 - driven stimulation of cancer cells and macrophages may elicit and reinforce a GM - P04141 / HB - P01133 paracrine loop , whereby macrophages contribute to cancer survival and expansion . The involvement of mixed M1 / M2 GM - P04141 - stimulated macrophages in a tumour - promoting loop may challenge the paradigm of tumour - favouring macrophages as polarized M2 mononuclear phagocytes .", "Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK69___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .", "___MASK51___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK51___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .", "DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic - P27361 / 2 systems . DB00674 , a drug used to treat Alzheimer ' s disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive - improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg / kg . d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg / kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth - treated mice . Donepezil , an P22303 inhibitor ( 1 mg / kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth - treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth - induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty - induced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . The ameliorating effect of galantamine on recognition memory in Meth - treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth - induced memory impairment is associated with indirect activation of dopamine D1 receptor - P27361 / 2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia / Meth psychosis , as well as Alzheimer ' s disease .", "Apigenin inhibits release of inflammatory mediators by blocking the NF - κB activation pathways in the HMC - 1 cells . Apigenin is a plant flavonoid and a pharmacologically active agent that has been isolated from several plant species . However , the molecular mechanism of apigenin - mediated immune modulation has not been fully understood . One of the possible mechanisms of its protective effects is the down - regulation of inflammatory responses . In this study , we used cells from the human mast cell line ( HMC - 1 ) to investigate this effect . Apigenin significantly inhibits the inductive effect of phorbol 12 - myristate 13 - acetate ( PMA ) plus A23187 on the production of inflammatory cytokines such as tumor necrosis factor ( P01375 ) - α , interleukin ( IL ) - 8 , P05231 , and granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) . Moreover , apigenin attenuated the cyclooxygenase ( P36551 ) - 2 expression and intracellular Ca ( 2 +) level . In activated HMC - 1 cells , apigenin inhibited the PMA plus A23187 - induced activation of nuclear factor ( NF ) - κB , IκB degradation , and luciferase activity . Furthermore , apigenin suppressed the expression of P01375 - α , P10145 , P05231 , GM - P04141 , and P35354 by decreasing the intracellular Ca ( 2 +) level and inhibiting NF - κB activation . These results indicate that apigenin has a potential regulatory effect on inflammatory reactions that are mediated by mast cells .", "Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK91___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .", "Cerebrospinal fluid proteomics in children during induction for acute lymphoblastic leukemia : A pilot study . BACKGROUND : Thrombosis in patients with acute lymphocytic leukemia ( ALL ) can develop after treatment with L - asparaginase ( asp ) and is often localized to the central nervous system ( CNS ) . We hypothesize that changes in the cerebrospinal fluid ( P04141 ) proteome will occur after asp therapy and will anticipate CNS clots . METHODS : Five newly diagnosed patients , ages 1 - 11 years , with ALL ( n = 4 ) or lymphoblastic lymphoma ( LL ) ( n = 1 ) underwent serial lumbar punctures during induction . P04141 was depleted of abundant plasma proteins and analyzed by gel - free , label - free quantitative proteomics . RESULTS : More than 600 proteins were quantified across all P04141 samples . In four subjects , the expression of proteins involved in coagulation such as protein C Inhibitor ( P05154 ) and heparin cofactor II ( P05546 ) changed over the course of asp therapy . Antithrombin III ( P01008 ) and plasminogen ( PLMN ) levels were shown to have decreased expression over time in one child who developed a CNS thrombosis , compared to other subjects . CONCLUSIONS : P04141 proteomics is feasible and reproducible in ALL and LL . P04141 P01008 and PLMN should be further investigated as predictive markers of CNS thrombosis .", "Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK43___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .", "___MASK100___ , an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening P42345 signaling pathway in a human xenograft murine model . Histone deacetylase ( HDAC ) inhibitors are potent anticancer agents and show efficacy against various human neoplasms . ___MASK100___ is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors . However , its effect on the growth of skin neoplasm remains undefined . In this study , we show that vorinostat ( 2 μM ) reduced expression of Q13547 , 2 , 3 , and 7 in epidermoid carcinoma A431 cells . Consistently , it increased acetylation of histone H3 and p53 . ___MASK100___ ( 100mg / kg body weight , IP ) treatment reduced human xenograft tumor growth in highly immunosuppressed nu / nu mice . Histologically , the vorinostat - treated tumor showed features of well - differentiation with large necrotic areas . Based on proliferating cell nuclear antigen ( P12004 ) staining and expression of cyclins D1 , D2 , E , and A , vorinostat seems to impair proliferation by down - regulating the expression of these proteins . However , it also induced apoptosis . The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis , involved inhibition of P42345 signaling which was accompanied by reduction in cell survival AKT and extracellular - signal regulated kinase ( P29323 ) signaling pathways . Our data provide a novel mechanism - based therapeutic intervention for cutaneous squamous cell carcinoma ( SCC ) . ___MASK100___ may be utilized to cure skin neoplasms in organ transplant recipient ( OTR ) . These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients , is difficult .", "Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK30___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK30___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK30___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK30___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK30___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .", "P04141 - 1 ( P09603 ) delivers a proatherogenic signal to human macrophages . P09603 / P09603 supports the proliferation and differentiation of monocytes and macrophages . In mice , P09603 also promotes proinflammatory responses in vivo by regulating mature macrophage functions , but little is known about the acute effects of this growth factor on mature human macrophages . Here , we show that in contrast to its effects on mouse bone marrow - derived macrophages , P09603 did not induce expression of urokinase plasminogen activator mRNA , repress expression of apolipoprotein E mRNA , or prime LPS - induced P01375 and P05231 secretion in human monocyte - derived macrophages ( HMDM ) from several independent donors . Instead , we show by expression profiling that P09603 modulates the HMDM transcriptome to favor a proatherogenic environment . P09603 induced expression of the proatherogenic chemokines P02778 / IFN - inducible protein 10 , P13500 , and P80098 but repressed expression of the antiatherogenic chemokine receptor P61073 . P09603 also up - regulated genes encoding enzymes of the cholesterol biosynthetic pathway ( P04035 , P53602 , Q13907 , P14324 , Q14534 , Q16850 , EBP , Q15738 , Q9UBM7 , and Q15392 ) , and expression of P45844 , encoding a cholesterol efflux transporter , was repressed . Consistent with these effects , P09603 increased levels of free cholesterol in HMDM , and the selective P07333 kinase inhibitor GW2580 ablated this response . These data demonstrate that P09603 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which P09603 , which is known to be present in atherosclerotic lesions , may contribute to plaque progression .", "Differential radiosensitisation by ZD1839 ( ___MASK83___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK83___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "Granulocyte macrophage - colony stimulating factor increases the expression of histamine and histamine receptors in monocytes / macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage - colony - stimulating factor ( GM - P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine - producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM - P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM - P04141 - induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC - expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM - P04141 was also detected in the lesions . In U937 cells , GM - P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM - P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM - P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis - related genes in monocytes and smooth muscle cells . The presence of histamine - producing macrophages and gene expression of histamine receptors and GM - P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM - P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM - P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression .", "Compound FLZ inhibits lipopolysaccharide - induced inflammatory effects via down - regulation of the P50750 - IKK and P50750 - JNK / p38MAPK pathways in RAW264 . 7 macrophages . AIM : The aim of this study was to investigate the effect of the squamosamide derivative FLZ ( N - 2 -( 4 - hydroxy - phenyl )- ethyl - 2 -( 2 , 5 - dimethoxy - phenyl )- 3 -( 3 - methoxy - 4 - hydroxy - phenyl )- acrylamide ) on lipopolysaccharide ( LPS ) - induced inflammatory mediator production and the underlying mechanism in RAW264 . 7 macrophages . METHODS : RAW264 . 7 cells were preincubated with non - toxic concentrations of compound FLZ ( 1 , 5 , and 10 micromol / L ) for 30 min and then stimulated with 10 microg / L LPS . The production of nitric oxide ( NO ) , the expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase 2 ( P35354 ) , and the activation of nuclear factor kappa - B ( NF - kappaB ) and mitogen - activated protein kinase ( MAPK ) pathways were examined . RESULTS : FLZ significantly inhibited the LPS - induced production of NO , as well as the expression of P35228 and P35354 at both the RNA and the protein levels in RAW264 . 7 cells . The LPS - induced increase in the DNA binding activity of NF - kappaB and activator protein 1 ( AP - 1 ) , the nuclear translocation of NF - kappaB p65 , the degradation of the inhibitory kappaBalpha protein ( P25963 ) and the phosphorylation of P25963 , O15111 ( IKK ) alpha / beta , c - Jun NH ( 2 )- terminal kinase ( JNK ) and p38 MAPKs were all suppressed by FLZ . However , the phosphorylation of extracellular signal - regulated kinase ( P29323 ) was not affected . Further study revealed that FLZ inhibited the phosphorylation of transforming growth factor - beta ( TGF - beta ) - activated kinase 1 ( TAK1 ) , which is an upstream signaling molecule required for IKKalpha / beta , JNK and p38 activation . CONCLUSION : FLZ inhibited the LPS - induced production of inflammatory mediators at least partly through the downregulation of the P50750 - IKK and P50750 - JNK / p38MAPK pathways .", "NFκB inhibitors induce cell death in glioblastomas . Identification of novel target pathways in glioblastoma ( GBM ) remains critical due to poor prognosis , inefficient therapies and recurrence associated with these tumors . In this work , we evaluated the role of nuclear - factor - kappa - B ( NFκB ) in the growth of GBM cells , and the potential of NFκB inhibitors as antiglioma agents . NFκB pathway was found overstimulated in GBM cell lines and in tumor specimens compared to normal astrocytes and healthy brain tissues , respectively . Treatment of a panel of established GBM cell lines ( U138MG , U87 , U373 and P13671 ) with pharmacological NFκB inhibitors ( BAY117082 , parthenolide , MG132 , curcumin and arsenic trioxide ) and NFκB - p65 siRNA markedly decreased the viability of GBMs as compared to inhibitors of other signaling pathways such as MAPKs ( P29323 , JNK and p38 ) , PKC , P00533 and PI3K / Akt . In addition , NFκB inhibitors presented a low toxicity to normal astrocytes , indicating selectivity to cancerous cells . In GBMs , mitochondrial dysfunction ( membrane depolarization , bcl - xL downregulation and cytochrome c release ) and arrest in the G2 / M phase were observed at the early steps of NFκB inhibitors treatment . These events preceded sub - P55008 detection , apoptotic body formation and caspase - 3 activation . Also , NFκB was found overstimulated in cisplatin - resistant P13671 cells , and treatment of GBMs with NFκB inhibitors overcame cisplatin resistance besides potentiating the effects of the chemotherapeutics , cisplatin and doxorubicin . These findings support NFκB as a potential target to cell death induction in GBMs , and that the NFκB inhibitors may be considered for in vivo testing on animal models and possibly on GBM therapy .", "Distinct signalling pathways of murine histamine H1 - and H4 - receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G - protein - coupled receptors , referred to as histamine H1 - receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro - inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre - clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse ( m ) P35367 or mH4R at similar levels and analyzed HA - induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen - activated protein kinases ( MAPKs ) P29323 1 / 2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA - induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA - induced P18146 gene expression only in Q9H3N8 - expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA - induced gene expression . In summary , using this system which allows a direct comparison of mH1R - and mH4R - induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident .", "Polymorphisms in genes implicated in dopamine , serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis . BACKGROUND : Homovanillic acid ( HVA ) , 5 - hydroxyindoleacetic acid ( 5 - HIAA ) and 3 - methoxy - 4 - hydroxyphenylglycol ( MHPG ) are the major monoamine metabolites in the central nervous system ( CNS ) . Their cerebrospinal fluid ( P04141 ) concentrations , reflecting the monoamine turnover rates in CNS , are partially under genetic influence and have been associated with schizophrenia . We have hypothesized that P04141 monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms ( SNPs ) in genes implicated in monoaminergic pathways and psychosis . METHODS : We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [ tryptophan hydroxylase 1 ( P17752 ) , Q8IWU9 , tyrosine hydroxylase ( TH ) , P20711 ( DDC ) , dopamine beta - hydroxylase ( P09172 ) , catechol - O - methyltransferase ( P21964 ) , monoamine oxidase A ( P21397 ) and P27338 ] and monoamine metabolite concentrations in P04141 in 74 patients with psychotic disorder . RESULTS : There were 42 nominally significant associations between SNPs and P04141 monoamine metabolite concentrations , which exceeded the expected number ( 20 ) of nominal associations given the total number of tests performed . The strongest association ( p = 0 . 0004 ) was found between P27338 rs5905512 , a SNP previously reported to be associated with schizophrenia in men , and MHPG concentrations in men with psychotic disorder . Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls . CONCLUSIONS : The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis .", "Clinical endocannabinoid deficiency ( CECD ) : can this concept explain therapeutic benefits of cannabis in migraine , fibromyalgia , irritable bowel syndrome and other treatment - resistant conditions ? OBJECTIVES : This study examines the concept of clinical endocannabinoid deficiency ( CECD ) , and the prospect that it could underlie the pathophysiology of migraine , fibromyalgia , irritable bowel syndrome , and other functional conditions alleviated by clinical cannabis . METHODS : Available literature was reviewed , and literature searches pursued via the National Library of Medicine database and other resources . RESULTS : Migraine has numerous relationships to endocannabinoid function . Anandamide ( AEA ) potentiates P08908 and inhibits 5 - Q13049 receptors supporting therapeutic efficacy in acute and preventive migraine treatment . Cannabinoids also demonstrate dopamine - blocking and anti - inflammatory effects . AEA is tonically active in the periaqueductal gray matter , a migraine generator . THC modulates glutamatergic neurotransmission via DB01221 receptors . Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia . Cannabinoids have similarly demonstrated the ability to block spinal , peripheral and gastrointestinal mechanisms that promote pain in headache , fibromyalgia , IBS and related disorders . The past and potential clinical utility of cannabis - based medicines in their treatment is discussed , as are further suggestions for experimental investigation of CECD via P04141 examination and neuro - imaging . CONCLUSION : Migraine , fibromyalgia , IBS and related conditions display common clinical , biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines .", "Repeated exposure of human fibroblasts to ionizing radiation reveals an adaptive response that is not mediated by interleukin - 6 or TGF - β . Exposing cells to a low dose can protect them against a subsequent higher exposure . This phenomenon is known as adaptive response and is frequently observed in a variety of cells . Even though similarities are suspected with other non - targeted effects , such as bystander effects , the exact mechanism behind adaptive response is not fully clarified . In this study human primary fibroblasts were tested for their response to ionizing radiation ( IR ) after administrating a low priming dose ( 0 . 1 - 0 . 5Gy ) . Both the abundance of γ P16104 as a marker for double - stranded breaks and the levels of cytokines , secreted in the medium , were monitored in time . Upon challenge , IR - primed cells showed modified γ P16104 spot size distributions and altered repair kinetics , consistent with an adaptive response . In addition , 24h after priming with IR , four cytokines were significantly upregulated in the medium - GM - P04141 ( 1 . 33 × ) ; P05231 ( 4 . 24 × ) ; P10145 ( 1 . 33 × ) ; TGF - β ( 1 . 46 × ) . In order to mimick the protective effect of IR priming , we primed the cells with either P05231 or TGF - β . This did not elicit an altered γ P16104 response as observed in IR - primed cells , indicating that the adaptive response in these primary fibroblasts is regulated in an P05231 and TGF - β independent manner .", "Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK100___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK100___ . Tubacin in combination with ___MASK100___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK100___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK100___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .", "Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK32___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .", "Multiple pathways of apolipoprotein E signaling in primary neurons . P02649 is a genetic risk factor for Alzheimer ' s disease , and the apoE protein is associated with beta - amyloid deposits in Alzheimer ' s disease brain . We examined signaling pathways stimulated by apoE in primary neurons in culture . ApoE and an apoE - derived peptide activated several intracellular kinases , including prominently extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . P27361 / 2 activation by apoE was blocked by an inhibitor of the low - density lipoprotein receptor family , the specific DB01221 glutamate receptor antagonist MK 801 and other calcium channel blockers . Activation of apoE receptors also induced tyrosine phosphorylation of Dab1 , an adaptor protein of apoE receptors , but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for P29323 activation . In contrast , apoE treatment of primary neurons decreased activation of c - Jun N - terminal kinase , a kinase that interacts with another apoE receptor adaptor protein , c - Jun N - terminal kinase - interacting protein . This change also depended on interactions with the low - density lipoprotein receptor family but was independent of calcium channels . c - Jun N - terminal kinase deactivation by apoE was blocked by gamma - secretase inhibitors and pertussis toxin . These results demonstrate that apoE affects several signaling cascades in neurons : increased disabled phosphorylation , activation of the P27361 / 2 pathway ( dependent on calcium influx via the DB01221 receptor ) and inhibition of the P45983 / 2 pathway ( dependent on gamma - secretase and G proteins ) .", "Inhibition of HCV by the serpin antithrombin III . BACKGROUND : Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection , interferon - α based therapy remains challenging for certain populations , including those with unfavorable Q8IZI9 genotypes , psychiatric co - morbidity , HIV co - infection , and decompensated liver disease . We have recently shown that P01008 , a serine protease inhibitor ( serpin ) , has broad antiviral properties . RESULTS : We now show that P01008 is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations . At a mechanistic level using gene - expression arrays , we found that P01008 treatment down - regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma , including Jun , Myc and P12643 . Using a protein interactive network analysis we found that changes in gene - expression caused by P01008 were dependent on three nodes previously implicated in HCV disease progression or HCV replication : NFκB , O75791 MAPK , and P27361 / 2 . CONCLUSIONS : Our findings suggest that P01008 stimulates a novel innate antiviral host cell defense different from current treatment options .", "A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor - mediated signal transduction . P14324 ( FPPS ) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways . Here we describe a novel role for this enzyme in fibroblast growth factor ( FGF ) - mediated signalling . We demonstrate the binding of FPPS to FGF receptors ( FGFRs ) using the yeast two - hybrid assay , pull - down assays and co - immunoprecipitation . The interaction between FPPS and FGFR is regulated by the cellular metabolic state and by treatment with P09038 . Overexpression of FPPS inhibits P09038 - induced cell proliferation , accompanied by a failure of the P09038 - mediated induction of cyclins D1 and E . Overexpression of FPPS in fibroblasts also promotes increased farnesylation of Ras , and temporally extends P09038 - stimulated activation of the Ras / P29323 ( extracellular - signal - regulated kinase ) cascade . These data suggest that , in addition to its role in isoprenoid biosynthesis , FPPS may function as a modulator of the cellular response to FGF treatment .", "P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK85___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK85___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .", "Iso - intense neuroenteric cyst in the lower cervical spine treated with ventral resection and anterior fusion utilising sternal notch exposure : case report , technical note and literature review . A 36 - year - old female patient with a long - standing asymptomatic lower thoracic scoliosis presented with sensory symptoms involving all limbs . Q9BWK5 scan demonstrated a rounded ventral intradural mass causing major deformity of the cervical cord at P13671 and P10643 levels . Unlike most previously reported neurenteric cysts , the Q9BWK5 signal characteristics of this mass were such that it could not be determined if it is cystic or solid , being iso - intense on T1 - and hyperintense P24752 - weighted images . Resection was performed through a median corporectomy of P13671 and P10643 , the lesion being found to be a neurenteric cyst with an attachment to the anterior median fissure of the cord . Strut graft and cervical locking plate fixation from P01031 to P13671 was facilitated by extending the cervical incision into the sternal notch , with detachment of left - sided strap muscle insertion . The patient made an excellent recovery with complete resolution of neurological symptoms and solid fusion . The postoperative course was complicated by an anterior cervical P04141 collection which resolved spontaneously within 2 months . The literature regarding this rare condition and its management is reviewed . Although the majority of intraspinal neurenteric cysts are situated ventral to the cord , most reports of excision have been from a dorsal approach . Drainage and subtotal excision of neurenteric cysts have been previously advocated ; however , the recurrence rate is such that complete excision is advocated . This is facilitated by a ventral approach . A simplified method of utilising the sternal notch exposure is reported . The literature regarding the anatomical peculiarities pertinent to the sternal notch approach , and the reported literature regarding spinal neurenteric cysts is reviewed .", "Different cholinesterase inhibitor effects on P04141 cholinesterases in Alzheimer patients . BACKGROUND : The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) activities and protein levels , in the cerebrospinal fluid ( P04141 ) of Alzheimer disease ( AD ) patients . METHODS AND FINDINGS : AD patients aged 50 - 85 years were randomized to open - label treatment with oral rivastigmine , donepezil or galantamine for 13 weeks . P22303 and BuChE activities were assayed by Ellman ' s colorimetric method . Protein levels were assessed by enzyme - linked immunosorbent assay ( ELISA ) . Primary analyses were based on the Completer population ( randomized patients who completed Week 13 assessments ) . 63 patients were randomized to treatment . DB00989 was associated with decreased P22303 activity by 42 . 6 % and decreased P22303 protein levels by 9 . 3 % , and decreased BuChE activity by 45 . 6 % and decreased BuChE protein levels by 21 . 8 % . DB00674 decreased P22303 activity by 2 . 1 % and BuChE activity by 0 . 5 % , but increased P22303 protein levels by 51 . 2 % and BuChE protein levels by 10 . 5 % . Donepezil increased P22303 and BuChE activities by 11 . 8 % and 2 . 8 % , respectively . Donepezil caused a 215 . 2 % increase in P22303 and 0 . 4 % increase in BuChE protein levels . Changes in mean P22303 - Readthrough / Synaptic ratios , which might reflect underlying neurodegenerative processes , were 1 . 4 , 0 . 6 , and 0 . 4 for rivastigmine , donepezil and galantamine , respectively . CONCLUSION : The findings suggest pharmacologically - induced differences between rivastigmine , donepezil and galantamine . DB00989 provides sustained inhibition of P22303 and BuChE , while donepezil and galantamine do not inhibit BuChE and are associated with increases in P04141 P22303 protein levels . The clinical implications require evaluation ." ]

[ "___MASK100___", "___MASK30___", "___MASK32___", "___MASK43___", "___MASK51___", "___MASK69___", "___MASK83___", "___MASK85___", "___MASK91___" ]

[ "Synergistic activity of ixabepilone plus other anticancer agents : preclinical and clinical evidence . DB04845 demonstrates marked synergistic activity in combination with capecitabine , which served as the rationale for the evaluation of this combination in the clinic . DB04845 plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer ( MBC ) progressing after treatment with an anthracycline and a taxane ; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy . An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab , bevacizumab , brivanib , and cetuximab ; with immune - modulating agents such as anti - P16410 antibody ; and with other chemotherapy drugs such as irinotecan and epirubicin . Notably , experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab - paclitaxel combined with bevacizumab . These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in P04626 - positive breast cancer ; with bevacizumab in breast cancer , endometrial cancer , renal cancer , and non - small cell lung cancer ( NSCLC ) ; with cetuximab in breast cancer , NSCLC , and pancreatic cancer ; and with brivanib , dasatinib , sorafinib , sunitinib , or vorinostat in MBC . Preliminary results from several of these trials suggest that ixabepilone - based combinations have promising anticancer activity .", "Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .", "Mass spectrometry and hydrogen / deuterium exchange measurements of alcohol - induced structural changes in cellular retinol - binding protein type I . To bind and release its ligand , cellular retinol - binding protein type I ( P09455 ) needs to undergo conformational and dynamic changes to connect the inner , solvent - shielded cavity , where retinol is found to bind , and the outside medium . DB00162 dissociation in vitro is favoured by water / alcohol mixtures whose moderately low dielectric constants mimic a property characteristic of the membrane microenvironment where this process occurs in vivo . Apo - and holo - P09455 , in either water / methanol or water / trifluoroethanol ( TFE ) mixtures , were analyzed at equilibrium by electrospray ionization with orthogonal quadrupole time - of - flight mass spectrometry ( P19957 - Q - TOFMS ) to identify the alcohol - induced species . The questions were asked whether the presence of alcohols affects protein dynamics , as reflected by hydrogen / deuterium ( H / D ) exchange monitored by continuous - labelling experiments , and to which extent retinol dissociation influences the process . With increasing methanol , at pH near neutrality , apo - P09455 exhibits a progressively more compact conformation , resulting in reduced H / D exchange with respect to the native protein in water . DB00162 dissociation from the holo - protein did not promote hydrogen replacement . Similarly , in the presence of the low TFE concentration sufficient to cause retinol dissociation , the hydrogen exchange of the resulting apo - protein was not exalted . However , in contrast with the alkanol , higher TFE concentrations induced a transition of apo - P09455 to a new alpha - helix conformation capable of exchanging all available hydrogen atoms .", "Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK80___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .", "Interaction of cyclooxygenase - 2 variants and smoking in pancreatic cancer : a possible role of nucleophosmin . BACKGROUND & AIMS : Overexpression of cyclooxygenase - 2 ( P35354 ) is implicated in cancer development . This study examined the functional relevance of genetic polymorphisms in the P35354 promoter and evaluated their associations with susceptibility to pancreatic cancer . METHODS : Genotypes and haplotypes of P35354 - 765G / C , - 1195G / A , and - 1290A / G were analyzed in 393 pancreatic cancer patients and 786 controls . Odds ratios ( ORs ) and 95 % confidence intervals ( CIs ) were computed by logistic regression . The function of the - 765G --> C polymorphism was examined by a set of biochemical assays . RESULTS : The - 1195AA or - 765GC genotype carriers had a 1 . 34 - fold ( 95 % CI : 1 . 12 - 1 . 60 ) or 1 . 63 - fold ( 95 % CI : 1 . 25 - 2 . 10 ) excess risk for developing pancreatic cancer . These 2 variants showed a cooperative effect in context of haplotype , with the ORs for the A (- 1195 )- C (- 765 )- containing haplotypes being significantly greater than those for the G (- 1195 )- G (- 765 )- containing haplotypes . The - 765C allele and smoking displayed a multiplicative joint effect , with an OR of 3 . 72 ( 95 % CI : 1 . 70 - 8 . 14 ) for heavy smokers carrying the - 765GC genotype . Biochemical assays suggest that the - 765G --> C change creates a binding site for nucleophosmin ( P06748 ) and phosphorylated P06748 ( p - P06748 ) , which acts as a transcriptional inhibitor . Cigarette smoke remarkably increased P35354 promoter activity , and this effect was more pronounced for the - 765C allele compared with the - 765G allele . Cigarette smoke reduced nuclear p - P06748 levels , which was reversely associated with P35354 expression . CONCLUSIONS : Functional P35354 polymorphisms are associated with susceptibility to pancreatic cancer and tobacco smoke specifically increases - 765C promoter activity , which might be mediated by p - P06748 .", "Microtubule - depolymerizing agents used in antibody - drug conjugates induce antitumor immunity by stimulation of dendritic cells . Antibody - drug conjugates ( ADC ) are emerging as powerful treatment strategies with outstanding target - specificity and high therapeutic activity in patients with cancer . DB08870 represents a first - in - class ADC directed against P28908 (+) malignancies . We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response . In this study , we demonstrate that the dolastatin family of microtubule inhibitors , from which the cytotoxic component of brentuximab vedotin is derived , comprises potent inducers of phenotypic and functional dendritic cell ( DC ) maturation . In addition to the direct cytotoxic effect on tumor cells , dolastatins efficiently promoted antigen uptake and migration of tumor - resident DCs to the tumor - draining lymph nodes . Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells . Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins , the antitumor effect was far less pronounced in immunocompromised mice . We observed substantial therapeutic synergies when combining dolastatins with tumor antigen - specific vaccination or blockade of the P18621 - Q9NZQ7 and P16410 coinhibitory pathways . Ultimately , treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients . Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin - based therapies , such as brentuximab vedotin , with immune - based therapies .", "[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK77___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .", "Proteome - wide changes induced by the Hsp90 inhibitor , geldanamycin in anaplastic large cell lymphoma cells . The molecular chaperone heat shock protein 90 ( Hsp90 ) affects the function of many oncogenic signaling proteins including nucleophosmin - anaplastic lymphoma kinase ( P06748 - Q9UM73 ) expressed in anaplastic large cell lymphoma ( ALCL ) . While Q9UM73 - positive ALCL cells are sensitive to the Hsp90 inhibitor and the geldanamycin ( GA ) analog , 17 - allylamino - 17 - demethoxygeldanamycin ( 17 - P29372 ) , the proteomic effects of these drugs on Q9UM73 - positive ALCL cells are unpublished . In this study , we investigated the cellular , biologic , and proteomic changes occurring in Q9UM73 - positive ALCL cells in response to GA treatment . GA induced G2 / M cell cycle arrest and caspase - 3 - mediated apoptosis . Furthermore , quantitative proteomic changes analyzed by cleavable isotope - coded affinity tag - LC - MS / MS ( cICAT - LC - MS / MS ) identified 176 differentially expressed proteins . Out of these , 49 were upregulated 1 . 5 - fold or greater and 70 were downregulated 1 . 5 - fold or greater in GA - treated cells . Analysis of biological functions of differentially expressed proteins revealed diverse changes , including induction of proteins involved in the 26S proteasome as well as downregulation of proteins involved in signal transduction and protein and nucleic acid metabolism . Pathway analysis revealed changes in MAPK , WNT , NF - kappaB , TGFbeta , Q07869 , and integrin signaling components . Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in Q9UM73 - positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects .", "Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case - control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population - based case - control study . We examined nutrient density - adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0 . 026 ) , cooked by pan - frying ( trend P = 0 . 035 ) , and cooked until well - done ( trend P = 0 . 013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0 . 023 ) . A gene - by - diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0 . 008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .", "The polymorphism IL - 1beta T - 31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto - P09683 . Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma ( MM ) . Therefore , it is possible that inborn genetic variations leading to a modified expression of these cytokines will influence the outcome for these patients . We investigated 348 MM patients undergoing high - dose melphalan treatment followed by Auto - P09683 and examined the influence of single nucleotide polymorphisms ( SNPs ) in genes involved in the inflammatory response . We found that the polymorphism IL - 1beta T - 31C significantly influenced overall survival ( OS ; P = 0 . 02 ) and that carriers of the variant C - allele had a significantly longer survival than homozygous wild - type allele TT - carriers ( relative risk 0 . 6 ( 95 % CI = 0 . 5 - 0 . 9 ) ; P = 0 . 008 ) . The polymorphisms P05231 G - 174C , P22301 C592A , PPARgamma2 Pro ( 12 ) Ala , P35354 A - 1195G , P35354 T8473C and P19838 ins / del did not influence the OS in this group of patients . Furthermore , homozygous carriers of the variant allele of IL - 1beta T - 31C were at 1 . 37 - fold ( CI = 1 . 05 - 1 . 80 ) increased risk of MM as compared with population - based controls ( P = 0 . 02 ) . Our results indicate that IL - 1beta is involved in the pathogenesis of MM .", "Reverse crosstalk of TGFβ and PPARβ / δ signaling identified by transcriptional profiling . Previous work has provided strong evidence for a role of peroxisome proliferator - activated receptor β / δ ( PPARβ / δ ) and transforming growth factor - β ( TGFβ ) in inflammation and tumor stroma function , raising the possibility that both signaling pathways are interconnected . We have addressed this hypothesis by microarray analyses of human diploid fibroblasts induced to myofibroblastic differentiation , which revealed a substantial , mostly reverse crosstalk of both pathways and identified distinct classes of genes . A major class encompasses classical Q07869 target genes , including Q9BY76 , P50416 , Q99541 and Q16654 . These genes are repressed by TGFβ , which is counteracted by PPARβ / δ activation . This is mediated , at least in part , by the TGFβ - induced recruitment of the corepressor Q9Y618 to Q07869 response elements , and its release by PPARβ / δ ligands , indicating that TGFβ and PPARβ / δ signals are integrated by chromatin - associated complexes . A second class represents TGFβ - induced genes that are downregulated by PPARβ / δ agonists , exemplified by Q9NZQ7 and P05231 , which is consistent with the anti - inflammatory properties of PPARβ / δ ligands . Finally , cooperative regulation by both ligands was observed for a minor group of genes , including several regulators of cell proliferation . These observations indicate that PPARβ / δ is able to influence the expression of distinct sets of both TGFβ - repressed and TGFβ - activated genes in both directions .", "The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer . It is now well established that cancer cells exhibit a number of genetic defects in the machinery that governs programmed cell death and that sabotage of apoptosis is one of the principal factors aiding in the evolution of the carcinogenic phenotype . A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer , whereby promoter hypermethylation silences genes essential for many processes including apoptosis . To date , studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast , colon and stomach , with only limited data available on prostate cancer . Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer . The most significant advances have involved the discovery of apoptotic gene targets of methylation , including Q6GPH4 , ( fragile histidine triad ( P49789 ) , cellular retinol binding protein 1 ( P09455 ) , decoy receptor 1 ( O14798 ) , decoy receptor 2 ( Q9UBN6 ) , target of methylation - induced silenceing 1 ( Q9ULZ3 ) , P01375 receptor superfamily , member 6 ( FAS ) , Reprimo ( Q9NS64 ) and P08151 pathogenesis - related 1 ( P48060 ) . These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers . We also introduce the concept of an ' apoptotic methylation signature ' for prostate cancer and evaluate its potential in a diagnostic , prognostic and therapeutic setting .", "Apoptosis induced by the myelodysplastic syndrome - associated P06748 - P58340 chimeric protein . The P06748 - P58340 chimeric protein is produced by the t ( 3 ; 5 )( q25 . 1 ; q34 ) chromosomal translocation , which is associated with myelodysplastic syndrome ( P43034 ) prior to progression into acute myeloid leukemia ( AML ) . Here we report that K562 human leukemia cells ectopically expressing P06748 - P58340 , but not those with wild - type P58340 , were gradually eliminated from the culture by undergoing apoptosis . NIH3T3 mouse fibroblasts engineered to overexpress P06748 - P58340 grew normally but serum deprivation triggered apoptotic cell death with slower kinetics than did other well - known apoptotic inducers such as c - Myc or Q01094 . Quantitative analysis of apoptotic induction confirmed that , neither P06748 nor P58340 , but the P06748 - P58340 fusion protein was able to induce apoptosis . Analyses using a variety of deletion mutants of P06748 - P58340 revealed that induction of apoptosis required the N - terminal domain of P58340 and the P06748 domain containing nuclear localization signal and that removal of the P06748 dimerization domain markedly impaired the ability to induce apoptosis . Co - expression of Bcl - 2 rescued NIH3T3 fibroblasts from P06748 - P58340 - mediated cell death without affecting the expression level or the subcellular localization of P06748 - P58340 and enabled cells to progress into S phase in low serum . These findings provide an P06748 - P58340 - mediated novel mechanism of apoptotic induction and imply that P06748 - MLFI in collaboration with anti - apoptotic oncoproteins may play an important role in multi - step progression from P43034 to AML .", "Molecular characterization of de novo Philadelphia chromosome - positive acute myeloid leukemia . Philadelphia chromosome - positive ( Ph + ) acute myeloid leukemia ( AML ) is a controversial diagnosis , as others propose that it represents chronic myelogenous leukemia in blast phase ( CML - BP ) . P06748 mutations occur in 25 - 35 % of patients with AML but are absent in patients with CML . Conversely , P00519 mutations occur in 25 % of imatinib - naive patients with CML - BP but are not described in patients with AML . We analyzed for P06748 and P00519 mutations in nine Ph + patients with AML and five patients with CML - BP initially presenting in BP . In six cases of Ph + AML , we screened for a panel of gene mutations using Sequenome (®)- based methods including P31749 , P31751 , Q9Y243 , P15056 , P00533 , P50148 , GNAS , O75874 , P48735 , P01116 , MET , P01111 , P42336 and P07949 . Two of nine ( 22 % ) patients with Ph + AML had P06748 mutations and were alive 36 and 71 months after diagnosis . All cases of Ph + AML were negative for P00519 and other gene mutations . One ( 20 % ) patient with CML - BP had P00519 mutation ; no patients had P06748 mutations . These data suggest that Ph + AML is distinct from CML - BP .", "Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK14___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .", "Human herpes virus 6 reactivation : important predictor for poor outcome after myeloablative , but not non - myeloablative allo - P09683 . Hematopoietic P09683 ( HSCT ) is often complicated by viral reactivations . In this retrospective cohort study ( January 2004 - August 2008 ) , predictors for human herpes virus 6 ( HHV6 ) - reactivation and associations between HHV6 - reactivation and clinical outcomes after allogeneic HSCT were studied . HHV6 DNA load in plasma was monitored weekly by quantitative real - time PCR . Associations between the main end point HHV6 - reactivation and other end points , that is , acute GVHD ( aGVHD ) and Q8IXM6 were analyzed using Cox proportional hazard models . In total , 108 patients receiving either a myeloablative ( MA ; n = 60 ) or non - myeloablative ( Q13145 ; n = 48 ) conditioning regimen were included . Median age was 40 years ( range 17 - 65 ) ; median follow - up was 20 months ( range 3 - 36 ) . In 16 / 60 ( 27 % ) patients with MA conditioning regimen , a HHV6 reactivation was observed ( mean viral load 50 323 cp / mL ) compared with 2 / 48 ( 4 % ) patients with a Q13145 conditioning regimen with low viral load ( mean 1100 cp / mL ) . In multivariate analysis , MA conditioning was the only predictor for HHV6 reactivation ( P = 0 . 02 ) . In addition , HHV6 reactivation was associated with grades 2 - 4 aGVHD ( P < 0 . 001 ) and Q8IXM6 ( P = 0 . 03 ) . Regular monitoring of HHV6 reactivation after HSCT might be important in MA HSCT patients to enable early initiation of antiviral treatment or to anticipate aGVHD , all of which may improve clinical outcome .", "Human lung fibroblasts increase P01730 (+) CD25 (+) Foxp3 (+) T cells in co - cultured P01730 (+) lymphocytes . Aim of this study was to evaluate functional modifications induced by human lung fibroblasts in co - cultured P01730 (+) T lymphocytes . P01730 (+) T cells , resting or stimulated with ionomycin / PMA for 6h , were co - cultured with fibroblasts isolated from pulmonary biopsies , in contact or separated by a semi - permeable membrane . The expression of CD25 , P16410 , TGF - β , IFNγ , P60568 , P05112 , P22301 and Foxp3 was evaluated by flow cytometric analysis . Fibroblasts induced a significant increment in CD25 (+) cells in co - cultured activated P01730 (+) T lymphocytes separated by a membrane . Moreover , fibroblasts treatment with a P35354 inhibitor abrogated the increment in CD25 (+) cells whereas exogenous DB00917 restored it . The CD25 (+) subpopulation was characterized by increased presence of Fox - P09131 , P16410 , P22301 and TGF - β positive cells while IFN - γ and P60568 positive cells were diminished . Proliferative response of P01730 (+) to the anti CD3 / P10747 - Abs was abrogated in P01730 (+) co - cultured with fibroblasts thus demonstrating a suppressive feature of the expanded CD25 (+) subpopulation .", "Mutant enrichment with 3 '- modified oligonucleotides a practical PCR method for detecting trace mutant DNAs . Many clinical situations necessitate highly sensitive and reliable molecular assays ; however , the achievement of such assays remains a challenge due to the inherent limitations of molecular testing methods . Here , we describe a simple and inexpensive enrichment technique that we call mutant enrichment with 3 '- modified oligonucleotides ( Q9Y316 ) . The method is based on the use of a 3 '- modified oligonucleotide primer that blocks extension of the normal allele but enables extension of the mutated allele . The performance of the technique was evaluated with respect to its ability to detect common cancer mutations in the P00533 , P01116 , P15056 , P04637 , O60674 , and P06748 genes . We achieved sensitivities of 10 (- 2 ) to 10 (- 6 ) using downstream Sanger sequencing , depending on the concentrations and thermodynamics of the primers . Q9Y316 may be applicable to the quantitative real - time PCR platform and other downstream assays . This technique may be practically applicable to various medical situations .", "Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK43___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK43___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK43___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .", "Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER - 2 and P00533 . ___MASK57___ is a potent dual inhibitor of HER - 2 and P00533 . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side - effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER - 2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER - 2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab - refractory metastatic breast cancer . ___MASK57___ may have a specific role in treating HER - 2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated .", "Q07869 - γ Regulates Trophoblast Differentiation in the BeWo Cell Model . Common pregnancy complications , such as severe preeclampsia and intrauterine growth restriction , disrupt pregnancy progression and impair maternal and fetal wellbeing . Placentas from such pregnancies exhibit lesions principally within the syncytiotrophoblast ( P09683 ) , a layer in direct contact with maternal blood . In humans and mice , glial cell missing - 1 ( GCM - 1 ) promotes differentiation of underlying cytotrophoblast cells into the outer P09683 layer . GCM - 1 may be regulated by the transcription factor peroxisome proliferator - activated receptor - gamma ( Q07869 - γ ) ; in mice , Q07869 - γ promotes labyrinthine trophoblast differentiation via Gcm - 1 , and , as we previously demonstrated , Q07869 - γ activation ameliorates disease features in rat model of preeclampsia . Here , we aimed to characterize the baseline activity of Q07869 - γ in the human choriocarcinoma BeWo cell line that mimics P09683 formation in vitro and modulate Q07869 - γ activity to study its effects on cell proliferation versus differentiation . We report a novel negative autoregulatory mechanism between Q07869 - γ activity and expression and show that blocking Q07869 - γ activity induces cell proliferation at the expense of differentiation , while these remain unaltered following treatment with the agonist rosiglitazone . Gaining a deeper understanding of the role and activity of Q07869 - γ in placental physiology will offer new avenues for the development of secondary prevention and / or treatment options for placentally - mediated pregnancy complications .", "Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK57___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .", "DB08870 in anaplastic large cell lymphoma . INTRODUCTION : DB08870 , a novel anti - P28908 antibody - drug conjugate , delivers a cytotoxic agent into P28908 (+) cells . P28908 expression is characteristic of anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . AREAS COVERED : We reviewed data on brentuximab vedotin , focusing on ALCL and discuss pharmacology , clinical trials leading to approval and future research directions . Systemic ALCL , 3 % of adult Q9NZ71 , is characterized by large anaplastic P28908 (+) cells . The fusion protein P06748 - Q9UM73 , when present in systemic ALCL , confers better prognosis , although even Q9UM73 - patients with IPI score ≥ 3 are high - risk . For patients with systemic ALCL , 25 - 45 % relapse after frontline therapy , and > 50 % of patients will relapse following high - dose chemotherapy with autologous stem - cell support . There has been no standard therapy for relapsed / refractory systemic ALCL . DB08870 , combines a monoclonal antibody targeted to P28908 with a microtubule disrupting agent and was recently approved for treatment of patients with systemic ALCL that is refractory or relapsed after at least one multiagent chemotherapy regimen . EXPERT OPINION : DB08870 provides targeted therapy to P28908 (+) lymphomas , including ALCL and HL , with high response rates and manageable toxicity , predominantly myelosuppression and peripheral neuropathy .", "[ Melanoma : from molecular studies to the treatment breakthrough ] . Melanoma holds a leading position in the mortality from skin tumors . Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients . Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and , consequently , to the development of novel targeted drugs . More than a half of melanomas contain amine acid substitutions in serine - threonine kinase P15056 . Clinical trials involving specific P15056 inhibitors -- vemurafenib and dabrafenib -- demonstrated high efficacy of these agents towards P15056 - mutated melanoma . MEK inhibitors may show activity against both P15056 -- and P01111 - driven tumors . Mucosal and acral melanomas frequently contain mutation in P10721 receptor and can be successfully treated by imatinib . There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules P16410 , P18621 and Q9NZQ7 . In some instances these drugs allow to obtain exceptionally prolonged responses . Whole genome sequencing led to the identification of new melanoma genes , e . g . Q12879 , Q9Y4A5 , Q70Z35 , P63000 , P49842 , O00743 , etc . Molecular testing , especially P15056 mutation analysis , has become a mandatory part of melanoma diagnosis . Nevertheless , despite the revolution in melanoma treatment , the prevention of excessive ultraviolet exposure , cancer awareness and early diagnosis remain the main tools for the management of this disease .", "Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin . BACKGROUND : Primary biliary cirrhosis ( P10515 ) is an organ specific autoimmune disease of still unidentified genetic etiology . We have shown that endothelins ( ETs ) , produced by the liver endothelial cells are increased in P10515 and may play a major pathogenetic role . AIMS : To study gene polymorphisms related to the endothelial cells ( P29474 , P10153 - 1 genes ) and , to investigate whether the previously reported association of P16410 gene polymorphisms is replicated in a genetically homogeneous Greek population . PATIENTS AND METHODS : Genomic DNA was extracted from 100 P10515 patients ( 83 females , 93 % AMA + , 74 / 100 Ludwig stage I - II ) and 158 healthy controls . P29474 , P16410 and ET1 polymorphisms were determined by PCR - RFLPs analysis . RESULTS : Both P29474 intron4 VNTR and P29474 exon7 G894T SNP were significantly associated with increased risk in P10515 . P10153 - 11 rs2071942 \" A \" and rs5370 \" T \" alleles appeared a tendency for association with disease progression . No association was found between P10515 and the P16410 SNPs analyzed . CONCLUSIONS : We demonstrated that P29474 , a gene related to the liver endothelium function is associated with P10515 . Contrarily , the important in adaptive immunity gene P16410 was not associated with the disease in the homogeneous population analyzed . These results are compatible partially with our previous hypothesis that defects of the liver endothelial system , leading to endothelin overproduction , may be a fundamental early pathogenetic mechanism in P10515 .", "Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .", "Direct and indirect striatal efferent pathways are differentially influenced by low and high dyskinetic drugs : behavioural and biochemical evidence . Clinical evidence suggests that stimulation of the D ( 1 ) rather than P14416 is related to the development of dyskinesias in Parkinson ' s disease ( PD ) . We evaluated , in the 6 - hydroxydopamine rat model of PD , sensitization of contralateral turning ( P09683 ) behaviour and abnormal involuntary movements ( AIMs ) as behavioural parameters of dyskinetic response , and changes in zif - 268 mRNA expression in striatonigral and striatopallidal neurons on subchronic administration of the D ( 2 )/ D ( 3 ) agonist ropinirole , defined as a mild dyskinetic drug in the clinic . Results were compared with previous findings on repeated L - dopa treatment . Ropinirole displayed a mild dyskinetic response characterized by P09683 only , which contrasted with the presence of P09683 in association with AIMs elicited by repeated L - dopa . Zif - 268 mRNA levels were decreased in both striatonigral and striatopallidal neurons by ropinirole , in contrast to hyper - expression of zif - 268 mRNA selectively induced by L - dopa in striatonigral neurons . Unbalanced responsiveness of striatal efferent neurons might represent a molecular correlate of high dyskinetic potential and AIMs in rats ; in contrast , a balanced striatal output might underlie the low dyskinetic potential displayed by ropinirole .", "Elevated CD3 + and CD8 + tumor - infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level . We characterized GBM patients ' tumor and systemic immune contexture with aim to reveal the mechanisms of immunological escape , their impact on patient outcome , and identify targets for immunotherapy . Increased CD3 (+) T - cell infiltration was associated with prolonged survival independent of age , P16455 promoter methylation and post - operative treatment that implies potential for immunotherapy for GBM . Several mechanisms of escape were identified : within the tumor microenvironment : induced CD8 (+) P10747 (-) Foxp3 (+) Tregs that may tolerize antigen presenting cells , elevated CD73 and P49961 ectonucleotidases that suppress T - cell function , and at the systemic level : elevated P22301 levels in serum , diminished helper T - cell counts , and upregulated inhibitory P16410 .", "DB00134 - stress : a pleiotropic approach in enhancing the efficacy of chemotherapy . Malignant cells fail to utilize homocysteine ( HCYS ) in place of methionine ( MET ) and they are dependent on exogenous MET for growth . In animals , reduction of plasma MET to < 5 microM can be induced by combined dietary restriction of MET and administration of L - methionine - alpha - deamino - gamma - lyase ( methioninase ) . This treatment , termed as MET - stress , inhibits the growth of brain tumor xenografts in athymic mice and enhances the efficacy of DNA alkylating chemotherapeutic agents . The response of tumors to MET - stress depends on their mutational status , however , it always involves inhibition of P06493 and in most cases the upregulation of P38936 , p27 , GADDs and 14 - 3 - 3sigma in response to upregulation of TGF - beta , P10914 , P01375 , Rb and / or Q13007 and the downregulation of PI3K , DB01367 and NF - kappaB . Although inhibition of the cell cycle and mitosis is not necessarily dependent on the tumor ' s p53 status , the expression of P38936 , P24522 and apoptosis related genes ( Q07812 , BCL - 2 ) are regulated by wt - p53 , in addition to their regulation by TGF - beta or Q13007 in mutated p53 tumors . Mutational variability determines the mode of death ( mitotic catastrophe versus apoptosis ) in tumor cells subjected to MET - stress . The increase of the efficacy of alkylating agents is related to marked inhibition of O6 - methylguanine - DNA methyltransferase ( P16455 ) expression , the induction of cell cycle check points and the inhibition of pro - survival pathways by MET - stress .", "___MASK57___ - mediated cyclooxygenase - 2 expression via epidermal growth factor receptor / Q15717 interaction enhances the aggressiveness of triple - negative breast cancer cells . ___MASK57___ , a dual epidermal growth factor receptor ( P00533 ) / human epidermal growth factor receptor 2 ( P04626 ) kinase inhibitor , showed clinical benefits in advanced P04626 - positive breast cancer patients . Because some triple - negative breast cancers ( TNBCs ) frequently overexpress P00533 , the antitumor activity of lapatinib in such diseases was also tested . However , the results showed a worse event - free survival rate . It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells . In this study , our results demonstrated that lapatinib facilitated axillary and lung metastases of triple - negative MDA - MB - 231 breast cancer cells without affecting their viability , leading to worse survival in orthotopic xenograft mice . The lapatinib - increased motility was attributed by the elevation of P00533 through the downregulation of microRNA - 7 and by the subsequent overexpression of cyclooxygenase - 2 ( P35354 ) . Strikingly , independent of its kinase activity , the elevated P00533 at least partly stabilized P35354 expression by enhancing the binding of Q15717 to P35354 mRNA . Our results suggest that lapatinib may increase the migration and invasion of MDA - MB - 231 cells by upregulating P00533 and P35354 through the downregulation of microRNA - 7 , providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib - based treatment . These findings also shed new light on the molecular mechanism of P35354 mRNA stabilization by P00533 in a kinase - independent manner .", "Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . DB00502 was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .", "DB08870 followed by allogeneic transplantation as salvage regimen in patients with relapsed and / or refractory Hodgkin ' s lymphoma . Patients with relapsed or refractory Hodgkin lymphoma ( RR - HL ) have poor outcomes . DB08870 ( BV ) , an antibody - drug conjugate comprising an anti - P28908 antibody conjugated to the potent anti - microtubule agent , monomethyl auristatin E , induces high tumour responses with moderate adverse effects . In a retrospective study , we describe objective response rates and subsequent allogeneic stem cell transplantation ( allo - P09683 ) in patients with RR - HL treated by BV in a named patient program in two French institutions . Twenty - four adult patients with histologically proven P28908 (+) RR - HL treated with BV were included from July 2009 to November 2012 . Response to BV treatment was evaluated after four cycles . Eleven patients were in complete response ( 45 . 8 % ) , while five patients were in partial response ( 20 . 8 % ) , with an overall response rate of 66 . 6 % . Eight patients failed to respond to BV ( 33 . 3 % ) . All of the responding patients could receive consolidation treatment after BV : three patients underwent autologous stem cell transplantation ( auto - P09683 ) , three patients received a tandem auto - P09683 / allo - P09683 , nine patients received allo - P09683 and one patient was treated with donor lymphocyte infusion . We found no treatment - related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation . With a median follow - up of 20 months ( range 10 . 5 - 43 . 2 ) , none of them relapsed or died . BV followed by allo - P09683 represents an effective salvage regimen in patients with RR - HL .", "A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK34___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .", "5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK21___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .", "Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .", "Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .", "Interaction of the cytoplasmic tail of P16410 ( P16410 ) with a clathrin - associated protein is negatively regulated by tyrosine phosphorylation . P16410 ( P16410 ) , high - avidity receptor for P33681 and P42081 , is a powerful regulator of T cell activation . While P16410 functions at the cell surface , it is primarily localized in intracellular vesicles and cycles to the cell surface . The P16410 cytoplasmic domain contains sequences that direct its intracellular localization and regulate its signaling . Here we demonstrate that effector molecules involved in receptor trafficking and signaling interact with distinct , but overlapping , sequences in the P16410 cytoplasmic domain . Using the yeast two - hybrid method , we demonstrate association of the mu2 subunit of P05549 , the clathrin - associated complex found in plasma membrane - associated coated pits , with the cytoplasmic tail of P16410 , but not P10747 . The mu1 subunit of AP - 1 , found in Golgi - associated coated pits , associated with neither P16410 nor P10747 . Sequences required for interaction of mu2 and P16410 were localized to residues , 161TTGVY in P16410 ; this sequence is N - terminal to , but overlaps with , a previously identified SH2 binding motif , 165YVKM , involved in P16410 signaling . Mu2 interacted preferentially with P16410 when residue 165Y was nonphosphorylated , whereas a P19957 kinase SH2 domain interacted preferentially when 165Y was phosphorylated . In co - transfection experiments , both tyrosine residues in the cytoplasmic tail of P16410 ( 165Y and 182Y ) were phosphorylated by the T lymphocyte - associated tyrosine kinase , p56lck . Thus , phosphorylation of P16410 residue 165Y may reciprocally regulate signaling and trafficking of P16410 by determining which effector molecules bind to its cytoplasmic tail .", "Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK21___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .", "Circulating apoptotic proteins are increased in long - term disease - free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis - related proteins and inflammation markers are increased in long - term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF - receptor ( sTNF - R ) 1 and 2 , sFas , sFas ligand , sTNF - related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High - sensitivity P02741 ( HS - CRP ) , fibrinogen , plasma B - type and N - terminal atrial natriuretic peptide ( NT - P01160 and DB04899 ) were also determined . Thirty - four patients with median 6 . 0 years follow - up and 12 healthy age - matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high - dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high - dose than in the standard - dose group . In conclusion , we observed increased circulating apoptotic protein levels in long - term disease - free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .", "P04818 genotype - directed chemotherapy for patients with gastric and gastroesophageal junction cancers . BACKGROUND : Retrospective studies indicate associations between TSER ( thymidylate synthase enhancer region ) genotypes and clinical outcomes in patients receiving ___MASK43___ based chemotherapy , but well - controlled prospective validation has been lacking . METHODS : In this phase II study ( NCT00515216 registered through ClinicalTrials . gov , http :// clinicaltrials . gov / show / NCT00515216 ) , patients with \" good risk \" TSER genotypes ( at least one TSER * 2 allele ) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates ( ORR ) in patients with gastric and gastroesophageal junction ( GEJ ) cancers , compared with historical outcomes in unselected patients ( estimated 43 % ) . RESULTS : The ORR in genotype - selected patients was Q04695 % ( 9 partial responses out of 23 evaluable patients , 95 % CI , 22 . 2 to 59 . 2 ) , not achieving the primary objective of improving ORR . An encouraging disease control rate ( DCR , consisting of partial responses and stable diseases ) of 95 . 7 % was noted and patients with homozygous TSER * 2 genotype showed better tumor response . CONCLUSIONS : In this first prospective , multi - institutional study in patients with gastric or GEJ cancers , selecting patients with at least one TSER * 2 allele did not improve the ORR but led to an encouraging DCR . Further studies are needed to investigate the utility of selecting patients homozygous for the TSER * 2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers . TRIAL REGISTRATION : ClinicalTrials . gov NCT00515216 .", "___MASK34___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK34___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .", "Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .", "Involvement of retinoic acid receptor alpha in the stimulation of tissue - type plasminogen - activator gene expression in human endothelial cells . Retinoids stimulate tissue - type plasminogen - activator ( t - PA ) gene expression in human endothelial cells , and are likely to do so by binding to one or more nuclear retinoid receptors . The present study was initiated to identify the retinoid receptor ( s ) involved in this process . Expression and regulation of retinoic acid receptors ( RARs ) and retinoid X receptors ( RXRs ) were analyzed by Northern - blot analysis of total or poly ( A )- rich RNA prepared from cultured human umbilical vein endothelial cells ( HUVEC ) . Prior to any exposure to retinoids , HUVEC express two transcripts for P10276 ( 3 . 6 kb and 2 . 8 kb ) , and low levels of transcripts for P10826 ( 3 . 4 kb and 3 . 2 kb ) and P13631 ( 3 . 3 kb and 3 . 1 kb ) . Two RXR subtypes were identified , RXR - alpha ( 4 . 8 kb ) and , at a much lower concentration , RXR - beta ( 2 . 4 kb ) ; no evidence for the presence of RXR - gamma was found . Furthermore , HUVEC express cellular retinol - binding protein I ( P09455 ) and cellular retinoic - acid - binding protein I ( P29762 ) mRNA . Exposure of HUVEC to 1 microM retinoic acid or the DB04942 , Ch55 , led to the induction of the two P10826 mRNAs , RXR - alpha mRNA and P09455 mRNA , whereas the expression of the other receptor and P29762 transcripts did not change appreciably . Using retinoid analogues that bind preferentially to one of the RAR or RXR subtypes , we found evidence that P10276 is involved in the retinoid - induced t - PA expression in HUVEC . This conclusion was strengthened by experiments in which blocking of P10276 with a specific P10276 antagonist , Ro 41 - 5253 , was demonstrated to suppress the induction of t - PA by retinoids .", "[ ___MASK39___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK39___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .", "Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK36___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK36___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK36___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK36___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK36___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK36___ increased the protein expression of hepatic P05181 and ___MASK36___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK36___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK36___ and RFP - induced hepatotoxicity .", "Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .", "Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \" nongenomic \" pathway which , is clearly discernable from the classical , \" genomic \" action pathway of the P35869 by not requiring the participation of P27540 .", "The nuclear chaperone nucleophosmin escorts an Epstein - Barr Virus nuclear antigen to establish transcriptional cascades for latent infection in human B cells . Epstein - Barr Virus ( EBV ) is an oncogenic γ - herpesvirus that capably establishes both latent and lytic modes of infection in host cells and causes malignant diseases in humans . Nuclear antigen 2 ( EBNA2 ) - mediated transcription of both cellular and viral genes is essential for the establishment and maintenance of the EBV latency program in B lymphocytes . Here , we employed a protein affinity pull - down and LC - MS / MS analysis to identify nucleophosmin ( P06748 ) as one of the cellular proteins bound to EBNA2 . Additionally , the specific domains that are responsible for protein - protein interactions were characterized as EBNA2 residues 300 to 360 and the oligomerization domain ( OD ) of P06748 . As in c - MYC , dramatic P06748 expression was induced in EBV positively infected B cells after three days of viral infection , and both EBNA2 and EBNALP were implicated in the transactivation of the P06748 promoter . Depletion of P06748 with the lentivirus - expressed short - hairpin RNAs ( shRNAs ) effectively abrogated EBNA2 - dependent transcription and transformation outgrowth of lymphoblastoid cells . Notably , the DB00171 - bound state of P06748 was required to induce assembly of a protein complex containing EBNA2 , P02753 - Jκ , and P06748 by stabilizing the interaction of EBNA2 with P02753 - Jκ . In a P06748 - knockdown cell line , we demonstrated that an EBNA2 - mediated transcription defect was fully restored by the ectopic expression of P06748 . Our findings highlight the essential role of P06748 in chaperoning EBNA2 onto the latency - associated membrane protein 1 ( LMP1 ) promoters , which is coordinated with the subsequent activation of transcriptional cascades through P02753 - Jκ during EBV infection . These data advance our understanding of EBV pathology and further imply that P06748 can be exploited as a therapeutic target for EBV - associated diseases .", "Mobilization of P29590 - P10276 negative blood stem cells and salvage with autologous peripheral blood stem cell transplantation in children with relapsed acute promyelocytic leukemia . BACKGROUND : Relapsed acute promyleocytic leukemia ( APL ) is treated with re - induction chemotherapy , commonly arsenic trioxide , and stem cell transplantation ( P09683 ) . The effect of arsenic trioxide on autologous peripheral blood stem cell collection is unknown . PROCEDURE : Five pediatric patients with relapsed APL had P29590 - P10276 negative peripheral blood stem cells mobilized ( four after arsenic trioxide ) and underwent autologous P09683 after cyclophosphamide ( 60 mg / kg x 2 ) and total body irradiation ( TBI - fractionated 1 , 200 cGy ) conditioning . RESULTS : All five patients remain in molecular remission a median of 20 months post - transplant . CONCLUSION : Autologous P09683 performed during molecular remission is a treatment option for pediatric patients with relapsed APL and may provide durable leukemia - free survival without the complications of allogeneic transplantation .", "Sickle cell trait in Ivory Coast athletic throw and jump champions , 1956 - 1995 . In order to assess the performance of subjects with sickle cell trait ( P09683 ) during brief and explosive exercise involving mainly alactic anaerobic metabolism , the percentage of athletes with P09683 was determined in Ivory Coast track and field throw and jump champions , both men and women , for the period 1956 - 1995 . Thirty - four ( 27 . 8 % ) sickle cell trait carriers ( SCTC ) were identified among the 122 national champions that we were able to contact . These 34 SCTC had won 78 national titles ( 24 . 5 % ) and established 37 national records ( 43 . 5 % ) , distributed among the throw and jump events . These percentages were significantly higher than the prevalence of P09683 in the general Ivory Coast population ( 12 . 0 % ) . The women ' s high jump and men ' s shot put events had the highest percentages of SCTC record holders ( 90 . 9 % and 87 . 5 % , respectively ) . Moreover , the two top national record holders and title winners , one man and one woman , were SCTC athletes , and their hemoglobin S percentage ( HbS : Q04695 % and 39 . 4 % , respectively ) and mean corpuscular volume ( MCV ) excluded an associated alpha - thalassemia . We conclude that the significantly higher percentage of SCTCs among Ivory Coast track and field champions , as compared to the percentage in the general population suggests that P09683 may be a determinant factor for success in brief and explosive track and field events involving mainly alactic anaerobic metabolism .", "Statin decreases endothelial microparticle release from human coronary artery endothelial cells : implication for the Rho - kinase pathway . OBJECTIVE : Elevated plasma levels of endothelial microparticles ( EMPs ) are associated with the presence of clinical atherosclerosis . Considering the anti - inflammatory properties of P04035 inhibitors on the endothelium , we studied the effect of fluvastatin on the release of EMPs in cultured human coronary artery endothelial cells ( HCAEC ) . METHODS AND RESULTS : EMPs were generated in P01375 - activated HCAECs . The absolute number of EMPs was enumerated using a novel two - color flow cytometric immunostaining technique with TruCount beads as an internal reference . EMPs are defined as EC membrane vesicles ( 1 - 2 microm in size ) with a characteristic immunophenotype . The addition of fluvastatin to P01375 - activated HCAECs significantly suppressed Q7L5Y9 release . ___MASK34___ suppressed P01375 - induced Rho activation . The Rho - kinase inhibitor , Y - 27632 , reproduced the effect of statin . CONCLUSION : Q7L5Y9 release from P01375 - activated HCAECs is suppressed by fluvastatin . In addition , the Rho / Rho - kinase may play an important role in modulating Q7L5Y9 release .", "Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .", "P10275 coregulator Q96L73 - alpha interacts with death receptor - 6 revealed by the yeast two - hybrid . Q96L73 - alpha is a newly identified androgen receptor coactivator . In order to further elucidate its precise role in cells , using the Q96L73 - alpha fragment containing four P20941 and one Q01105 conserved domains as bait we revealed an Q96L73 - alpha - P20941 - Q01105 - interacting protein , death receptor - 6 ( O75509 ) , in the yeast two - hybrid screening . O75509 is the member of P01375 receptor family and has a death domain in its intracellular cytoplasmic portion ( DR6cp ) to mediate the cell apoptosis . The interaction between Q96L73 - alpha - P20941 - Q01105 and DR6cp was confirmed in vitro and in vivo . Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between Q96L73 - alpha and O75509 .", "P06748 - Q9UM73 oncogenic kinase promotes cell - cycle progression through activation of JNK / cJun signaling in anaplastic large - cell lymphoma . Anaplastic large - cell lymphoma ( ALCL ) frequently carries the t ( 2 ; 5 )( p23 ; q35 ) , resulting in aberrant expression of nucleophosmin - anaplastic lymphoma kinase ( P06748 - Q9UM73 ) . We show that in 293T and Jurkat cells , forced expression of active P06748 - Q9UM73 , but not kinase - dead mutant P06748 - Q9UM73 ( 210K > R ) , induced JNK and cJun phosphorylation , and this was linked to a dramatic increase in AP - 1 transcriptional activity . Conversely , inhibition of Q9UM73 activity in P06748 - Q9UM73 (+) ALCL cells resulted in a concentration - dependent dephosphorylation of JNK and cJun and decreased AP - 1 DNA - binding . In addition , JNK physically binds P06748 - Q9UM73 and is highly activated in cultured and primary P06748 - Q9UM73 (+) ALCL cells . cJun phosphorylation in P06748 - Q9UM73 (+) ALCL cells is mediated by JNKs , as shown by selective knocking down of P45983 and P45984 genes using siRNA . Inhibition of JNK activity using SP600125 decreased cJun phosphorylation and AP - 1 transcriptional activity and this was associated with decreased cell proliferation and G2 / M cell - cycle arrest in a dose - dependent manner . Silencing of the cJun gene by siRNA led to a decreased S - phase cell - cycle fraction associated with upregulation of P38936 and downregulation of cyclin D3 and cyclin A . Taken together , these findings reveal a novel function of P06748 - Q9UM73 , phosphorylation and activation of JNK and cJun , which may contribute to uncontrolled cell - cycle progression and oncogenesis .", "P04818 inhibition induces p53 - dependent and p53 - independent apoptotic responses in human urinary bladder cancer cells . PURPOSE : In search for more effective clinical protocols , the antimetabolite drug 5 - fluorouracil ( ___MASK43___ ) has been successfully included in new regimens of bladder cancer combination chemotherapy . In the present study , we have investigated the effects of ___MASK43___ treatment on apoptosis induction in wild - type and mutant p53 urinary bladder cancer cells . METHODS : We have used MTT - based assays , FACS analysis , Western blotting and semi - quantitative RT - PCR in RT4 and RT112 ( grade I , wild - type p53 ) , as well as in T24 ( grade III , mutant p53 ) and TCCSUP ( grade IV , mutant p53 ) human urinary bladder cancer cell lines . RESULTS : In the urothelial bladder cancer cell lines RT4 and T24 , ___MASK43___ - induced TS inhibition proved to be associated with cell type - dependent ( a ) sensitivity to the drug , ( b ) Caspase - mediated apoptosis , ( c ) p53 stabilization and activation , as well as Rb phosphorylation and Q01094 expression and ( d ) transcriptional regulation of p53 target genes and their cognate proteins , while an E2F - dependent transcriptional network did not seem to be critically engaged in such type of responses . CONCLUSIONS : We have shown that in the wild - type p53 context of RT4 cells , ___MASK43___ - triggered apoptosis was prominently efficient and mainly regulated by p53 - dependent mechanisms , whereas the mutant p53 environment of T24 cells was able to provide notable levels of resistance to apoptosis , basically ascribed to E2F - independent , and still unidentified , pathways . Nevertheless , the differential vulnerability of RT4 and T24 cells to ___MASK43___ administration could also be associated with cell - type - specific transcriptional expression patterns of certain genes critically involved in ___MASK43___ metabolism .", "In vivo cytokine responses to interleukin - 2 immunotherapy after autologous stem cell transplantation in children with solid tumors . The potent immunostimulatory cytokine interleukin - 2 ( P60568 ) has been extensively investigated for its potential to induce anti - tumor immunity in a number of tumor models . Only recently the complex interplay of mutually suppressive or supportive cytokines of the P60568 - induced network of cytokines has been better characterized . The aim of this study was to assess which of these in vitro findings are reproducible in vivo in recipients of stem cell transplants ( P09683 ) , since in these patients long - lasting impairments in cytokine inducibility have been described . We have therefore studied the kinetics of putative modulators and mediators of P60568 - induced immune activation , namely IL - 1beta , P05112 , P05113 , P22301 , IL - 12 , soluble P48023 ( sFasL ) , and GM - P04141 during P60568 therapy . All patients were children or adolescents suffering from solid tumors with poor prognosis who received three 5 - day courses of high - dose intravenous P60568 as an adjuvant to their radio - chemotherapy and autologous P09683 . While IL - 1beta , P05112 and IL - 12 were not , and sFasL was only mildly affected by the P60568 therapy , we observed a consistent and early rise of P22301 , P05113 , and GM - P04141 . These increases were rapidly reversible after discontinuation of P60568 therapy . The inducibility of P22301 , P05113 and GM - P04141 was more pronounced with increasing time from the P09683 , and in the third cycle reached an order of magnitude as in high - dose P60568 patients without P09683 . Together with the abundant in vitro data , these findings may help devise a combination immunotherapy permitting stronger anti - tumor effects , but lesser adverse effects .", "DB08870 : its role in the treatment of anaplastic large cell and Hodgkin ' s lymphoma . DB08870 is being developed in a joint collaboration between Seattle Genetics and Millennium : The Takeda Oncology Company . In August 2011 , it was approved by the FDA for the treatment of patients with Hodgkin ' s lymphoma ( HL ) and anaplastic large cell lymphoma ( ALCL ) . DB08870 is an antibody - drug conjugate that specifically targets the P01375 receptor superfamily member 8 ( P28908 ) antigen on the surface of cancer cells to induce cell death . DB08870 has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express P28908 and reducing tumor size in preclinical models . DB08870 is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children . It is being investigated for use as a combination agent with pre - existing frontline chemotherapies and as a stand - alone salvage therapy for use prior to autologous stem cell transplant . Treatment with brentuximab vedotin is generally well tolerated although it is associated with grade 1 - 2 adverse reactions such as neutropenia and there have been reports of grade 3 - 4 serious adverse events . In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects .", "Highly efficient , in - vivo Fas - mediated apoptosis of B - cell lymphoma by hexameric P16410 - P48023 . Non - Hodgkin lymphomas ( NHLs ) account for 4 % of all malignancies . 5 - year survival rate increased to 50 % with new treatment modalities , however there is need for new effective treatment for the more aggressive , relapsing forms . Recently , P16410 - P48023 , that can bind to P33681 and Fas receptor ( Fas ) , was shown to induce robust apoptosis of cell lines originating from B cell lymphomas expressing both P33681 and Fas , by activating pro - apoptotic signals in parallel to abrogating anti - apoptotic ones . The present study focuses on the unique properties of P16410 - P48023 as a potent apoptosis inducer of malignant cells in - vitro and in a xenograft model . P16410 - P48023 was found to naturally form a stable homo - hexamer . P16410 - P48023 induces robust apoptosis of a large variety of malignant cells while relatively sparing non - malignant ones , being more efficient when both receptors ( P33681 and Fas ) are expressed on target cells . Even in non - P33681 expressing cells , P16410 - P48023 exhibited better apoptotic activity than its parts , alone or in combination , however , only in P33681 expressing cells apoptosis occurs at low concentrations and P16410 - P48023 induces activation of apoptotic signals and reduces anti - apoptotic ones . Importantly , P16410 - P48023 efficiently inhibited the growth of human B cell lineage tumors in a xenograft model , by provoking tumor cells ' apoptosis . Thus , P16410 - P48023 , a natural homo - hexamer protein , induces robust apoptosis of malignant cells , in - vitro and in - vivo . In B - cell lymphoma , its potency stems from the combination of its synergistic effect of activating the caspases while abrogating the anti - apoptotic signaling , with its unique hexameric structure , making P16410 - P48023 a promising candidate for aggressive B cell lymphomas treatment .", "Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin ' s lymphoma . PURPOSE : DB08870 is an antibody - drug conjugate ( ADC ) that selectively delivers monomethyl auristatin E , an antimicrotubule agent , into P28908 - expressing cells . In phase I studies , brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory P28908 - positive lymphomas . PATIENTS AND METHODS : In this multinational , open - label , phase II study , the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin ' s lymphoma ( HL ) after autologous stem - cell transplantation ( auto - P09683 ) . Patients had histologically documented P28908 - positive HL by central pathology review . A total of 102 patients were treated with brentuximab vedotin 1 . 8 mg / kg by intravenous infusion every 3 weeks . In the absence of disease progression or prohibitive toxicity , patients received a maximum of 16 cycles . The primary end point was the overall objective response rate ( ORR ) determined by an independent radiology review facility . RESULTS : The ORR was 75 % with complete remission ( CR ) in 34 % of patients . The median progression - free survival time for all patients was 5 . 6 months , and the median duration of response for those in CR was 20 . 5 months . After a median observation time of more than 1 . 5 years , 31 patients were alive and free of documented progressive disease . The most common treatment - related adverse events were peripheral sensory neuropathy , nausea , fatigue , neutropenia , and diarrhea . CONCLUSION : The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75 % of patients with relapsed or refractory HL after auto - P09683 . Durable CRs approaching 2 years were observed , supporting study in earlier lines of therapy .", "Novel therapeutic options in anaplastic large cell lymphoma : molecular targets and immunological tools . Anaplastic large cell lymphoma ( ALCL ) is a P28908 - positive , aggressive T - cell lymphoma , and about half of the patients with this disease harbor the t ( 2 ; 5 )( P38936 ; q35 ) translocation . This chromosomal aberration leads to fusion of the P06748 gene with the Q9UM73 tyrosine kinase , leading to its constitutive activation . To date , treatment options include polychemotherapy ( e . g . , cyclophosphamide , doxorubicin , vincristine , and prednisone ) , which is sometimes combined with radiation in the case of bulky disease , leading to remission rates of ∼ 80 % . However , the remaining patients do not respond to therapy , and some patients experience chemo - resistant relapses , making the identification of new and better treatments imperative . The recent discovery of deregulated Q9UM73 in common cancers such as non - small cell lung cancer and neuroblastoma has reinvigorated industry interest in the development of Q9UM73 inhibitors . Moreover , it has been shown that the Q9UM73 protein is an ideal antigen for vaccination strategies due to its low expression in normal tissue . The characterization of microRNAs that are deregulated in ALCL will yield new insights into the biology of ALCL and open new avenues for therapeutic approaches in the future . Also , P28908 antibodies that have been tested in ALCL for quite a while will probably find a place in forthcoming treatment strategies ." ]

[ "___MASK14___", "___MASK21___", "___MASK34___", "___MASK36___", "___MASK39___", "___MASK43___", "___MASK57___", "___MASK77___", "___MASK80___" ]

[ "Guggulsterone inhibits angiogenesis by blocking P40763 and P15692 expression in colon cancer cells . The plant sterol guggulsterone has been shown to exert anti - tumor effects , making it a candidate chemotherapeutic agent . We investigated the anti - tumor effects of guggulsterone on colon cancer cells and elucidated the underlying molecular mechanisms related to angiogenesis . The apoptotic effects of guggulsterone were examined by cell survival assay . Western blot analysis was used to determine the levels of various down - stream intracellular proteins involved in angiogenesis , including signal transducer and activator of transcription 3 ( P40763 ) , vascular endothelial growth factor ( P15692 ) , hypoxia - inducible factor - 1alpha ( HIF - 1alpha ) and aryl hydrocarbon receptor nuclear translocator ( P27540 ) . Using chromatin immunoprecipitation assay , we tested whether guggulsterone affects the recruitment of P40763 , P27540 and HIF - 1alpha to the human P15692 promoter . To investigate the effect of guggulsterone on vascular endothelial cell migration and invasion , tube formation and migration assays were conducted using human umbilical vein endothelial cells ( HUVECs ) . Matrix metalloproteinase ( MMP ) - 2 and - 9 activities were measured by gelatin zymography . Guggulsterone significantly reduced cell viability in colon cancer cells in a dose - dependent manner and blocked P15692 , P27540 and P40763 expression prominently in hypoxic conditions . The recruitment of P40763 and P27540 , but not HIF - 1alpha , to the P15692 promoter was inhibited by guggulsterone treatment . HUVECs produced much foreshortened and severely broken tubes and showed decreased migration activity under guggulsterone effects . In addition , zymography revealed that P08253 and - 9 enzyme activities were markedly lower in the presence of guggulsterone . The results of this study suggest that guggulsterone not only induces apoptosis , but also inhibits angiogenesis and metastasis in colon cancer cells by blocking P40763 and P15692 expression , suggesting its therapeutic potential in the treatment of colorectal cancer .", "Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . ___MASK22___ , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol - treated group ( p less than 0 . 05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0 . 05 ) and the testosterone ( p less than 0 . 01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone .", "Chromosome 8p as a potential hub for developmental neuropsychiatric disorders : implications for schizophrenia , autism and cancer . Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia . Presumably , owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult . However , the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established . There are 484 annotated genes located on 8p ; many are most likely oncogenes and tumor - suppressor genes . Molecular genetics and developmental studies have identified 21 genes in this region ( ADRA1A , O15013 , Q15822 , Q15825 , Q05901 , Q9UBT3 , Q16555 , Q06889 , O60258 , Q9NP95 , P11362 , FZD3 , LDL , NAT2 , P07197 , Q02297 , PCM1 , P00750 , P48454 , Q8N474 and P54219 / P54219 ) that are most likely to contribute to neuropsychiatric disorders ( schizophrenia , autism , bipolar disorder and depression ) , neurodegenerative disorders ( Parkinson ' s and Alzheimer ' s disease ) and cancer . Furthermore , at least seven nonprotein - coding RNAs ( microRNAs ) are located at 8p . Structural variants on 8p , such as copy number variants , microdeletions or microduplications , might also contribute to autism , schizophrenia and other human diseases including cancer . In this review , we consider the current state of evidence from cytogenetic , linkage , association , gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease . We also describe how a mutation in an 8p gene ( Fgf17 ) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex . We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer , despite the shortcomings of this evidence .", "Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK73___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .", "Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK31___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .", "Inhibition of the liver expression of arylalkylamine N - acetyltransferase increases the expression of angiogenic factors in cholangiocytes . BACKGROUND AND AIMS : Reduction of biliary serotonin N - acetyltransferase ( Q16613 ) expression and melatonin administration / secretion in cholangiocytes increases biliary proliferation and the expression of SR , P13569 and Cl (-)/ HCO3 ( - ) P04920 . The balance between biliary proliferation / damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor - A / C ( P15692 / C ) . VEGFs are secreted by several epithelia , where they modulate cell growth by autocrine and paracrine mechanisms . No data exists regarding the effect of Q16613 modulation on the expressions of VEGFs by cholangiocytes . METHODS : In this study , we evaluated the effect of local modulation of biliary Q16613 expression on the cholangiocytes synthesis of P15692 / C . RESULTS : The decrease in Q16613 expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of P15692 / C . Overexpression of Q16613 in cholangiocyte lines decreased the expression of P15692 / C . CONCLUSIONS : Modulation of melatonin synthesis may affect the expression of P15692 / C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of P15692 / C expression regulating biliary functions .", "P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .", "Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK10___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK10___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK10___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK10___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK10___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK10___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK10___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK10___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK10___ in the treatment of changes in hypervigilance following severe stress .", "Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .", "Levels of angiopoietins 1 and 2 in induced sputum supernatant in patients with P48444 . Pathological features of chronic obstructive pulmonary disease ( P48444 ) include lung vascular remodeling and angiogenesis . Q15389 ( Ang - 1 ) , is an essential mediator of angiogenesis by establishing vascular integrity , whereas angiopoietin - 2 ( Ang - 2 ) acts as its natural inhibitor . We determined the levels of angiopoietins in sputum supernatants of patients with P48444 and investigated their possible association with mediators and cells involved in the inflammatory and remodeling process . Fifty - nine patients with P48444 , 25 healthy smokers and 20 healthy non - smokers were studied . All subjects underwent lung function tests , sputum induction for cell count identification and Ang - 1 , Ang - 2 , P15692 , TGF - β1 , P08253 , LTB4 , P10145 , albumin measurement in sputum supernatants . Airway vascular permeability ( AVP ) index was also assessed . Ang - 2 levels were significantly higher in patients with P48444 compared to healthy smokers and healthy non - smokers [ median , interquartile ranges pg / ml , 267 ( 147 - 367 ) vs . 112 ( 67 - 171 ) and 98 ( 95 - 107 ) , respectively ; p < 0 . 001 ] . Regression analysis showed a significant association between Ang - 2 levels and AVP index , P15692 , P10145 and P08253 levels in P48444 , the strongest being with P15692 . Our results indicate that induced sputum Ang - 2 levels are higher in P48444 compared to healthy smokers and healthy non - smokers . Moreover , Ang - 2 is associated with AVP , P10145 , P08253 , and P15692 , indicating a possible role for Ang - 2 in the pathogenesis of the disease .", "A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .", "Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK33___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .", "Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK75___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .", "DB09079 , a triple angiokinase inhibitor , enhances cytotoxic therapy response in pancreatic cancer . Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma ( PDAC ) therapy . P15692 , PDGF , FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC . DB09079 is a triple angiokinase inhibitor that targets P17948 / 2 / 3 , P11362 / 2 / 3 and PDGFRα / β signaling . We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC . DB09079 inhibited proliferation of cells from multiple lineages found in PDAC , with gemcitabine enhancing inhibitory effects . DB09079 blocked PI3K / MAPK activity and induced apoptosis in vitro and in vivo . In a heterotopic model , net local tumor growth compared to controls ( 100 % ) was 60 . 8 ± 10 . 5 % in the gemcitabine group , - 2 . 1 ± 9 . 9 % after nintedanib therapy and - 12 . 4 ± 16 % after gemcitabine plus nintedanib therapy . Effects of therapy on intratumoral proliferation , microvessel density and apoptosis corresponded with tumor growth inhibition data . In a PDAC survival model , median animal survival after gemcitabine , nintedanib and gemcitabine plus nintedanib was 25 , 31 and 38 days , respectively , compared to 16 days in controls . The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib - controlled mechanisms as targets for improved clinical PDAC therapy .", "Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK95___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .", "Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .", "Nicotinic acetylcholine receptors containing the α6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons . ___MASK93___ and alcohol are often co - abused suggesting a common mechanism of action may underlie their reinforcing properties . Both drugs acutely increase activity of ventral tegmental area ( VTA ) dopaminergic ( DAergic ) neurons , a phenomenon associated with reward behavior . Recent evidence indicates that nicotinic acetylcholine receptors ( nAChRs ) , ligand - gated cation channels activated by ACh and nicotine , may contribute to ethanol - mediated activation of VTA DAergic neurons although the nAChR subtype ( s ) involved has not been fully elucidated . Here we show that expression and activation of nAChRs containing the α6 subunit contribute to ethanol - induced activation of VTA DAergic neurons . In wild - type ( WT ) mouse midbrain sections that contain the VTA , ethanol ( 50 or 100 mM ) significantly increased firing frequency of DAergic neurons . In contrast , ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express Q15825 , the gene encoding the α6 nAChR subunit ( α6 knock - out ( KO ) mice ) . DB00898 - induced activity in WT slices was also reduced by pre - application of the α6 subtype - selective nAChR antagonist , α - conotoxin MII [ E11A ] . When co - applied , ethanol potentiated the response to ACh in WT DAergic neurons ; whereas co - application of ACh and ethanol failed to significantly increase activity of DAergic neurons in α6 KO slices . Finally , pre - application of α - conotoxin MII [ E11A ] in WT slices reduced ethanol potentiation of ACh responses . Together our data indicate that α6 - subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons . These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement , providing a potential common therapeutic molecular target to reduce nicotine and alcohol co - abuse .", "___MASK84___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK84___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK84___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK84___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK84___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase ." ]

[ "___MASK10___", "___MASK22___", "___MASK31___", "___MASK33___", "___MASK73___", "___MASK75___", "___MASK84___", "___MASK93___", "___MASK95___" ]

[ "DB00998 Vernalis . Vanguard ( now Vernalis ) has developed frovatriptan , a selective P28222 / 1D partial agonist licensed from GlaxoSmithKline as a potential treatment for migraine [ 188478 ] , [ 194382 ] , [ 377863 ] .", "DB00998 , a P28222 / 1D receptor agonist for migraine . DB00998 is one of the most recent serotonin receptor agonists to receive FDA , approved labelling for use in the acute management of migraine with or without aura in adults . The mechanism of action of frovatriptan is thought to be similar to that of a serotonin agonist . However , frovatriptan has distinctive pharmacokinetic and pharmacologic properties , chiefly , a high affinity for serotonin receptors 1B and 1D and a long elimination half - life ; frovatriptan was shown to be more selective for cerebral than coronary arteries , a property which makes frovatriptan more favourable in patients at risk of coronary artery disease . Additionally , frovatriptan has a half - life of approximately 25 h , substantially longer than that of any other agent within its class . This property makes frovatriptan suitable for patients who typically suffer migraines of long duration and / or those who suffer migraine recurrence . The efficacy of frovatriptan in the treatment of acute migraine was demonstrated in five double - blind , randomised , placebo - controlled trials . At 2h , headache response rates for frovatriptan 2 . 5 mg ranged from 38 to 40 % compared to 22 - 35 % for placebo . Headache recurrence for frovatriptan 2 . 5 mg at 24h ranged from 9 to 14 % compared with 18 % in placebo subjects . DB00998 has no clinically significant pharmacokinetic interactions with drugs used for migraine prophylaxis or with commonly prescribed medications . Adverse effects of frovatriptan including dizziness , paresthesia , dry mouth , fatigue and flushing were generally mild and well tolerated . Given the fact that patient response to serotonin agonists is individualised , and selecting an effective agent may involve trial and error , frovatriptan is a welcome alternative in the acute management of migraine .", "The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 / 1D receptors and a long half - life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti - inflammatory drug with a relatively short half - life and rapid onset of action , blocking the action of cyclo - oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2 . 5 mg plus dexketoprofen 25 or 37 . 5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2 - h pain free rates of 51 % , and a high persistence in the 48 - h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24 - and 33 % at 48 - h .", "Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium . NO , produced by endothelial NO synthase ( P29474 ) , is a key mediator of pulmonary vasodilation during cardiopulmonary transition at birth . The capacity for NO production is maximal at term because pulmonary P29474 expression increases during late gestation . Since fetal estrogen levels rise markedly during late gestation and there is indirect evidence that the hormone enhances nonpulmonary NO production in adults , estrogen may upregulate P29474 in fetal pulmonary artery endothelium . Therefore , we studied the direct effects of estrogen on P29474 expression in ovine fetal pulmonary artery endothelial cells ( PAECs ) . ___MASK67___ caused a 2 . 5 - fold increase in NOS enzymatic activity in PAEC lysates . This effect was evident after 48 hours , and it occurred in response to physiological concentrations of the hormone ( 10 (- 10 ) to 10 (- 6 ) mol / L ) . The increase in NOS activity was related to an upregulation in P29474 protein expression , and P29474 mRNA abundance was also enhanced . P03372 antagonism with DB00947 completely inhibited estrogen - mediated P29474 upregulation , indicating that estrogen receptor activation is necessary for this response . In addition , immunocytochemistry revealed that fetal PAECs express estrogen receptor protein . Furthermore , transient transfection assays with a specific estrogen - responsive reporter system have demonstrated that the endothelial estrogen receptor is capable of estrogen - induced transcriptional transactivation . Thus , estrogen upregulates P29474 gene expression in fetal PAECs through the activation of PAEC estrogen receptors . This mechanism may be responsible for pulmonary P29474 upregulation during late gestation , thereby optimizing the capacity for NO - mediated pulmonary vasodilation at birth .", "Constitutively active Gq / 11 - coupled receptors enable signaling by co - expressed G ( i / o )- coupled receptors . Co - expression of guanine nucleotide - binding regulatory ( G ) protein - coupled receptors ( GPCRs ) , such as the G ( i / o )- coupled human P28222 ( 5 - HT ( 1B ) R ) , with the G ( q / 11 )- coupled human histamine 1 receptor ( P35367 ) results in an overall increase in agonist - independent signaling , which can be augmented by 5 - HT ( 1B ) R agonists and inhibited by a selective inverse 5 - HT ( 1B ) R agonist . Interestingly , inverse P35367 agonists inhibit constitutively P35367 - mediated as well as 5 - HT ( 1B ) R agonist - induced signaling in cells co - expressing both receptors . This phenomenon is not solely characteristic of 5 - HT ( 1B ) R ; it is also evident with muscarinic M2 and adenosine A1 receptors and is mimicked by mastoparan - 7 , an activator of G ( i / o ) proteins , or by over - expression of Gbetagamma subunits . Likewise , expression of the G ( q / 11 )- coupled human cytomegalovirus ( HCMV ) - encoded chemokine receptor US28 unmasks a functional coupling of G ( i / o )- coupled P32246 receptors that is mediated via the constitutive activity of receptor US28 . Consequently , constitutively active G ( q / 11 )- coupled receptors , such as the P35367 and HCMV - encoded chemokine receptor US28 , constitute a regulatory switch for signal transduction by G ( i / o )- coupled receptors , which may have profound implications in understanding the role of both constitutive GPCR activity and GPCR cross - talk in physiology as well as in the observed pathophysiology upon HCMV infection .", "Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .", "5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .", "The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK74___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK74___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .", "Exposure to an organophosphate ( ___MASK65___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK65___ ( ___MASK65___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK65___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK65___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK65___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .", "Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK89___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .", "Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24 / 48 - h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8 . 2 ) and the longer half - life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans .", "P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK80___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .", "Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .", "DB00998 : a selective type 1B / 1D serotonin receptor agonist for the treatment of migraine headache . DB00998 belongs to an innovative family of compounds aimed at breaking through the long - standing barrier of migraine headache understanding and treatment . While a typology of headaches has been recognized for some time , and a number of therapies have been introduced for reduction of headache pain and duration , the causes of migraine remain a subject of debate . Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation . DB00998 , like all the triptans , acts by inducing vasoconstriction of the meningeal arteries . It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin P28222 / 1D receptors . DB00998 has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials , which have also indicated that dose adjustments for age or gender are not necessary for the drug . Patients have found the use of frovatriptan acceptable over the long - term , and overall a low - incidence of adverse effects has been reported . Though not a prophylactic , frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine .", "Meta - analysis of oral DB00669 therapy for migraine : number needed to treat and relative cost to achieve relief within 2 hours . OBJECTIVE : To determine the cost - effectiveness of the P28222 / 1D agonists , or triptans , in the acute treatment of migraine . METHODS : To determine the cost - effectiveness of the triptans , a meta - analysis was conducted of the efficacy data from 27 oral DB00669 trials , using the endpoint of \" pain - free \" status within 2 hours after initial dosing as the indicator of efficacy . Efficacy data were used to determine the number needed to treat ( Q13423 ) to achieve pain - free status in 1 patient within 2 hours postdose and then applied the per - dose costs for each DB00669 to the Q13423 values . RESULTS : Rizatriptan 10 mg and almotriptan 12 . 5 mg were the most cost - effective of the triptans , costing $ 48 . 34 and $ 48 . 57 US dollars , respectively , to achieve pain - free status in 1 patient within 2 hours postdose . DB00998 2 . 5 mg was the most costly , with a cost - effective ratio of $ 162 . 49 US dollars . All other triptans fell between these extremes : zolmitriptan 5 mg ( $ 65 . 18 US dollars ) , sumatriptan 100 mg ( $ 70 . 83 US dollars ) , sumatriptan 50 mg ( $ 75 . 67 US dollars ) , zolmitriptan 2 . 5 mg ( $ 78 . 74 US dollars ) , and naratriptan 2 . 5 mg ( $ 141 . 43 US dollars ) , in decreasing order of cost - effectiveness . CONCLUSION : Using an Q13423 analysis , the least - costly drugs to achieve migraine cure within 2 hours are rizatriptan 10 mg and almotriptan 12 . 5 mg . From a population health perspective , the lower acquisition cost of almotriptan 12 . 5 mg allows for effective treatment of more patients than rizatriptan 10 mg for no additional medication cost .", "DB00998 . black triangle DB00998 , a new serotonin receptor agonist developed for the acute treatment of migraine , has high affinity for serotonin P28222 and P28221 receptor subtypes and is a potent stimulator of contraction in human basilar arteries . black triangle A long terminal elimination half - life ( approximately 26 hours ) is a distinctive pharmacokinetic feature of frovatriptan which appears to be independent of dose , age , gender and renal function . black triangle A single oral dose of frovatriptan 2 . 5mg was effective in the acute treatment of migraine providing meaningful relief within 2 hours to approximately twice as many recipients as placebo in clinical trials . black triangle Consistent relief of migraine symptoms was achieved in patients who treated a number of consecutive attacks with frovatriptan and the incidence of 24 - hour migraine recurrence was reduced . black triangle DB00998 was well tolerated in clinical trials , with the overall incidence of adverse events occurring with frovatriptan 2 . 5mg only slightly higher than that reported with placebo . Mild to moderate fatigue , nausea and paraesthesia were the most commonly reported drug - related adverse events .", "Chk2 - dependent phosphorylation of P18887 in the DNA damage response promotes base excision repair . The DNA damage response ( DDR ) has an essential function in maintaining genomic stability . Ataxia telangiectasia - mutated ( Q13315 ) - checkpoint kinase 2 ( Chk2 ) and Q13315 - and Rad3 - related ( ATR ) - Chk1 , triggered , respectively , by DNA double - strand breaks and blocked replication forks , are two major DDRs processing structurally complicated DNA damage . In contrast , damage repaired by base excision repair ( BER ) is structurally simple , but whether , and how , the DDR is involved in repairing this damage is unclear . Here , we demonstrated that Q13315 - Chk2 was activated in the early response to oxidative and alkylation damage , known to be repaired by BER . Furthermore , Chk2 formed a complex with P18887 , the BER scaffold protein , and phosphorylated P18887 in vivo and in vitro at DB00156 ( 284 ) . A mutated P18887 lacking DB00156 ( 284 ) phosphorylation was linked to increased accumulation of unrepaired BER intermediate , reduced DNA repair capacity , and higher sensitivity to alkylation damage . In addition , a phosphorylation - mimic form of P18887 showed increased interaction with glycosylases , but not other BER proteins . Our results are consistent with the phosphorylation of P18887 by Q13315 - Chk2 facilitating recruitment of downstream BER proteins to the initial damage recognition / excision step to promote BER .", "Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .", "The Mek1 phosphorylation cascade plays a role in meiotic recombination of Schizosaccharomyces pombe . Mek1 is a Chk2 / Rad53 / Cds1 - related protein kinase that is required for proper meiotic progression of Schizosaccharomyces pombe . However , the molecular mechanisms of Mek1 regulation and Mek1 phosphorylation targets are unclear . Here , we report that Mek1 is phosphorylated at serine - 12 ( P28222 ) , Q92748 and threonine - 15 ( T15 ) by Rad3 ( ATR ) and / or Tel1 ( Q13315 ) kinases that are activated by meiotic programmed double - strand breaks ( DSBs ) . Mutations of these sites by alanine replacement caused abnormal meiotic progression and recombination rates . Phosphorylation of these sites triggers autophosphorylation of Mek1 ; indeed , alanine replacement mutations of Mek1 - T318 and - T322 residues in the activation loop of Mek1 reduced Mek1 kinase activity and meiotic recombination rates . Substrates of Mek1 include Mus81 - T275 , Rdh54 - Q8NHM4 and Rdh54 - T673 . Mus81 - T275 is known to regulate the Mus81 function in DNA cleavage , whereas Rdh54 - T6A / T673A mutant cells showed abnormal meiotic recombination . Taken together , we conclude that the phosphorylation of Mek1 by Rad3 or Tel1 , Mek1 autophosphorylation and Mus81 or Rdh54 phosphorylation by Mek1 regulate meiotic progression in S . pombe .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK20___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK95___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .", "Involvement of P28222 receptors in DB00669 - induced contractile responses in guinea - pig isolated iliac artery . Using a series of triptans we characterized in vitro the 5 - hydroxytryptamine ( 5 - HT ) receptor that mediates the contraction in guinea - pig iliac arteries moderately precontracted by prostaglandin F2alpha ( PGF2alpha ) . Additionally , we investigated by reverse - transcriptase polymerase chain reaction ( RT - PCR ) which DB00669 - sensitive receptor is present in this tissue . DB00998 , zolmitriptan , rizatriptan , naratriptan , sumatriptan , and almotriptan contracted guinea - pig iliac arteries with pD2 values of 7 . 52 +/- 0 . 04 , 6 . 72 +/- 0 . 03 , 6 . 38 +/- 0 . 06 , 6 . 22 +/- 0 . 05 , 5 . 86 +/- 0 . 05 and 5 . 26 +/- 0 . 04 respectively . For comparison , the pD2 values for 5 - HT and 5 - carboxamidotryptamine ( 5 - CT ) were 7 . 52 +/- 0 . 02 and 7 . 55 +/- 0 . 03 respectively . In contrast to all other triptans tested , the concentration - response curve for eletriptan was biphasic ( first phase : 0 . 01 - 3 microM , pD2 approximately 6 . 6 ; second phase : > or = 10 microM ) . Contractions to 5 - HT , 5 - CT , frovatriptan , zolmitriptan , rizatriptan , naratriptan , sumatriptan , almotriptan , and eletriptan ( first phase ) were antagonized by the P28222 / 1D receptor antagonist GR127935 ( 10 nM ) and the P28222 receptor antagonist SB216641 ( 10 nM ) . RT - PCR studies in guinea - pig iliac arteries showed a strong signal for the P28222 receptor while expression of P28221 and P30939 receptors was not detected in any sample . The present results demonstrate that DB00669 - induced contraction in guinea - pig iliac arteries is mediated by the P28222 receptor . The guinea - pig iliac artery may be used as a convenient in vitro model to study the ( cardio ) vascular side - effect potential of anti - migraine drugs of the DB00669 family .", "[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK92___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .", "Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK88___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .", "A review of the use of frovatriptan in the treatment of menstrually related migraine . Menstrual migraine ( MM ) is a highly prevalent condition associated with considerable disability . Migraine attacks occur exclusively around the menstrual period in approximately 10 % of women with migraine , that is , pure menstrual migraine , while at least 50 % of them also experience migraine at other times of the month , that is , menstrually related migraine ( MRM ) . The therapeutic approach to patients with MRM is based on treatment of the attack , or prophylactic strategies . Triptans are recommended as first - line treatments for moderate to severe migraine attacks , including MM . DB00998 is one of the newest triptans . Its high affinity for P28222 / 1D receptors and long half - life contribute to its distinctive clinical effect , characterized by a more sustained and prolonged effect than other triptans . Indeed , frovatriptan proved to be effective in treating the acute attack , but was particularly effective in the short - term preventive therapy of MM . In addition , frovatriptan is one of the safest triptans , with the lowest risk of treatment - emergent adverse events . Following extensive evidence from randomized pharmacological trials , frovatriptan has now gained a grade A recommendation from the guidelines for short - term prophylaxis of MM . Recent post - hoc analyses of direct comparative trials also suggest that frovatriptan might have an important role in the acute treatment of MRM . In these studies , frovatriptan showed pain relief and pain - free rates similar to those of zolmitriptan , rizatriptan , and almotriptan , but with significantly lower recurrence rates . More well - designed , randomized , prospective studies , specifically enrolling women with MM , will be needed in the near future to confirm the efficacy of frovatriptan in this migraine subtype ." ]

[ "___MASK20___", "___MASK65___", "___MASK67___", "___MASK74___", "___MASK80___", "___MASK88___", "___MASK89___", "___MASK92___", "___MASK95___" ]

[ "Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK71___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .", "P09919 attenuates oxidative stress - induced apoptosis in vascular endothelial cells and exhibits functional and morphologic protective effect in oxygen - induced retinopathy . P09919 ( DB00099 ) is a known hematopoietic glycoprotein , and recent studies have revealed that G - P04141 possesses other interesting properties . Oxidative stress is involved in many diseases , such as atherosclerosis , heart failure , myocardial infarction , Alzheimer disease , and diabetic retinopathy . This study was designed to examine whether G - P04141 has a protective effect on endothelial cells against oxidative stress and to investigate whether G - P04141 has a therapeutic role in ischemic vascular diseases . Expression of DB00099 ( P < . 01 ) and Q99062 ( P < . 05 ) mRNA in human retinal endothelial cells ( HRECs ) was significantly up - regulated by oxidative stress . Treatment with 100 ng / mL G - P04141 significantly reduced H ( 2 ) O ( 2 )- induced apoptosis in HRECs from 61 . 7 % to 41 . 4 % ( P < . 05 ) . Akt was phosphorylated in HRECs by G - P04141 addition , and LY294002 , a PI3K inhibitor , significantly attenuated the antiapoptotic effect of DB00099 ( by 44 . 1 % , P < . 05 ) . The rescue effect was also observed in human umbilical vein endothelial cells . In mouse oxygen - induced retinopathy model , G - P04141 significantly reduced vascular obliteration ( P < . 01 ) and neovascular tuft formation ( P < . 01 ) . G - P04141 treatment also clearly rescued the functional and morphologic deterioration of the neural retina . A possibility of a novel therapeutic strategy for ischemic diseases through attenuating vascular regression using G - P04141 was proposed .", "___MASK27___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK27___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .", "The effects of inhaled budesonide on circulating eosinophil progenitors and their expression of cytokines after allergen challenge in subjects with atopic asthma . Allergen inhalation by dual responder subjects with atopic asthma is associated with an increase in circulating eosinophil / basophil colony - forming units ( Eo / B CFU ) and granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) immunolocalization in Eo / B colony cells grown in vitro . The current study examined the effect of the inhaled corticosteroid , budesonide , on the number of allergen - induced circulating eosinophils and Eo / B CFU , and immunolocalization of GM - P04141 and interleukin - 5 ( P05113 ) in Eo / B colony cells grown in vitro . Sixteen subjects with mild atopic asthma were treated for either 7 or 8 d with 200 microg inhaled budesonide or placebo twice a day . Peripheral blood was collected before and 24 h after allergen inhalation challenge and nonadherent mononuclear cells ( NAMC ) were grown in methylcellulose culture . Eo / B CFU were enumerated after 14 d in culture , and prepared on slides for immunocytochemistry . DB01222 attenuated the allergen - induced increase in circulating eosinophils ( 4 . 0 +/- 0 . 4 x 10 ( 5 )/ ml versus 6 . 5 +/- 0 . 7 x 10 ( 5 )/ ml , p = 0 . 0001 ) , circulating Eo / B CFU ( 12 . 4 +/- 2 . 3 / 10 ( 6 ) NAMC versus 18 . 8 +/- 4 . 6 / 10 ( 6 ) NAMC , p = 0 . 05 ) , and immunolocalization of GM - P04141 in Eo / B colony cells ( 11 . 8 +/- 1 . 9 % positive versus 18 . 0 +/- 2 . 2 % , p = 0 . 01 ) but not immunolocalization of P05113 ( 7 . 9 +/- 1 . 4 % versus 4 . 5 +/- 0 . 6 % , p > 0 . 05 ) . Inhaled budesonide attenuated the number of allergen - induced circulating eosinophils and their progenitors grown in the presence of GM - P04141 , which may partially be a result of regulating eosinophil progenitor expression of the autocrine growth factor GM - P04141 .", "How I treat patients who mobilize hematopoietic stem cells poorly . Transplantation with 2 - 5 × 10 ( 6 ) mobilized P28906 (+) cells / kg body weight lowers transplantation costs and mortality . Mobilization is most commonly performed with recombinant human G - P04141 with or without chemotherapy , but a proportion of patients / donors fail to mobilize sufficient cells . BM disease , prior treatment , and age are factors influencing mobilization , but genetics also contributes . Mobilization may fail because of the changes affecting the P19526 / progenitor cell / BM niche integrity and chemotaxis . Poor mobilization affects patient outcome and increases resource use . Until recently increasing G - P04141 dose and adding P21583 have been used in poor mobilizers with limited success . However , plerixafor through its rapid direct blockage of the P61073 / P48061 chemotaxis pathway and synergy with G - P04141 and chemotherapy has become a new and important agent for mobilization . Its efficacy in upfront and failed mobilizers is well established . To maximize P19526 harvest in poor mobilizers the clinician needs to optimize current mobilization protocols and to integrate novel agents such as plerixafor . These include when to mobilize in relation to chemotherapy , how to schedule and perform apheresis , how to identify poor mobilizers , and what are the criteria for preemptive and immediate salvage use of plerixafor .", "Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .", "Q99062 mutations in patients with severe congenital neutropenia do not abrogate Jak2 activation and stat1 / stat3 translocation . Severe congenital neutropenia ( SCN ) is an inherited disorder of myelopoiesis , characterized by a maturation arrest at the stage of promyelocytes and myelocytes in bone marrow , and absence or low levels of mature neutrophil granulocytes in peripheral blood . Recently , studies of patients with SCN who subsequently developed acute myeloid leukemia ( AML ) revealed nonsense mutations in the cytoplasmic domain of the granulocyte colony - stimulating factor ( DB00099 ) receptor messenger RNA . We focused our interest on the G - P04141 - mediated signaling cascade to examine the consequences of the observed point mutations for the nuclear translocation of the transcription factors Stat1 and Stat3 . Expression vectors encoding for truncated G - P04141 receptors were transfected in the murine fibroblast cell line C243 expressing a fusion protein consisting of the transcription factor Stat1 and Stat3 , respectively , and the green fluorescent protein ( GFP ) . Nuclear translocation of the GFP fusion proteins was examined after G - P04141 stimulation of the transfected cells .", "Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK82___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .", "The Severe Chronic Neutropenia International Registry : 10 - Year Follow - up Report . BACKGROUND : The Severe Chronic Neutropenia International Registry ( SCNIR ) was organized 10 years ago to improve understanding and treatment of the group of rare hematologic disorders causing blood neutrophil counts to be < 500 / muL for months or years . PATIENTS AND METHODS : Patients now enrolled include those with severe congenital neutropenia ( n = 526 ) , cyclic neutropenia ( n = 205 ) , idiopathic neutropenia ( n = 349 ) , autoimmune neutropenia ( n = 68 ) , and other ( n = 15 ) . More than 90 % ( 1053 of 1163 ) of patients in the SCNIR have been treated with granulocyte colony - stimulating factor ( DB00099 ) , median dose 3 . 33 mug / kg per day . RESULTS : P09919 has reduced the occurrence of infection , hospitalization , and antibiotics and improved patients ' quality of life . Most patients have noted few adverse effects with G - P04141 treatment . Osteoporosis / osteopenia has been reported in 14 % of all patients , and myelodysplastic syndrome and acute myelocytic leukemia have occurred in 57 patients , including severe congenital neutropenia ( 11 . 8 % ; 50 of 422 ) , Shwachman - Diamond syndrome ( 8 . 1 % ; 3 of 37 ) , and 4 others . The SCNIR is an important resource for studies on the genetic and molecular basis for the disorders causing chronic neutropenia . CONCLUSION : The findings of mutations in the gene for neutrophil elastase as causing cyclic and congenital neutropenia , the role of mutations in the gene for the Q99062 in the evolution of severe congenital neutropenia to acute myelocytic leukemia , and the importance of apoptosis as the cellular mechanism for several diseases causing severe chronic neutropenia have come from studies on these patients .", "P09919 improves left ventricular function of doxorubicin - induced cardiomyopathy . It is not well - known yet how granulocyte colony - stimulating factor ( DB00099 ) affects nonischemic cardiomyopathy , though its beneficial effects on acute myocardial infarction are well - established . We hypothesize that G - P04141 beneficially might affect nonischemic cardiomyopathy through the direct cardioprotective effects . Here , we show that a single injection of doxorubicin ( DOX , 15 mg / kg ) induced left ventricular dilatation and dysfunction in mice within 2 weeks , and that these effects were significantly attenuated by human recombinant DB00099 ( 100 microg / kg / day for 5 days ) . G - P04141 also protected hearts against DOX - induced cardiomyocyte atrophy / degeneration , fibrosis , inflammatory cell infiltration and down regulation of GATA - 4 and sarcomeric proteins , myosin heavy chain , troponin I and desmin , both in vivo and in vitro . Cardiac cyclooxygenase - 2 was upregulated and Q99062 was downregulated in DOX - induced cardiomyopathy , but both of those effects were largely reversed by DB00099 . No DOX - induced apoptotic effects were seen , nor were there any changes in tumor necrosis factor - alpha or transforming growth factor - beta1 levels . Among downstream mediators of Q99062 signaling , DOX - induced cardiomyopathy involved inactivation of extracellular signal - regulated protein kinase ( P29323 ) ; the P29323 inactivation was reversed by DB00099 . Inhibition of P29323 activation , but not cyclooxygenase - 2 inhibition , completely abolished beneficial effect of G - P04141 on cardiac function . G - P04141 did not promote differentiation of bone marrow cells into cardiomyocytes according to the experiment using green fluorescent protein - chimeric mice , and inhibition of P61073 + cell homing using DB06809 did not diminish the effect of DB00099 . Finally , G - P04141 was also effective when administered after cardiomyopathy was established . In conclusion , these findings imply the therapeutic usefulness of G - P04141 mainly through restoring P29323 activation against DOX - induced nonischemic cardiomyopathy .", "Hyperecho - turbo spin - echo sequences at 3T : clinical application in neuroradiology . BACKGROUND AND PURPOSE : Hyperecho - turbo spin - echo ( hyperTSE ) sequences were developed to reduce the specific absorption rate ( SAR ) , especially at high fields such as 3T and above . The purpose of this study was to quantitatively and qualitatively assess the detection of neuroradiologic pathologies by hyperTSE in comparison with standard turbo spin - echo ( TSE180 degrees ) sequences . MATERIALS AND METHODS : TSE180 degrees and hyperTSE images with parameters adapted for equal P24752 contrast were acquired on a 3T whole - body system in 51 patients with 54 cerebral pathologies . Region - of - interest analysis was performed of signal intensities of pathologies , normal white and gray matter , P04141 , and the SD of noise . Signal intensity - to - noise ratios ( SNRs ) and contrast - to - noise ratios ( CNRs ) for healthy tissues and pathologies were determined . A qualitative rating concerning artifacts , lesion conspicuity , and image quality was performed by 2 experienced neuroradiologists . RESULTS : HyperTSE sequences were equivalent to standard TSE180 degrees sequences for the P21554 of pathologies and of the contrast between gray and white matter . The SNR of gray and white matter and P04141 were also the same . The CNRs of the pathologies in hyperTSE and TSE180 degrees images were strongly correlated with each other ( r = 0 . 93 , P = . 001 ) . The visual rating of images revealed no significant differences between hyperTSE and TSE180 degrees . CONCLUSION : HyperTSE sequences proved to be qualitatively and quantitatively equivalent to TSE180 degrees sequences in the detection of high - and low - signal - intensity lesions . They provide equal P21554 of pathologies and of gray minus white matter and reduce the imaging restrictions of conventional TSE180 degrees imposed by SAR limitations at 3T .", "Regulation of the human P38936 ( waf1 / cip1 ) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor . The main regulator of the human tumor suppresser gene P38936 ( waf1 / cip1 ) is the transcription factor p53 , but more recently it has been suggested to be a primary anti - proliferative target for the nuclear receptor P11473 in the presence of its ligand 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) . To identify P11473 responding regions , we analyzed 20 overlapping regions covering the first 7 . 1 kb of the P38936 ( waf1 / cip1 ) promoter in MCF - 7 human breast cancer cells using chromatin immuno - precipitation assays ( ChIP ) with antibodies against p53 and P11473 . We confirmed two known p53 binding regions at approximate positions - 1400 and - 2300 and identified a novel site at position - 4500 . In addition , we found three P11473 - associated promoter regions at positions - 2300 , - 4500 and - 6900 , i . e . two regions showed binding for both p53 and P11473 . In silico screening and in vitro binding assays using recombinant and in vitro translated proteins identified five p53 binding sites within the three p53 - positive promoter regions and also five DB00136 response elements within the three P11473 - positive regions . Reporter gene assays confirmed the expected responsiveness of the respective promoter regions to the p53 inducer 5 - fluorouracil and DB00136 . Moreover , re - ChIP assays confirmed the functionality of the three DB00136 - reponsive promoter regions by monitoring simultaneous occupancy of P11473 with the co - activator proteins CBP , Q15788 and Q15648 . Taken together , we demonstrated that the human P38936 ( ( waf1 / cip1 ) ) gene is a primary DB00136 - responding gene with at least three P11473 binding promoter regions , in two of which also p53 co - localizes .", "Granulocyte - colony - stimulatory factor : a strong inhibitor of natural killer cell function . BACKGROUND : The human cytokine granulocyte - colony stimulatory factor ( DB00099 ) has found widespread application in the medical treatment of neutropenia and to mobilize hematopoietic stem cells used for transplantation . So far , the effect of G - P04141 on natural killer ( NK ) cells has not been fully investigated . STUDY DESIGN AND METHODS : The effect of G - P04141 on the phenotype , cytokine secretion profile , and cytotoxicity of NK cells was assessed . NK cells incubated in vitro in presence of G - P04141 for 48 hours as well as NK cells isolated from peripheral blood of G - P04141 - mobilized stem cell donors ( in vivo ) were used . RESULTS : In vitro , G - P04141 caused a strongly altered phenotype in NK cells with 49 % down regulation of O95944 frequency . Furthermore , the expression of the activating receptors O76036 and P26718 decreased 40 and 64 % , respectively . The expression of P43626 and P43627 decreased by 46 % each . In cytotoxicity assays , the lytic capacity of G - P04141 - exposed NK cells is reduced by up to 68 % in vitro and up to 83 % in vivo . Accordingly , granzyme B levels of in vivo G - P04141 - exposed NK cells were reduced by up to 87 % in comparison to nonstimulated NK cells . Cytokine production of in vitro and in vivo incubated NK cells was strongly decreased for interferon - γ , tumor necrosis factor - α , and granulocyte macrophage colony - stimulating factor as well as interleukin ( IL ) - 6 and P10145 . Furthermore , we observed a reduction in proliferation and a positive feedback loop that increased the expression of the Q99062 . CONCLUSION : G - P04141 was demonstrated to be a strong inhibitor of NK cells activity and may prevent their graft - versus - leukemia effect after transplantation .", "Granulocyte - colony stimulating factor upregulates ErbB2 expression on breast cancer cell lines and converts primary resistance to trastuzumab . The recombinant monoclonal antibody trastuzumab has antiproliferative effect on breast cancer ( BC ) cells with ErbB2 overexpression . We postulated that a mechanism able to modify ErbB2 expression enhances the antitumor effect of trastuzumab . We analyzed whether granulocyte - colony stimulating factor ( DB00099 ) , widely used in adjuvant cancer therapy to alleviate chemotherapy - induced myelotoxicity , could influence ErbB2 expression in BC cells and patients . The expression of ErbB2 ( Herceptest ) was analyzed in four BC cell lines ( BT474 , SKBR3 , ZR75 . 1 , and T47D ) treated with G - P04141 and in five samples biopsies from BC patients subjected to G - P04141 rescue after chemotherapy . The effects of G - P04141 and trastuzumab alone or their combination on cell growth and apoptosis were investigated . Q99062 was detected on all cell lines and BC patients . G - P04141 induced upregulation of ErbB2 in SKBR3 , ZR75 , and T47D cells . This modulation was not associated with an increase in tumor cell growth in vitro . DB00072 alone inhibited colony formation in soft agar but did not induce apoptosis on BC cells with no or low ErbB2 genomic amplification . The combination of trastuzumab and G - P04141 enhanced the inhibition of tumor colony formation and induced apoptosis on these cells . This effect was further increased by G - P04141 pretreatment . Five of nine BC patients showed an increase of Herceptest score after G - P04141 administration . G - P04141 treatment increases ErbB2 expression in vitro and in vivo enhancing the activity of trastuzumab on BC cell lines inducing apoptosis of BC cells with low or no ErbB2 genomic amplification .", "P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK7___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .", "___MASK53___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK53___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK53___ is a promising pharmacological tool in the treatment of renal edema .", "Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK93___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .", "Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK32___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .", "Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK41___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .", "P40763 - mediated differentiation and survival and of myeloid cells in response to granulocyte colony - stimulating factor : role for the cyclin - dependent kinase inhibitor p27 ( Kip1 ) . The signal transducer and activator of transcription ( P35610 ) proteins have been implicated in cytokine - regulated proliferation , differentiation and cell survival . P09919 ( DB00099 ) , a regulator of granulocytic differentiation , induces a robust and sustained activation of P40763 . Here , we show that introduction of dominant negative ( DN ) forms of P40763 interferes with G - P04141 - induced differentiation and survival in murine 32D cells . G - P04141 induces expression of the cyclin - dependent kinase ( cdk ) inhibitor p27 ( KiP1 ) ( but not P38936 ( CiP1 ) ) , which is completely blocked by DN - P40763 . The ability of tyrosine - to - phenylalanine substitution mutants of the Q99062 to activate P40763 strongly correlated with their capacity to induce p27 expression and their ability to mediate differentiation and survival , suggesting a causal relationship between P40763 activation , p27 expression and the observed cellular responses . We identified a putative P35610 binding site in the promoter region of p27 that showed both P40763 binding in electrophoretic mobility shift assays and functional activity in luciferase reporter assays . Finally , we studied G - P04141 - induced responses in primary bone marrow and spleen cells of p27 - deficient mice . Compared with wild - type , myeloid progenitors from p27 - deficient mice showed significantly increased proliferation and reduced differentiation in response to DB00099 . These findings indicate that P40763 controls myeloid differentiation , at least partly , via upregulation of p27 ( Kip1 ) .", "Benzyl isothiocyanate ( BITC ) inhibits migration and invasion of human gastric cancer AGS cells via suppressing P29323 signal pathways . Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases . Benzyl isothiocyanate ( BITC ) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables . BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in humans . Here , the purpose of this study was to investigate the effects of BITC on cell proliferation , migration , invasion and mitogen - activated protein kinase ( MAPK ) pathways of AGS human gastric cancer cells . Wound healing and Boyden chamber ( migration and invasion ) assays demonstrated that BITC exhibited an inhibitory effect on the abilities of migration and invasion in AGS cancer cells . BITC suppressed cell migration and invasion of AGS cells in a dose - dependent manner . Results from Western blotting indicated that BITC exerted an inhibitory effect on the P27361 / 2 , Ras , P62993 , Rho A , P35228 , P35354 for causing the inhibitions of P08253 , - 7 and - 9 then followed by the inhibitions of invasion and migration of AGS cells in vitro . BITC also promoted O14733 , Q99759 , c - jun , P45983 / 2 , P15692 , Sos1 , phosphoinositide 3 - kinase ( PI3K ) , PKC , nuclear factor - kappaB ( NF - κB ) p65 in AGS cells . Results from real - time polymerized chain reaction ( PCR ) showed that BITC inhibited the gene expressions of P08253 ,- 7 - 9 , Q05397 , Q13464 and RhoA after BITC treatment for 24 and 48 hours in AGS cells . Taken together , the finding may provide new mechanisms and functions of BITC , which inhibit migration and invasion of human gastric cancer AGS cells .", "Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK83___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .", "Human gray matter : feasibility of single - slab 3D double inversion - recovery high - spatial - resolution MR imaging . The purpose of this study was to develop and prospectively evaluate the feasibility of a single - slab three - dimensional ( 3D ) double inversion - recovery , or P30518 , sequence for magnetic resonance imaging at 1 . 5 T . The study was approved by the local ethics committee , and informed consent was obtained from six healthy control subjects ( one woman , five men ; age range , 26 - 47 years ) and two patients with multiple sclerosis ( one woman , aged 39 ; one man , aged 56 ) . Gray matter ( GM ) - only images were obtained by selectively suppressing cerebrospinal fluid ( P04141 ) and white matter ( WM ) signals . Whole - brain high - spatial - resolution 3D images ( 1 . 2 x 1 . 2 x 1 . 3 mm ) were acquired within 10 minutes . Cortical and deep GM structures were clearly delineated from WM and P04141 , and there were regional differences in GM signal intensity . No flow artifacts from blood or P04141 were observed . These GM images with high spatial resolution are suitable to identify cortical pathologic conditions and can potentially be used for segmentation purposes to determine cortical thickness or volume .", "Transfer of recombinant human granulocyte colony stimulating factor ( rhG - P04141 ) from the maternal to the fetal circulation is not dependent upon a functional G - P04141 - receptor . Administration of granulocyte colony stimulating factor ( DB00099 ) , a haematopoietic growth factor , to pregnant rats increases neutrophil production in the pups . The mechanism for the placental transfer is unknown , but it has been speculated to involve the placental Q99062 ( G - CSFR ) . The purpose of this study was to test that hypothesis . Pregnant mice were treated with a single subcutaneous dose of 50 microg / kg recombinant human DB00099 ( rhG - P04141 ) . Mice with an intact G - CSFR ( \" wild type \" , WT ) and those with a homozygous deletion in the G - CSFR gene ( G - CSFR deficient , \" knock - out \" , KO ) were studied . At intervals after injection , fetuses were delivered and maternal blood , amniotic fluid ( AF ) and fetal blood collected . G - P04141 concentrations were measured using an enzyme linked immunosorbent assay specific for human DB00099 . Thirty minutes after injection , G - P04141 was measurable in the AF ( 167 +/- 50 versus 445 +/- 217 pg / ml , mean +/- sem , WT versus KO ) and fetal plasma ( 774 +/- 673 versus 427 +/- 121 pg / ml , WT versus KO ) . Peak concentrations occurred 2 h after injection in WT dams ( 572 542 +/- 41 262 pg / ml ) and 4 h in KO dams ( 616 100 +/- 96 300 pg / ml ) . Therefore , in mice , a functional G - CSFR is not essential for the transfer of rhG - P04141 from pregnant dams to their fetuses .", "Clinical endocannabinoid deficiency ( CECD ) : can this concept explain therapeutic benefits of cannabis in migraine , fibromyalgia , irritable bowel syndrome and other treatment - resistant conditions ? OBJECTIVES : This study examines the concept of clinical endocannabinoid deficiency ( CECD ) , and the prospect that it could underlie the pathophysiology of migraine , fibromyalgia , irritable bowel syndrome , and other functional conditions alleviated by clinical cannabis . METHODS : Available literature was reviewed , and literature searches pursued via the National Library of Medicine database and other resources . RESULTS : Migraine has numerous relationships to endocannabinoid function . Anandamide ( AEA ) potentiates P08908 and inhibits 5 - Q13049 receptors supporting therapeutic efficacy in acute and preventive migraine treatment . Cannabinoids also demonstrate dopamine - blocking and anti - inflammatory effects . AEA is tonically active in the periaqueductal gray matter , a migraine generator . THC modulates glutamatergic neurotransmission via DB01221 receptors . Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia . Cannabinoids have similarly demonstrated the ability to block spinal , peripheral and gastrointestinal mechanisms that promote pain in headache , fibromyalgia , IBS and related disorders . The past and potential clinical utility of cannabis - based medicines in their treatment is discussed , as are further suggestions for experimental investigation of CECD via P04141 examination and neuro - imaging . CONCLUSION : Migraine , fibromyalgia , IBS and related conditions display common clinical , biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines .", "Influence of P09874 polymorphisms in patients after traumatic brain injury . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) plays an important role in the cellular response to stress and DNA damage . However , excessive activity of P09874 exacerbates brain injury via NAD + depletion and energy failure . The purpose of this study was to determine if tagging single nucleotide polymorphisms ( tSNPs ) covering multiple regions of the P09874 gene are related to outcome after traumatic brain injury ( TBI ) in humans . DNA from 191 adult patients with severe TBI was assayed for four tSNPs corresponding to haplotype blocks spanning the P09874 gene . Categorization as favorable or poor outcome was based on Glasgow Outcome Scale ( GOS ) score assigned at 6 months . P09874 enzyme activity was indirectly evaluated by quantifying poly - ADP - ribose ( PAR ) - modified proteins in cerebrospinal fluid ( P04141 ) using an enzyme - linked immunosorbent assay . In multiple logistic regression analysis controlling for age , initial Glasgow Coma Scale score , and gender , the AA genotype of SNP rs3219119 was an independent predictor of favorable neurologic outcome . This SNP tags a haplotype block spanning the automodification and catalytic domains of the P09874 gene . SNP rs2271347 correlated with P04141 PAR - modified protein level . This SNP , which did not correlate with outcome , tags a haplotype block spanning the promoter region of the P09874 gene . We conclude that after severe TBI in humans , a P09874 polymorphism within the automodification - catalytic domain is associated with neurological outcome , while a polymorphism within the promoter region was associated with P04141 PAR - modified protein level . These findings must be replicated in a prospective study before the relevance of P09874 polymorphisms after TBI can be established .", "P08246 enzymatically antagonizes the in vitro action of DB00099 : implications for the regulation of granulopoiesis . There is evidence that neutrophil production is a balance between the proliferative action of granulocyte - colony - stimulating factor ( DB00099 ) and a negative feedback from mature neutrophils ( the chalone ) . Two neutrophil serine proteases have been implicated in granulopoietic regulation : pro - proteinase 3 inhibits granulocyte macrophage - colony - forming unit ( CFU - GM ) growth , and elastase mutations cause cyclic and congenital neutropenia . We further studied the action of the neutrophil serine proteases ( proteinase 3 , elastase , azurocidin , and cathepsin G ) on granulopoiesis in vitro . Elastase inhibited CFU - GM in methylcellulose culture . In serum - free suspension cultures of P28906 + cells , elastase completely abrogated the proliferation induced by G - P04141 but not that of GM - P04141 or stem cell factor ( P21583 ) . The blocking effect of elastase was prevented by inhibition of its enzymatic activity with phenylmethylsulfonyl fluoride ( PMSF ) or heat treatment . When exposed to enzymatically active elastase , DB00099 , but not GM - P04141 or P21583 , was rapidly cleaved and rendered inactive . These results support a role for neutrophil elastase in providing negative feedback to granulopoiesis by direct antagonism of DB00099 ." ]

[ "___MASK27___", "___MASK32___", "___MASK41___", "___MASK53___", "___MASK71___", "___MASK7___", "___MASK82___", "___MASK83___", "___MASK93___" ]

[ "A Q8NBP7 - binding antibody that structurally mimics the P01133 ( A ) domain of LDL - receptor reduces LDL cholesterol in vivo . Proprotein convertase subtilisin - like / kexin type 9 ( Q8NBP7 ) regulates LDL cholesterol levels by inhibiting P01130 ( LDLr ) - mediated cellular LDL uptake . We have identified a fragment antigen - binding ( Fab ) 1D05 which binds Q8NBP7 with nanomolar affinity . The fully human antibody 1D05 - IgG2 completely blocks the inhibitory effects of wild - type Q8NBP7 and two gain - of - function human Q8NBP7 mutants , S127R and D374Y . The crystal structure of 1D05 - Fab bound to Q8NBP7 reveals that 1D05 - Fab binds to an epitope on the Q8NBP7 catalytic domain which includes the entire LDLr P01133 ( A ) binding site . Notably , the 1D05 - Fab CDR - H3 and CDR - H2 loops structurally mimic the P01133 ( A ) domain of LDLr . In a transgenic mouse model ( P11597 / LDLr - hemi ) , in which plasma lipid and Q8NBP7 profiles are comparable to those of humans , 1D05 - IgG2 reduces plasma LDL cholesterol to 40 % and raises hepatic LDLr protein levels approximately fivefold . Similarly , in healthy rhesus monkeys , 1D05 - IgG2 effectively reduced LDL cholesterol 20 % - 50 % for over 2 weeks , despite its relatively short terminal half - life ( t ( 1 / 2 ) = 3 . 2 days ) . Importantly , the decrease in circulating LDL cholesterol corresponds closely to the reduction in free Q8NBP7 levels . Together these results clearly demonstrate that the LDL - lowering effect of the neutralizing anti - Q8NBP7 1D05 - IgG2 antibody is mediated by reducing the amount of Q8NBP7 that can bind to the LDLr .", "___MASK63___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK63___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK63___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK63___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .", "Comparison of the effects of cytoprotective drugs on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure . Cetraxate hydrochloride ( cetraxate ) , ecabet sodium ( ecabet ) , and sulpiride , which are cytoprotective drugs , have been used to treat peptic ulcers and acute or chronic gastritis . They are reported to improve mucosal blood flow in the stomach . One of the most important factors believed to cause gastric ulcers is mental and / or physiological stress . When people feel stress , the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis is activated . Therefore , corticotropin - releasing hormone ( P06850 ) , adrenocorticotropic hormone ( ___MASK84___ ) , and cortisol can be indicators of stress . We examined the effects of cetraxate , ecabet and sulpiride on the plasma levels of ___MASK84___ and cortisol under stress conditions by repetitive blood sampling . Venous blood samples were taken before and 20 - 240 min after a single administration of the drugs or a placebo . A single dose of ecabet caused significant suppression of increases in plasma ___MASK84___ - like immunoreactive substance ( IS ) levels at 90 to 120 min and cortisol levels at 240 min , compared with the response to placebo . DB00391 only suppressed increases in plasma cortisol levels at 180 to 240 min , compared with the response to placebo . A single dose of cetraxate had no effect on plasma ___MASK84___ - IS and cortisol levels . Ecabet may have a modulatory effect on the Q9Y251 axis while sulpiride may have a partial modulatory effect on the Q9Y251 axis . These effects might be beneficial in stress - related disease .", "Differential expression of urokinase - type plasminogen activator and plasminogen activator inhibitor - 1 in early and late gestational mouse skin and skin wounds . Early gestation fetal mouse skin heals without scars . P00747 activator inhibitor - 1 ( P05121 ) has been associated with postnatal organ fibrosis . We hypothesized that the relative balance between urokinase - type plasminogen activator ( uPA ) and P05121 expression in favor of uPA prevents scarring in early fetal skin wounds , whereas a change in favor of P05121 in late gestation results in wound scarring . To evaluate uPA and P05121 expression , 1 - mm skin wounds were made in Q14207 . 5 and E18 mice and harvested 24 , 48 , or 96 hours postwounding . DB06692 ( 2 mg / ml ) - coated beads were injected into selected Q14207 . 5 wounds . Normal skin and skin wounds were evaluated for uPA , P05121 , and collagen expression . We showed that in normal skin uPA level is higher in Q14207 . 5 than in E18 mice , while P05121 is lower in Q14207 . 5 than in E18 mice . After wounding , Q14207 . 5 wounds show a moderate increase in uPA and a minimal increase in P05121 . E18 wounds show a transient increase in uPA but a significant , sustained increase in P05121 . Addition of aprotinin to Q14207 . 5 wounds causes an increase in collagen deposition . We conclude that the differential expression of uPA and P05121 in the skin of early vs . late gestation mice may contribute to the degree of scar formation seen after cutaneous injury .", "Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK84___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK84___ peptide content within the pituitary , and plasma ___MASK84___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK84___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK84___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK84___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .", "Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK63___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK63___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK63___ .", "P06850 signaling in synovial tissue vascular endothelium is mediated through the DB02527 / CREB pathway . Modulation of locally produced corticotropin - releasing hormone ( P06850 ) is a component of the cytokine network in human inflammatory arthritis . P06850 signaling , through the P06850 - receptor subtype R1alpha , may play a role in both vascular changes and pathologic mechanisms associated with joint inflammation . Furthermore , the peripheral actions of P06850 may be mediated in part through the NURR subfamily of nuclear orphan receptors . The aim of this study was to establish the signaling mechanisms through which P06850 receptor - mediated responses contribute to gene regulation in inflamed synovial vasculature . Immunohistochemical analysis of serial rheumatoid arthritis ( RA ) tissue sections demonstrates P06850 and P43354 expression in the synovial lining layer , subsynovial lining layer , and the vascular endothelium . The identical pattern of immunolocalization confirms that P43354 is produced at the same synovial sites shown to produce P06850 . The distribution of specific P43354 staining on the synovial vasculature parallels that observed for P34998 expression . Using primary synovial tissue endothelial cells , we demonstrate that P06850 induces specific P16220 and P39905 - 2 binding to the P43354 promoter . We further provide evidence that P06850 signaling can be mimicked by activation of DB02527 / PKA / CREB using forskolin in primary human microvascular endothelial cells . These data indicate that the P06850 receptor - dependent inflammatory response in synovial tissue endothelium is mediated through the DB02527 / CREB signaling pathway .", "Red cell and serum protein polymorphisms in three population groups of South Korea . Genetic markers P24666 , P36871 with subtypes , P10768 , Q04760 , P52209 , GPT , A6NDG6 , P01024 , TF and GC with subtypes , BF , HP , Q9BXS0 , P00747 and PI , were studied in three populations in South Korea , one being the population of the industrial capital Seoul , the second a rural group from Taejon and the third the population of Cheju Island . For the polymorphic systems studied in the present work , a general similarity was observed among the three populations , with the exception of GPT and P24666 ( Taejon vs . Seoul ) and subtypes of GC ( Taejon vs . Cheiu ) .", "Involvement of Stat3 in interleukin - 6 - induced IgM production in a human B - cell line . P05231 ( P05231 ) is an important B - cell growth and differentiation factor . P05231 treatment of the human lymphoblastoid cell line , SKW6 . 4 , leads to increased IgM production . We have previously shown that P05231 induces activation of P23458 and O60674 in human B cell lines . A chimeric P05231 receptor , comprised of the intracellular tail of the P05231 receptor subunit P40189 fused to the extracellular domain of the epidermal growth factor ( P01133 ) receptor , was stably transfected into SKW6 . 4 cells . P01133 treatment induced IgM production in cells transfected with an intact P40189 cytoplasmic tail , but not in untransfected cells or cells transfected with a cytoplasmic tail lacking all four signal transducers and activators of transcription ( Stat ) binding sites . Moreover , P01133 treatment induced Stat3 phosphorylation in cells transfected with the intact chimeric P01133 - P40189 receptor along with induction of DNA - mobility shift of a classical interferon - gamma - activated site . To define further the relation between Stat3 activation and enhanced IgM production , we determined the effect of chimeric P40189 on the transcriptional activation of a genetic element linked to immunoglobulin production , namely the immunoglobulin heavy chain enhancer ( IgH - enhancer ) . Parental as well as transfected SKW6 . 4 cells were transiently transfected with an IgH - enhancer - luciferase construct . The transcriptional activity of the IgH - luciferase construct was induced upon ligation of the full - length chimeric receptor but not by truncated P40189 receptors . Moreover , the P40189 - induced activity of this reporter gene was abrogated by Stat3EE , a mutant Stat3 incapable of binding DNA . These results indicate that P05231 - induced B - cell differentiation , as measured by IgM production , may be controlled by Stat3 proteins .", "Epidermal growth factor enhances androgen receptor ‑ mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock - out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N - butyl - N -( 4 - hydroxybutyl ) nitrosamine ( BBN ) carcinogen - induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and / or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 was able to potentiate AR transactivation through P00533 by activating PI3K / AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 inhibitor of PD168393 on AR function after addition of anti - androgen , DB01128 , further suggested AR might play a key role in the effects of P01133 on BCa progression and metastasis . Collectively , our results indicate that P01133 may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 and AR signaling .", "P00747 activator is involved in the hCG - induced neutrophil extravasation and vasopermeability increase in the rat testis . The role of proteolytic enzymes in the hCG - induced increase in testicular vasopermeability and neutrophil extravasation was studied using protease inhibitors . An intra - testicular injection of hCG together with incubation medium conditioned by polymorphonuclear leucocytes ( PMNs ) caused a significant increase in vasopermeability and a coincident extravasation of PMN ' s from the postcapillary venules in the rat testis . When p - aminobenzamidine , a serine protease inhibitor which inhibits urokinase - type plasminogen activator , was administered together with hCG in the incubation medium , both the permeability increase and PMN extravasation were prevented . DB06692 , another serine protease inhibitor , and Eglin C , a specific neutrophil elastase and cathepsin G inhibitor were , however , without effect . None of these inhibitors caused any non - specific vascular effects in the testis at the concentrations used . These results support the concept that the hCG - induced increase in vasopermeability in the rat testis is related to extravasation of PMNs and suggest that urokinase - type plasminogen activator is involved in migration of these cells through the postcapillary venular walls .", "Effect of endothelin receptor antagonist ___MASK99___ on chronic hypoxia - induced inflammation and chemoafferent neuron adaptation in rat carotid body . Chronic hypoxia ( CH ) induces an inflammatory response in rat carotid body that is characterized by immune cell invasion and the expression of pro - inflammatory cytokines . In the present study , we have investigated the role of type - A endothelin ( P25101 ) receptors in the development of CH - induced inflammation . After 7 days of CH ( 380 Torr ) , double - label immunofluorescence studies demonstrated elevated levels of P25101 receptor and tyrosine hydroxylase ( TH ) in O ( 2 )- sensitive type I cells . Following CH , P25101 receptors were also expressed on resident and invasive P08575 + immune cells distributed in tissue surrounding chemosensory cell lobules . Immnofluorescence and quantitative PCR studies showed that concurrent treatment with the P25101 / B receptor antagonist , ___MASK99___ ( 200 mg / kg / day ) , blocked CH - induced ED - 1 + macrophage invasion and the upregulation of cytokines , including interleukin - 1β ( IL - 1β ) , interleukin - 6 ( P05231 ) , tumor necrosis factor α ( TNFα ) , and monocyte chemoattractant protein - 1 ( P13500 ) . Moreover , ___MASK99___ treatment blocked the CH - induced increases in expression of acid - sensitive ion channels ( ASICs ) in chemoafferent neurons in the petrosal ganglion ( PG ) . Our findings are consistent with the hypothesis that CH - induced inflammation involves the upregulation and release of ET - 1 from type I cells . ET - 1 may act in an autocrine / paracrine mechanism via P25101 receptors on chemosensory type I cells and immune cells to promote an inflammatory response .", "The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .", "Encapsulation of viral vectors for gene therapy applications . In gene therapy , a number of viruses are currently being used as vectors to provide transient expression of therapeutic proteins . A drawback of using free virus is that it gives a potent immune response , which reduces gene transfer and limits re - administration . An alternative delivery system is to encapsulate the virus in poly ( lactide - co - glycolide ) ( P00747 ) microspheres prior to administration . A recombinant adenovirus ( Ad ) expressing green fluorescent protein ( GFP ) was used to test the transduction efficiency of Ad encapsulated in microspheres on target cells . The number of infected cells that expressed GFP was measured by flow cytometry . It was demonstrated that encapsulated viral vectors could successfully transduce target cells with encapsulation efficiencies up to 23 % and that the level of transduction could be controlled by varying both the quantity of microspheres and the amount of Ad in the microspheres . High transduction efficiencies and its recognized biocompatibility make P00747 - encapsulated Ad an attractive alternative to the use of free virus in gene therapy applications . The infectivity of Ad was found to be significantly influenced by the processing conditions and changes in environmental factors . Free Ad and encapsulated Ad were able to infect both E1 complimenting cells ( P29320 293 ) and non - complimenting cells ( A549 ) , with the viral expression in P29320 293 cells being 2 . 1 times greater than for A549 cells .", "Physical exercise improves synaptic dysfunction and recovers the loss of survival factors in 3xTg - AD mouse brain . Physical exercise has become a potentially beneficial therapy for reducing neurodegeneration symptoms in Alzheimer ' s disease . Previous studies have shown that cognitive deterioration , anxiety and the startle response observed in 7 - month - old 3xTg - AD mice were ameliorated after 6 months of free access to a running wheel . Also , alterations in synaptic response to paired - pulse stimulation were improved . The present study further investigated some molecular mechanisms underlying the beneficial effects of 6 months of voluntary exercise on synaptic plasticity in 7 - month - old 3xTg - AD mice . Changes in binding parameters of [ ( 3 ) H ] - flunitrazepam to GABAA receptor and of [ ( 3 ) H ] - MK - 801 to DB01221 receptor in cerebral cortex of 3xTgAD mice were restored by voluntary exercise . In addition , reduced expression levels of DB01221 receptor Q13224 subunit were reestablished . The synaptic proteins synaptophysin and P78352 and the neuroprotective proteins P39905 and Q96EB6 were downregulated in 3xTgAD mice and were recovered by exercise treatment . Overall , in this paper we highlight the fact that different interrelated mechanisms are involved in the beneficial effects of exercise on synaptic plasticity alterations in the 3xTg - AD mouse model .", "High mobility group box protein - 1 promotes cerebral edema after traumatic brain injury via activation of toll - like receptor 4 . Traumatic brain injury ( TBI ) is a major cause of mortality and morbidity worldwide . Cerebral edema , a life - threatening medical complication , contributes to elevated intracranial pressure ( ICP ) and a poor clinical prognosis after TBI . Unfortunately , treatment options to reduce post - traumatic edema remain suboptimal , due in part , to a dearth of viable therapeutic targets . Herein , we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI . Our results demonstrate that high - mobility group box protein 1 ( P09429 ) was released from necrotic neurons via a Q13224 - mediated mechanism . P09429 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice . The detrimental effects of P09429 were mediated , at least in part , via activation of microglial toll - like receptor 4 ( O00206 ) and the subsequent expression of the astrocytic water channel , aquaporin - 4 ( P55087 ) . Genetic or pharmacological ( VGX - 1027 ) O00206 inhibition attenuated the neuroinflammatory response and limited post - traumatic edema with a delayed , clinically implementable therapeutic window . Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal P09429 initiates the microglial release of interleukin - 6 ( P05231 ) in a O00206 dependent mechanism . In turn , microglial P05231 increased the astrocytic expression of P55087 . Taken together , these data implicate microglia as key mediators of post - traumatic brain edema and suggest P09429 - O00206 signaling promotes neurovascular dysfunction after TBI .", "P12821 inhibition suppresses plasminogen activator inhibitor - 1 expression in the neointima of balloon - injured rat aorta . BACKGROUND : P00747 activator inhibitor - 1 ( P05121 ) , an important regulator of fibrinolysis and extracellular matrix turnover , has been implicated in a number of vascular diseases . Studies demonstrating angiotensin II ( Ang II ) to be a potent stimulator of P05121 expression in cultured vascular cells suggests that the renin - angiotensin system may modulate vascular P05121 expression . METHODS AND RESULTS : We examined the effects of the P12821 inhibitor captopril on P05121 expression in control and balloon - injured rat aorta . Northern blot analysis demonstrated that aortic P05121 mRNA expression was 7 . 6 - fold elevated 3 hours ( P < . 05 ) after balloon injury , back to baseline at 2 days , increased again at 4 days , and by 7 days after balloon injury was 3 . 2 - fold elevated ( P < . 05 ) when compared with control . In captopril - treated rats , the induction of P05121 expression by balloon injury was significantly suppressed by 44 % ( P < . 05 ) in the 7 day group but was not altered in the 3 - hour group . ___MASK25___ also reduced baseline aortic P05121 mRNA . In situ hybridization and immunohistochemistry revealed dense P05121 staining of 7 - day neointima in untreated rats and a dramatic decrease in P05121 in neointima of captopril - treated rats . CONCLUSIONS : This report demonstrates that balloon injury results in both a rapid P12821 inhibitor - independent induction of aortic P05121 expression and a later increase in P05121 in the neointima that is significantly suppressed by captopril . This provides the first evidence that the renin - angiotensin system regulates neointimal P05121 expression and that P12821 inhibitors can reduce P05121 in the vessel wall in vivo .", "Deficiency in endothelin receptor B reduces proliferation of neuronal progenitors and increases apoptosis in postnatal rat cerebellum . Endothelins regulate cellular functions in the mammalian brain through the endothelin receptors A and B ( P25101 and P24530 ) . In this study , we investigated the role of P24530 on cell proliferation in the cerebellum by using the spotting lethal ( sl ) rat , which carries a naturally occurring deletion in the P24530 gene . Proliferating cells in the three genotypes , wild - type ( +/+ ) , heterozygous ( +/ sl ) and homozygous mutant ( sl / sl ) rats were labelled by intraperitoneal injection of 5 - bromo - 2 '- deoxyuridine ( BrdU ) at postnatal day 2 . The density of BrdU - positive cells ( per mm ( 2 ) ) in the external germinal layer of sl / sl rats ( Mean +/- SEM , 977 +/- 388 ) was significantly reduced compared to +/+ ( 4915 +/- 631 ) and +/ sl ( 2304 +/- 557 ) rats . Subsequently , we examined the effects of P24530 mutation on neural apoptosis by terminal deoxynucleotidyltransferase - mediated dUTP nick end - labelling assay . This showed that the density of apoptotic cells in the cerebella of sl / sl rats ( 9 . 3 +/- 0 . 5 / mm ( 2 ) ) was significantly more increased than +/+ rats ( 4 +/- 0 . 7 ) . The expression of brain - derived neurotrophic factor ( P23560 ) and glial cell line - derived neurotrophic factor ( P39905 ) were measured with standard ELISA , but were unchanged in all genotypes . These results suggest that ENDRB mediates neural proliferation and have anti - apoptotic effects in the cerebellum of the postnatal rat , and that these effects are independent of changes in the expression of P23560 and P39905 . Our findings will lead to better understanding of the morphological changes in the cerebellum of Hirschsprung ' s disease patients with congenital P24530 mutation .", "Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .", "P05305 activates P25101 receptors on human vascular smooth muscle cells to yield proteoglycans with increased binding to LDL . OBJECTIVE : Lipid retention in the vessel wall by glycosaminoglycan ( GAG ) chains on chondroitin / dermatan sulfate proteoglycans synthesized by vascular smooth muscle cells ( VSMC ) have recently been established as an early event in human coronary artery atherosclerosis . GAG structure can be altered by growth factors resulting in enhanced binding to low density lipoprotein ( LDL ) . The aim of this study was to determine if proteoglycans produced by endothelin - 1 treated VSMCs had increased binding to human LDL , to examine the effect of endothelin - 1 on the synthesis and structure of proteoglycans and to elucidate the signalling pathway . METHODS AND RESULTS : P05305 stimulated an increase in [( 35 ) S ] sulfate and [( 3 ) H ] glucosamine incorporation into proteoglycans produced by human VSMC . The increase was due to an increase in GAG chain size assessed by SDS - PAGE and size exclusion chromatography . Increased radiolabel incorporation was inhibited by an ET ( A ) but not an ET ( B ) receptor antagonist . P05305 stimulated an increase in the 6 : 4 position sulfation ratio on the disaccharides of the GAG chains , an effect that was blocked by ___MASK99___ . The P01133 receptor antagonist AG1478 did not affect the increase in GAG size mediated by endothelin - 1 . Inhibition of protein kinase C ( PKC ) with GF109203X or down regulation by PMA pre - treatment attenuated the effect of endothelin - 1 on GAG synthesis . CONCLUSION : These data demonstrate that endothelin - 1 stimulates changes in GAG chain structure that increase binding to LDL . This action of endothelin - 1 may represent a new target for the prevention of lipid binding within the vascular wall and the associated complications resulting from this interaction .", "Splenic autonomic denervation increases inflammatory status but does not aggravate atherosclerotic lesion development . The brain plays a prominent role in the regulation of inflammation . Immune cells are under control of the so - called cholinergic anti - inflammatory reflex , mainly acting via autonomic innervation of the spleen . Activation of this reflex inhibits the secretion of proinflammatory cytokines and may reduce the development of atherosclerosis . Therefore , the aim of this study was to evaluate the effects of selective parasympathetic ( Px ) and sympathetic ( Sx ) denervation of the spleen on inflammatory status and atherosclerotic lesion development . Female P02649 * 3 - Leiden . P11597 mice , a well - established model for human - like lipid metabolism and atherosclerosis , were fed a cholesterol - containing Western - type diet for 4 wk after which they were subdivided into three groups receiving either splenic Px , splenic Sx , or sham surgery . The mice were subsequently challenged with the same diet for an additional 15 wk . Selective Px increased leukocyte counts ( i . e . , dendritic cells , B cells , and T cells ) in the spleen and increased gene expression of proinflammatory cytokines in the liver and peritoneal leukocytes compared with Sx and sham surgery . Both Px and Sx increased circulating proinflammatory cytokines IL - 1β and P05231 . However , the increased proinflammatory status in denervated mice did not affect atherosclerotic lesion size or lesion composition . CONCLUSION : Predominantly selective Px of the spleen enhances the inflammatory status , which , however , does not aggravate diet - induced atherosclerotic lesion development .", "DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .", "Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo . The mechanisms through which blockade of metabotropic glutamate receptors 5 ( P41594 ) results in anxiolytic and antidepressant effects are currently unknown . In the present study , we therefore hypothesized that the anxiolytic - and antidepressant - like profile of the noncompetitive P41594 receptor antagonist 2 - ethyl - 6 -( phenylethynyl )- pyridine ( MPEP ) may be mediated by inhibition of the norepinephrine transporter ( NET ) . Accordingly , we first examined the potency of MPEP to bind to or inhibit uptake at the NET as well as the dopamine and serotonin transporters ( Q01959 and P31645 , respectively ) . We also examined the simultaneous in vivo effects of MPEP and desipramine ( ___MASK82___ ) on both NE - like oxidation current in the amygdala ( Q9BXS0 ) and cell firing in the locus coeruleus ( LC ) by means of differential pulse voltammetry ( DPV ) coupled with electrophysiology . MPEP completely displaced the binding of [ 3H ] - nisoxetine on human NET with a pKi of 6 . 63 +/- 0 . 02 . In addition , MPEP was able to inhibit [ 3H ] - NE uptake in LLCPK cells expressing human NET , with a pIC50 of 5 . 55 +/- 0 . 09 . In vivo DPV data revealed that both MPEP ( 30 mg / kg i . p . ) and ___MASK82___ ( 10 mg / kg i . p . ) significantly increased NE - like voltammetric responses levels in the Q9BXS0 , whereas both compounds also significantly decreased cell firing monitored concomitantly from the second microelectrode in the LC . Collectively , the results of the present study provide potential new mechanisms through which MPEP exerts its anxiolytic and antidepressant effects .", "[ Expressions of receptor tyrosine kinases mRNA and protein in carcinoma of bladder ] . OBJECTIVE : To detect the expressions of receptor tyrosine kinases ( RTKs ) mRNA and protein and to explore potentially promising tumor markers and conceivable drug target in bladder cancer . METHODS : The expressions of RTKs mRNA and protein in tissue from invasive urothelial carcinoma of the bladder were examined by real - time quantitative PCR array and cytokine antibody array , with normal bladder tissue as control . The Results were analyzed using bioinformatic approaches . RESULTS : The expressions of P01135 , Q9NY15 , P05121 , O15123 , Q9NQ38 , O95841 , P58294 , P21741 , Q07325 , P28799 , Q01196 , P15692 , and P01137 were obviously upregulated in bladder cancer tissue , while those of O43854 , P21246 , P13500 , Q9GZP0 , Q92913 , P21583 , P09038 , P36955 , and P01375 were downregulated . Q9UM73 , Btk , EphB2 , ErbB4 , P09619 - α , ROS , Tie - 2 , Tyk2 , and P35916 were over - expressed in bladder cancer , while P42685 , Fyn , IGF - IR , P01308 R , Itk , P23458 , P52333 , and P06239 were low - expressed . CONCLUSION : Vascular endothelial growth factor / platelet - derived growth factor - targeted therapies may play an active role in treating carcinoma of bladder .", "Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK82___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK82___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .", "Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .", "Effects of addition of tissue - type plasminogen activator in in vitro fertilization medium on bovine embryo development and quality . P00747 activators / Plasmin system plays pivotal role in regulating reproductive functions of mammals . Here , we examined the effects of modification of in vitro fertilization medium ( IVF medium ) with the addition of tissue - type plasminogen activator ( t - PA ) , on bovine embryo development and quality , assessed by quantification of expression of various genes related to metabolism , oxidation , implantation and apoptosis . In addition , plasminogen activator activity ( PAA ) and plasminogen activator inhibition ( P05121 ) were measured in the spent media . After conventional IVM , 2016 cumulus - oocyte complexes ( COCs ) were divided into four groups with modified composition of the IVF medium containing t - PA and / or its inhibitor epsilon - aminocaproic acid ( control , t - PA , t - PA + ε - ACA , ε - ACA ) . Presumptive zygotes were cultured for 8 days in synthetic oviductal fluid ( SOF ) medium ; gene expression studies were carried out on morulae and blastocysts . t - PA alone significantly suppressed cleavage and blastocyst formation rates , but this effect was neutralized by the addition of ε - ACA . PAA in the treated group was significantly reduced by ε - ACA , but without total elimination . Significant differences were detected in the expression of genes related to apoptosis and / or cell cycle arrest ( Q07812 , Q07817 , Q92831 ) between embryos produced in t - PA - modified media and controls , giving an overall notion that the inferior developmental competence of treated embryos may be attributed to apoptotic phenomena induced by t - PA . In conclusion , it appears that excessive t - PA content in the IVF media , suppresses blastocyst formation rate , possibly due to induction of apoptotic phenomena .", "Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK61___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .", "Effect of glial cell line - derived neurotrophic factor on behavior and key members of the brain serotonin system in mouse strains genetically predisposed to behavioral disorders . The effect of glial cell line - derived neurotrophic factor ( P39905 ) on behavior and on the serotonin ( 5 - HT ) system of a mouse strain predisposed to depressive - like behavior , ASC / Icg ( Antidepressant Sensitive Cataleptics ) , in comparison with the parental \" nondepressive \" CBA / Lac mice was studied . Within 7 days after acute administration , P39905 ( 800 ng , i . c . v . ) decreased cataleptic immobility but increased depressive - like behavioral traits in both investigated mouse strains and produced anxiolytic effects in ASC mice . The expression of the gene encoding the key enzyme for 5 - HT biosynthesis in the brain , tryptophan hydroxylase - 2 ( Tph - 2 ) , and P08908 receptor gene in the midbrain as well as 5 - Q13049 receptor gene in the frontal cortex were increased in P39905 - treated ASC mice . At the same time , P39905 decreased P08908 and 5 - Q13049 receptor gene expression in the hippocampus of ASC mice . P39905 failed to change Tph2 , P08908 , or 5 - Q13049 receptor mRNA levels in CBA mice as well as 5 - HT transporter gene expression and P08908 and 5 - Q13049 receptor functional activity in both investigated mouse strains . The results show 1 ) a P39905 - induced increase in the expression of key genes of the brain 5 - HT system , Tph2 , P08908 , and 5 - Q13049 receptors , and 2 ) significant genotype - dependent differences in the 5 - HT system response to P39905 treatment . The data suggest that genetically defined cross - talk between neurotrophic factors and the brain 5 - HT system underlies the variability in behavioral response to P39905 .", "Mechanisms of Nattokinase in protection of cerebral ischemia . In vivo , the level of cyclic DB00640 Monophosphate ( DB02527 ) and the pathway of the Janus Kinase1 / Signal Transducers and Activators of Transcription1 ( P23458 / P42224 ) were studied . In vitro , the Ca ( 2 +) mobilization in human platelet stimulated by thrombin was observed . In addition , vasomotion of vascular smooth muscle was measured by adding DB00761 or norepinephrine ( NE ) under the Ca ( 2 +) contained bath solutions . The effect induced by NE in the presence of N - nitro - L - arginine methyl ester ( L - NAME ) or indometacin ( Indo ) was also detected . At last , the levels of tissue plasminogen activator ( t - PA ) and P00747 activator inhibitor - 1 ( P05121 ) in cultured supernatans in Human umbilical vein endothelial cells ( Huvecs ) were measured by means of ELISA kit . Results showed that Nattokinase ( NK ) significantly increased the DB02527 level , activated the signal passage of P23458 / P42224 in injured part and inhibited remarkably the rise of platelet intracellular Ca ( 2 +) ( [ Ca ( 2 +)] i ) in human platelet . Furthermore , NK relaxed rat thoracic aortic artery in the dose - dependent manner and in the endothelium dependent manner and its effect could be attenuated by L - NAME . Also , the secretion of t - PA and P05121 were reduced stimulated by Adr on Huvecs . These data indicated that the neuroprotective effect of NK was associated with its antiplatelet activity by elevating DB02527 level and attenuating the calcium release from calcium stores ; with its anti - apoptotic effect through the activation of P23458 / P42224 pathway ; with its relaxing vascular smooth muscle by promoting synthesis and release of NO , reducing ROC calcium ion influx and with its protection on endothelial cells through increasing fibrinolytic activity and facilitating spontaneous thrombolysis .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "miR - 17 - 5p targets the p300 / CBP - associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells . BACKGROUND : P10275 ( AR ) signalling is critical to the initiation and progression of prostate cancer ( PCa ) . Transcriptional activity of AR involves chromatin recruitment of co - activators , including the p300 / CBP - associated factor ( Q92831 ) . Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease . Whether miRNAs regulate Q92831 expression in PCa cells to regulate AR transcriptional activity is still unclear . METHODS : Expression of Q92831 was investigated in several PCa cell lines by qRT - PCR , Western blot , and immunocytochemistry . The effects of Q92831 expression on AR - regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation , reporter gene construct analysis , and MTS assay . Targeting of Q92831 by miR - 17 - 5p was evaluated using the luciferase reporter assay . RESULTS : Q92831 was upregulated in several PCa cell lines . Upregulation of Q92831 promoted AR transcriptional activation and cell growth in cultured PCa cells . Expression of Q92831 in PCa cells was associated with the downregulation of miR - 17 - 5p . Targeting of the 3 '- untranslated region of Q92831 mRNA by miR - 17 - 5p caused translational suppression and RNA degradation , and , consequently , modulation of AR transcriptional activity in PCa cells . CONCLUSIONS : Q92831 is upregulated in cultured PCa cells , and upregulation of Q92831 is associated with the downregulation of miR - 17 - 5p . Targeting of Q92831 by miR - 17 - 5p modulates AR transcriptional activity and cell growth in cultured PCa cells .", "Development of peptidomimetic ligands of Pro - DB00149 - DB00145 - NH ( 2 ) as allosteric modulators of the dopamine D ( 2 ) receptor . A variety of stable , small - molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro - DB00149 - DB00145 - NH ( 2 ) ( P00747 ) modulates dopaminergic neurotransmission . Photoaffinity labeling ligands based upon P00747 peptidomimetics have been used to establish that P00747 binds to the P14416 at a site that is different from the orthosteric site , thus making P00747 and its peptidomimetics allosteric modulators of the dopamine receptor . Through the design , synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam , bicyclic , and spiro - bicyclic scaffolds , support was provided for the hypothesis that the bioactive conformation of P00747 is a type II β - turn . In addition , studies with peptidomimetics designed to mimic either a type VI β - turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH ( 2 ) pharmacophore in the same topological space as that seen in the type II β - turn . Extensive studies with the spiro - bicyclic P00747 peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold . This information was used to transform existing positive modulators into negative modulators , which demonstrated that small structural changes in the spiro - bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of P00747 peptidomimetics .", "Blocking dopamine D2 receptors by haloperidol curtails the beneficial impact of calorie restriction on the metabolic phenotype of high - fat diet induced obese mice . Calorie restriction is the most effective way of expanding life - span and decreasing morbidity . It improves insulin sensitivity and delays the age - related loss of dopamine receptor D ( 2 ) ( P14416 ) expression in the brain . Conversely , high - fat feeding is associated with obesity , insulin resistance and a reduced number of P14416 binding sites . We hypothesised that the metabolic benefit of calorie restriction involves the preservation of appropriate P14416 transmission . The food intake of wild - type C57Bl6 male mice was restricted to 60 % of ad lib . intake while they were treated with the P14416 antagonist haloperidol or vehicle using s . c . implanted pellets . Mice with ad lib . access to food receiving vehicle treatment served as controls . All mice received high - fat food throughout the experiment . After 10 weeks , an i . p . glucose tolerance test was performed and , after 12 weeks , a hyperinsulinaemic euglycaemic clamp . Hypothalamic P14416 binding was also determined after 12 weeks of treatment . Calorie - restricted ( CR ) vehicle mice were glucose tolerant and insulin sensitive compared to ad lib . ( AL ) fed vehicle mice . CR mice treated with haloperidol were slightly heavier than vehicle treated CR mice . ___MASK27___ completely abolished the beneficial impact of calorie restriction on glucose tolerance and partly reduced the insulin sensitivity observed in CR vehicle mice . The metabolic differences between AL and CR vehicle mice were not accompanied by alterations in hypothalamic P14416 binding . In conclusion , blocking P14416 curtails the metabolic effects of calorie restriction . Although this suggests that the dopaminergic system could be involved in the metabolic benefits of calorie restriction , restricting access to high - fat food does not increase ( hypothalamic ) P14416 binding capacity , which argues against this inference .", "Novel function of androgen receptor - associated protein 55 / O43294 as a negative regulator of P84022 signaling . P10275 - associated protein 55 ( O43294 / O43294 ) belongs to the LIM protein superfamily and is featured by three or four N - terminal LD motifs and four C - terminal zinc finger - like LIM domains . Both LD motifs and LIM domains can serve as protein - protein interaction interfaces . Recently , we found that enforced expression of O43294 inhibits transforming growth factor - beta - mediated up - regulation of Smad binding element - luciferase reporter activity in NRP - 154 and NRP - 152 rat prostate and LNCaP human prostate cell lines . Moreover , O43294 also inhibits the induction of Smad - binding element 4 - luciferase and 3TP - luciferase ( a plasminogen activator inhibitor - 1 ( P05121 ) promoter construct ) reporters by constitutively active ( CA ) - P84022 in these cell lines . Co - immunoprecipitation studies suggest an interaction between O43294 and either CA - P84022 or wild - type P84022 in HEK293 cells that occurs through the MH2 domain of P84022 and the C terminus of O43294 with wild - type P84022 having stronger affinity than CA - P84022 to O43294 . O60760 pull - down assays demonstrate that this interaction can occur in a cell - free system . These results are consistent with the luciferase data showing that the C terminus of O43294 is critical for suppression of P84022 activity . Furthermore , using a mammalian two - hybrid system , we confirmed that O43294 interacts with the MH2 domain of P84022 and suppresses CA - P84022 - induced transcriptional responses . In conclusion , these results support that O43294 selectively intercepts transforming growth factor - beta signaling through an interaction of the LIM domain of O43294 with the MH2 domain of P84022 .", "Recombinant growth hormone : a new cardiovascular drug therapy . GH has an important role in normal cardiovascular physiologic functioning , working indirectly through effects on DB01277 . An excess or deficiency of GH causes an increased rate of cardiovascular disease , including cardiomyopathy . A relative GH deficiency in older subjects may also increase cardiovascular morbidity and mortality risk . In replacement doses , GH can enhance myocardial contractility ; can decrease peripheral vascular resistance ; and can reduce total cholesterol and LDL - cholesterol values and fibrinogen and P05121 levels . These effects of GH , coupled with the ability to improve skeletal muscle function and reduce adiposity , make it an attractive treatment for patients with CHF and a potential maintenance drug for elderly people . Clinical trials , including studies with P01286 that may reduce the adverse effects of GH therapy , such as hyperglycemia and hypertension , are now in progress .", "[ Conditions of the primary culture for rat hepatocytes and plasminogen activator release ] . The conditions of primary culture for rat hepatocytes was investigated on the releasing effect of P00747 Activator ( PA ) . The culture method using Collagen Coated Dish ( CCD - method ) which is currently available and the ordinary culture method using Plastic Culture Dish ( P61457 - method ) were employed for that purpose in a comparative way . The effect of the addition of some supplements , that is FN , DB06692 , P01133 were also investigated . The following results were obtained . The dissociated rat hepatocytes formed a monolayer with pavementlike morphology at 24 - 48 hours after seeding . No difference was observed in the morphology of hepatocytes during the culture period between the two methods , although CCD - method allowed 120 hours culture , whereas P61457 - method allowed 72 hours . The PA activity was demonstrated on the hepatocytes by either culture method according to the fibrinolysis autography . The cultured hepatocytes released PA into the medium continuously as long as the viability and morphology of the cells were maintained in good state . The PA activity reached the maximum after 96 hours culture in CCD - method , whereas it reached the maximum after 48 hours in P61457 - method . The addition of DB06692 to the culture medium was not necessary for PA release in CCD - method in contrast to P61457 - method . When P01133 was discontinued in the culture medium , the release of PA was reduced in association with the occurring of morphological disintegration of hepatocytes .", "[ Vascular inflammation : effect of proatherogenic dyslipidemic trio or quartet ] . Atherosclerosis is a vascular inflammatory disease resulting from lipid deposition within vascular wall and changes in structure and function of the vascular wall . Atherosclerosis is accelerated when total and LDL cholesterol are elevated and / or HDL is low . Free radical production is increased in hypercholesterolemia leading to oxidative transformation of both parts of LDL particles , protein and lipid part . Small , dense LDL particles have extreme atherogenic potential ; they can be easily oxidized and strongly maintain vascular inflammation . Oxidized LDL particles ( oxLDL ) support further free radical production . OxLDL are removed by macrophages into sub epithelial space . During that process macrophages produce inflammatory cytokines and induce the production of adhesion molecules , which further cause adherences of new macrophages and further support inflammation . OxLDL also induce sinthesis of endothelial growth factor receptors , which enable transduction of different signals important for : vascular remodeling , cellular migration , mitosis and NF - kappaB activation and increased metalloproteinase activity . HDL particles have an important role in the reverse cholesterol path and protective effects in vascular inflammation and atherogenesis . The ratio of apoprotein AI and AII , amount of P11597 , P04180 and paraoxsonase , determine the function of HDL particles . Increased levels of triglycerides in the morning and especially postprandial levels are an independent risk factor for coronary heart disease , and heighten the risk when associated with other lipid disturbances . An increased triglyceride level is associated with the increased P05121 I and reduced fibrinolisis . The ratio of total cholesterol / HDL cholesterol , as well as the levels of markers of inflammation such as CRP or P05231 , have great predictive value for the development of ischemic heart disease and cardiovascular diseases .", "Adenoviral expression of a urokinase receptor - targeted protease inhibitor inhibits neointima formation in murine and human blood vessels . BACKGROUND : Smooth muscle cell migration , in addition to proliferation , contributes to a large extent to the neointima formed in humans after balloon angioplasty or bypass surgery . P00747 activator / plasmin - mediated proteolysis is an important mediator of this smooth muscle cell migration . Here , we report the construction of a novel hybrid protein designed to inhibit the activity of cell surface - bound plasmin , which can not be inhibited by its natural inhibitors , such as alpha ( 2 )- antiplasmin . This hybrid protein , consisting of the receptor - binding amino - terminal fragment of uPA ( P39905 ) , linked to the potent protease inhibitor bovine pancreas trypsin inhibitor ( DB06692 ) , can inhibit plasmin activity at the cell surface . METHODS AND RESULTS : The effect of adenovirus - mediated P39905 . DB06692 expression on neointima formation was tested in human saphenous vein organ cultures . Infection of human saphenous vein segments with Ad . CMV . P39905 . DB06692 ( 5x10 ( 9 ) pfu / mL ) resulted in 87 . 5 +/- 3 . 8 % ( mean +/- SEM , n = 10 ) inhibition of neointima formation after 5 weeks , whereas Ad . CMV . P39905 or Ad . CMV . DB06692 virus had only minimal or no effect on neointima formation . The efficacy of P39905 . DB06692 in vivo was demonstrated in a murine model for neointima formation . Neointima formation in the femoral artery of mice , induced by placement of a polyethylene cuff , was strongly inhibited ( 93 . 9 +/- 2 % ) after infection with Ad . CMV . mATF . DB06692 , a variant of P39905 . DB06692 able to bind specifically to murine uPA receptor ; Ad . CMV . mATF and Ad . CMV . DB06692 had no significant effect . CONCLUSIONS : These data provide evidence that adenoviral transfer of a hybrid protein that binds selectively to the uPA receptor and inhibits plasmin activity directly on the cell surface is a powerful approach to inhibiting neointima formation and restenosis .", "___MASK27___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK27___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .", "[ A novel function of anti - fibrinolytic factor , P05121 , in the central nervous system : a possible role as the neurotrophic factor ] . P00747 activator inhibitor - 1 ( P05121 ) is a serpin that suppresses fibrinolysis by inhibiting the activity of plasminogen activator ( PA ) . Together with PA , P05121 is expressed in the central nervous system and may play a role in the regulation of PA activity . Our present study has demonstrated that , in cultures of PC - 12 neurons , depletion of P05121 from the culture medium induces disappearance of the cell ' s neurites and the cell death . DB06692 and antipain , the inhibitors of PA , were not counterparts of P05121 in the protection of neurite disappearance . We also found that P05121 had the abilities to promote release of the survival factors of neurons , P05231 and P15692 and activation of a survival serine / threonine kinase Akt . These results suggest that P05121 has physiological functions other than its role as PA inhibitor for the survival of neurons .", "Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK99___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK99___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .", "___MASK25___ reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin - converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU / ml ) , tissue plasminogen activator ( t - PA ) antigen ( ng / ml ) , and serum P12821 activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37 . 5 mg daily ) and compared them with the values in 15 placebo - treated patients chosen at random . Blood sampling was performed at 07 . 00 h . In the captopril - treated group , serum P12821 activity decreased significantly , from 14 . 0 +/- 0 . 8 to 11 . 5 +/- 1 . 2 IU / L 24 h after captopril therapy ( p < 0 . 01 ) , and those of P05121 activity and t - PA antigen also decreased significantly - from 11 . 9 +/- 2 . 8 to 5 . 5 +/- 2 . 2 IU / ml ( p < 0 . 02 ) and from 9 . 9 +/- 1 . 0 to 7 . 5 +/- 0 . 9 ng / ml ( p < 0 . 05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t - PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .", "Respective role of humoral factors and blood pressure in aortic remodeling of DOCA hypertensive rats . Hypertension results in increased thickness and stiffness of large artery walls . The goal of our study was to assess the respective roles of humoral factors such as Ang II , endothelin and blood pressure in these aortic modifications . For this purpose , uninephrectomized rats received DOCA and high salt diet , and when hypertension was installed , they were treated for 5 weeks with either a long - acting calcium antagonist , mibefradil ( 30 mg / kg / day ) , an P12821 inhibitor , enalapril ( 3 mg / kg / day ) , or a mixed P25101 and ETB endothelin receptor antagonist , ___MASK99___ ( 100 mg / kg / day ) . A group of hypertensive rats was left untreated and a sham - operated group of normotensive rats was used for control . At the end of treatment , aortic medial thickness and elastin as well as collagen were evaluated by quantitative morphometry . DOCA - salt hypertensive rats exhibited a marked increase in medial thickness associated with no change in absolute content in extracellular matrix . P15502 relative density decreased in DOCA rats . Enalapril had no effect on arterial pressure . ___MASK99___ decreased slightly ( by 12 mm Hg ) , but not significantly , blood pressure . None of these drugs had an effect on medial thickness suggesting that in DOCA hypertensive rats neither Ang II nor endothelin play a significant role in the remodeling of the aorta . In contrast , mibefradil almost normalized arterial pressure , prevented medial hypertrophy and increased elastin density . Further studies are required in order to assess if this effect is directly linked to the blood pressure decrease or to another mechanism related to the calcium antagonistic property of mibefradil .", "Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF - B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( ___MASK84___ ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF - B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti - oCRF and anti - rCRF antibodies . CRF - B cross - reacted well with anti - oCRF antibodies but poorly with anti - rCRF antibodies . Purification of CRF - B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4 . 7 ) , B - 2 ( pH 5 . 5 ) , B - 3 ( pH 6 . 3 ) , and B - 4 ( pH 7 . 0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF - B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .", "Involvement of both heparanase and plasminogen activator in lymphoma cell - mediated degradation of heparan sulfate in the subendothelial extracellular matrix . The effect of plasminogen on the ability of highly metastatic ESb mouse lymphoma cells to degrade heparan sulfate ( HS ) in the subendothelial extracellular matrix ( Q13201 ) was studied . A metabolically sulfate - labeled Q13201 was incubated with the lymphoma cells , and labeled degradation products were analyzed by gel filtration on Sepharose 6B . Q9Y251 - mediated release of low - Mr ( 0 . 5 less than Kav less than 0 . 85 ) HS cleavage products was stimulated fourfold in the presence of plasminogen . Incubation of plasminogen alone with the Q13201 resulted in its conversion into plasmin , which released high - Mr ( Kav less than 0 . 33 ) labeled proteoglycans from the Q13201 . Heating the Q13201 ( 80 degrees C , 1 hr ) abolished its ability to convert plasminogen into plasmin , yet plasminogen stimulated , through its activation by the ESb plasminogen activator , heparanase - mediated release of low - Mr HS fragments . DB01109 inhibited both the basal and plasminogen - stimulated degradation of HS side chains but not the total amount of labeled material released from the Q13201 . In contrast , aprotinin inhibited the plasminogen - stimulated release of high - as well as low - Mr material . In the absence of plasminogen , degradation of heated Q13201 by ESb cells was completely inhibited by aprotinin , but there was only a partial inhibition of the degradation of native Q13201 and no effect on the degradation of soluble HS proteoglycan . These results demonstrate that proteolytic activity and heparanase participate synergistically in the sequential degradation of Q13201 HS and that the ESb proteolytic activity is crucial for this degradation when the Q13201 - associated protease is inactivated . P00747 may serve as a source for the proteolytic activity that produces a more accessible substrate to the heparanase .", "A prospective case - control study analyzes 12 thrombophilic gene mutations in Turkish couples with recurrent pregnancy loss . PROBLEM : Recurrent pregnancy loss ( RPL ) is a heterogeneous disorder . The contribution of specific thrombophilic genes to the pathophysiology of RPL has remained controversial . We evaluated the prevalences of 12 thrombophilic gene mutations among homogenous Caucasian couples with RPL and fertiles . METHOD : of study This was a prospective case - control study evaluating 272 women with RPL and 152 of their male partners , and a control group of 56 fertile couples . We investigated mutations including FV Leiden , factor V H1299R , factor II prothrombin G20210A , F XIII V34L , beta - fibrinogen - 455G > A , plasminogen activator inhibitor - 1 , P05106 L33P ( Q9Y251 - 1 a / b L33P ) , P42898 C677T , P42898 A1298C , P12821 I / D , Apo B R3500Q , and Apo E . RESULTS : Overall , heterozygous mutations of FV Leiden , FXIII V34L , P05106 L33P , Apo E4 , and prothrombin G20210A and homozygous mutations of P05121 - 1and P42898 C677T were associated with RPL . There was no meaningful association between RPL and other studied genes . CONCLUSION : In contrast to the other mutations and polymorphisms , FV Leiden , FXIII V34L , P05106 L33P , Apo E , prothrombin G20210A , P05121 and P42898 C677T gene mutations may help to identify the couples at risk for recurrent pregnancy loss .", "Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK77___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .", "Prevalence of genetic risk factors for coronary artery disease in Corsica island ( France ) . We have investigated the frequencies of seven markers among 100 unrelated individuals with angiographically documented CAD ( Coronary Artery Disease ) and among 100 unrelated healthy blood donors in the central region of Corsica island ( France ) . The seven polymorphisms analyzed were chosen from six candidate genes involved in ( 1 ) P00797 - Angiotensin system : Angiotensin converting enzyme ( P12821 I / D ) , ( 2 ) Lipid metabolism : DB04540 Ester Transfer Protein gene ( P11597 TAQ1B ) , ( 3 ) Platelet aggregation : alpha and beta subunits of the platelet GpIIb / GpIIIa integrin complex ( GpIIb HPA3 and GpIIIa Pl ( A1 / A2 ) ) , ( 4 ) Coagulation fibrinolysis : P00747 Activator Tissue ( P00750 TPA25 I / D ) and Methylenetetrahydrofolate Reductase ( P42898 C677T and A1298C ) . The samples were genotyped using the polymerase chain reaction followed by restriction enzyme analysis for the RFLPs . No significant difference in allele frequencies between patient and control groups was observed . The occurrence of the P42898 T677T genotype and of the T677T / A1298A compound genotype is higher in cases ( 20 % ) than in the controls ( 4 % ) . Odds ratio seems to indicate that individuals with the P42898 T677T genotype and the T677T / A1298A compound genotype had a 6 - fold increased risk for developing CAD ( ORs = 6 ; 95 % CIs = 1 . 96 - 18 . 28 ) suggesting a possible association of P42898 C677T with the risk of CAD in Corsican population .", "___MASK14___ block of cloned human T - type voltage - gated calcium channels . ___MASK14___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .", "The retinoblastoma protein modulates expression of genes coding for diverse classes of proteins including components of the extracellular matrix . The product of the retinoblastoma susceptibility gene , P06400 , is a negative regulator of cell growth . It functions by regulating the activity of transcription factors . Rb represses some genes by sequestering or inactivating the positive transcription factor E2F and seems to activate some others by interacting with factors like Sp1 or P39905 - 2 . However , there are only a few examples of genes which are positively regulated by P06400 . In order to find out if there are common mechanisms for promoter regulation by P06400 , we were interested to identify more genes which are either stimulated or repressed by P06400 . Using the method of differential display ( DDRT - PCR ) in combination with nuclear run - on analyses we were able to detect a number of genes which are upregulated by ectopic expression of the Rb gene in Rb - deficient mammary carcinoma cells . We could demonstrate not only stimulation of the endogenous mutant Rb gene but also positive regulation of genes coding for diverse classes of proteins , including the endothelial growth regulator endothelin - 1 and the proteoglycans versican and P07585 . As a second approach , we investigated gene expression in cell lines established from Rb deficient heterozygous and homozygous knockout mouse embryos and normal mice . We have identified several genes the expression of which correlates positively or negatively with the presence of Rb . These data provide further evidence for P06400 being a master regulator of a complex network of gene activities defining the difference between dividing and resting or differentiated cells .", "Endocytosis of the vasopressin receptor by anterior pituitary cells is increased by DB05394 ( CRF ) . Endocytosis of certain receptors such as the transferrin receptor and the P01133 - receptor appears to be influenced by second messengers . If second messengers are involved in modulation of endocytosis , not only endocytosis of the stimulated receptor itself but also of receptors for other ligands on the cell surface may be influenced by receptor occupancy . P06850 ( CRF ) and vasopressin act synergistically on secretion of ___MASK84___ from the anterior pituitary . The results presented here demonstrate that CRF increases retrieval of the vasopressin receptor in anterior pituitary cells in primary culture without influencing the surface binding of vasopressin . This is not a function of an increased membrane turnover since endocytosis of the transferrin receptor is not influenced by CRF .", "Evaluation of platelet activation , coagulation , and fibrinolytic activation in patients with symptomatic lacunar stroke . BACKGROUND : It is unclear whether hemostasis plays a role in the pathogenesis of ischemic stroke subtypes . OBJECTIVE : We aimed to investigate the possible relationship between different hemostatic markers and lacunar stroke . RESULTS : The study consisted of 30 patients with symptomatic lacunar stroke and 30 healthy age - matched healthy individuals . We analyzed the values of \" Mean Platelet Volume , \" D - dimer , \" soluble p - selectin , \" \" P00747 Activator Inhibitor Type - 1 \" ( P05121 ) , \" Thrombin - Activatable DB06692 \" ( Q96IY4 ) , and \" Platelet Factor 4 \" ( P02776 ) in patients with lacunar infarct and compared these values to those of control individuals . There were significant differences for D - dimer , mean platelet volume , thrombin - activatable fibrinolysis inhibitor , and platelet factor 4 values in symptomatic lacunar stroke group compared with the control group ( P < 0 . 01 ) . CONCLUSIONS : Different hemostatic factors may play a role in the pathogenesis of lacunar stroke . Evaluating the role of hemostatic factors on different types of strokes may help us identify new therapeutic strategies and different prognostic stratifications for ischemic stroke .", "Growth factors stimulate expression of neuronal and glial miR - 132 . Brain - specific microRNAs ( miRs ) and brain - derived neurotrophic factor ( P23560 ) are both involved in synaptic function . We previously reported that upregulation of miR - 132 is involved in P23560 - increased synaptic proteins , including glutamate receptors ( Q12879 , Q13224 , and GluR1 ) in mature cortical neurons [ 7 ] . However , the potential role of other growth factors in miR - 132 induction has not been clarified . Here , we examined the effect of growth factors including basic fibroblast growth factor ( P09038 ) , insulin - like growth factor - 1 ( DB01277 ) , glial cell line - derived neurotrophic factor ( P39905 ) , and epidermal growth factor ( P01133 ) , on expression of miR - 132 and glutamate receptors in immature cortical neurons . We found that P23560 and P09038 upregulated levels of miR - 132 in cortical cultures , though P09038 failed to increase glutamate receptors such as Q12879 , Q13224 , and GluR1 . DB01277 , P39905 , and P01133 did not have a positive influence on miR - 132 and glutamate receptors in neuronal cultures . Furthermore , P09038 significantly upregulated miR - 132 in cultured astroglial cells , while other growth factors failed to elicit such a response . It is possible that the growth factor - stimulated neuronal and glial action of miR - 132 plays a critical role in brain function .", "[ Endothelial progenitor cells related gene expression changes before and early after revascularization in patients with acute myocardial infarction ] . OBJECTIVE : The purpose of this study was to observe the endothelial progenitor cells ( EPCs ) related gene expression changes before and early after revascularization in patients with acute myocardial infarction . METHODS : Peripheral blood samples were taken from patients with acute anterior myocardial infarction 6 hours and 7 days after P05154 and stenting . Mononuclear cells ( MNCs ) were isolated by Ficoll - density centrifugation and cultured in M - 199 medium . After 14 days culture , attaching cells incorporated DiI - acetylated low - density lipoprotein ( EPCs ) were collected and RNA was isolated by Trizol for microarray analysis on 24 genes associated with permissibility / vessel tone ( angiotensin system : P12821 , AGTR - 1 , AGTR - 2 ; NO system : P29474 ; prostacyclin system : P35354 ; endothelin system : ET - 1 , P25101 , ETB ; superoxide anions system : SOD - 1 ) , angiogenesis ( adhesion molecule : P33151 ; growth factors and receptors : P17948 , P35968 , P15692 ) and endothelial cell activation ( adhesion molecules expression : P05362 , P13598 , P32942 , P16284 , E - Selectin , L - Selection , P19320 ; change phenotype from antithrombotic to prothrombotic : tPA , uPA , P05121 , P04275 ) . P35968 , P16284 and P33151 positive cells were identified by flow cytometry . RESULT : Eight gene expressions ( AGTR - 1 , AGTR - 2 , P35354 , P29474 , ET - 1 , P25101 , P15692 ) were significantly downregulated 7 days post P05154 compared to pre - P05154 ( P < 0 . 05 ) . Flow cytometry results showed that P35968 positive cells were also significantly reduced post P05154 than that of before P05154 ( P < 0 . 05 ) . CONCLUSION : P05154 down - regulated endothelial progenitor cells related gene expressions in patients with acute myocardial infarction ." ]

[ "___MASK14___", "___MASK25___", "___MASK27___", "___MASK61___", "___MASK63___", "___MASK77___", "___MASK82___", "___MASK84___", "___MASK99___" ]

[ "Relative Expression of Vitamin D Hydroxylases , O15528 and Q07973 , and of P35354 and Heterogeneity of Human Colorectal Cancer in Relation to Age , Gender , Tumor Location , and Malignancy : Results from Factor and Cluster Analysis . Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1 , 25 -( OH ) 2D3 and prostaglandin cellular signaling networks . The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases , i . e . , O15528 - encoded 25 - hydroxyvitamin D - 1a - hydroxylase and Q07973 - encoded 25 - hydroxyvitamin D - 24 - hydroxylase , and inflammation - induced cyclooxygenase - 2 ( P35354 ) . Data from 105 cancer patients on O15528 , P11473 , Q07973 , and P35354 mRNA expression in relation to tumor grade , anatomical location , gender and age were fit into a multivariate model of exploratory factor analysis . Nearly identical results were obtained by the principal factor and the maximum likelihood method , and these were confirmed by hierarchical cluster analysis : Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis : ( i ) Escape of P35354 activity from restraints by the O15528 / P11473 system can initiate cancer growth anywhere in the colorectum regardless of age and gender ; ( ii ) variations in P35354 expression are mainly responsible for differences in cancer incidence in relation to tumor location ; ( iii ) advancing age has a strong gender - specific influence on cancer incidence ; ( iv ) progression from well differentiated to undifferentiated cancer is solely associated with a rise in Q07973 expression .", "[ ___MASK82___ sodium ( Photofrin - II ) ] . ___MASK82___ sodium ( ___MASK82___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK82___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .", "Effects of 25 - hydroxyvitamin D3 and 1 , 25 - dihydroxyvitamin D3 on cytokine production by human decidual cells . The active form of vitamin D , 1 , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 [ OH ]( 2 ) D ( 3 ) ) is a potent immunomodulatory seco - steroid . We have demonstrated that several components of vitamin D metabolism and signaling are strongly expressed in human uterine decidua from first trimester pregnancies , suggesting that locally produced 1 , 25 ( OH )( 2 ) D ( 3 ) may exert immunosuppressive effects during early stages of gestation . To investigate this further , we used primary cultures of human decidual cells from first and third trimester pregnancies to demonstrate expression and activity of the enzyme that catalyzes synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) , 1alpha - hydroxylase ( O15528 ) . Synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) was higher in first trimester decidual cells ( 41 +/- 11 . 8 fmoles / h / mg protein ) than in third trimester cells ( 8 +/- 4 . 4 fmoles / h / mg protein ; P < 0 . 05 ) . Purification of decidual cells followed by quantitative RT - PCR analysis showed that O15528 was expressed by both CD10 (+ VE ) stromal - enriched and CD10 (- VE ) stromal - depleted cells , with higher levels of mRNA in first trimester pregnancies . Expression of O15528 correlated with O00206 and P14902 . Functional responses to 1 , 25 ( OH )( 2 ) D ( 3 ) were studied using CD56 (+ VE ) natural killer ( NK ) cells isolated from first trimester decidua . Decidual NK cells treated with 1 , 25 ( OH )( 2 ) D ( 3 ) or precursor 25 - hydroxyvitamin D ( 3 ) ( 25OHD ( 3 ) ) for 28 h showed decreased synthesis of cytokines , such as granulocyte - macrophage colony stimulating factor 2 ( P04141 ) , tumor necrosis factor , and interleukin 6 , but increased expression of mRNA for the antimicrobial peptide cathelicidin antimicrobial peptide . These data indicate that human decidual cells are able to synthesize active 1 , 25 ( OH )( 2 ) D ( 3 ) , particularly in early gestation , and this may act in an autocrine / paracrine fashion to regulate both acquired and innate immune responses at the fetal - maternal interface .", "Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis - affected brain tissue . Vitamin D deficiency has been implicated as a risk factor for multiple sclerosis ( MS ) , but how vitamin D metabolism affects MS pathophysiology is not understood . We studied the expression of vitamin D receptor ( P11473 ) and related enzymes , including 1 , 25 ( OH )( 2 ) D - 24 - hydroxylase ( Q07973 ; Q07973 ) and 25 ( OH ) D - 1α - hydroxylase ( O15528 ) , in CNS tissues of 39 MS patients and 20 controls and in primary human glial cells in vitro . In control and MS normal - appearing white matter ( NAWM ) , nuclear P11473 immunostaining was observed in oligodendrocyte - like cells , human leukocyte antigen ( HLA ) - positive microglia , and glial fibrillary acidic protein - positive astrocytes . There was a 2 - fold increase in P11473 transcripts in MS NAWM versus control white matter ( p = 0 . 03 ) . In chronic active MS lesions , HLA - positive microglia / macrophages showed nuclear P11473 staining ; astrocytes showed nuclear and cytoplasmic P11473 staining . Staining for Q07973 was restricted to astrocytes . P11473 and O15528 mRNA expressions were increased in active MS lesions versus NAWM ( p < 0 . 01 , p = 0 . 04 , respectively ) . In primary human astrocytes in vitro , the active form of vitamin D , 1 , 25 ( OH )( 2 ) D ( 3 ) , induced upregulation of P11473 and Q07973 . P01375 and interferon - γ upregulated O15528 mRNA in primary human microglia and astrocytes . Increased P11473 expression in MS NAWM and inflammatory cytokine - induced amplified expression of P11473 and O15528 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions .", "Prevention of atherosclerosis by the P42345 inhibitor everolimus in P01130 -/- mice despite severe hypercholesterolemia . ___MASK17___ inhibits the mammalian target of rapamycin ( P42345 ) in proliferating cells . It is widely used in transplant patients and has also been exploited by drug - eluting stents for the treatment of cardiovascular disease . However , there is only limited data on the pathophysiological effects of P42345 - inhibitors on the vascular wall . We aimed to unravel the effects of everolimus on cholesterol - induced atherosclerosis and on circulating cell mediators in LDL - receptor - deficient ( P01130 (-/-) ) mice . Male hypercholesterolemic P01130 (-/-) mice received either solvent ( group A ; n = 28 ) or everolimus at 0 . 05 mg / kg ( group B , n = 22 ) and 1 . 5 mg / kg ( group C , n = 29 ) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks . Group B showed 44 % reduction of atherosclerotic lesions at the brachiocephalic artery ( BCA ) . In group C atherosclerotic lesions were reduced by 85 % in the BCA and by 60 % at the aortic root . This was associated with a significantly lower complexity of lesions in both treated groups ( p < 0 . 001 ) and despite a 40 % increase of plasma cholesterol . ___MASK17___ caused a significant reduction of circulating cell mediators such as interleukin - 1alpha , interleukin - 5 , GM - P04141 and interleukin - 12p40 . ___MASK17___ increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied . ___MASK17___ strongly inhibits atherosclerosis development in LDL - receptor (-/-) mice despite severe hypercholesterolemia . ___MASK17___ application had only small effects on circulating cell mediators . The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques .", "Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK36___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .", "[ Anti - cholesterol agents , new therapeutic approaches ] . Statins and fibrates constitute the two major families of lipid - lowering agents . Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia . Both drugs are also used for the treatment of mixed dyslipidemia . Some fibrates efficiently lower serum LDL - cholesterol . Statins inhibit P04035 and decrease cellular cholesterol synthesis . The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the P01130 gene . This over expression of the P01130 in the liver increases the clearance of circulating LDL thus decreasing the LDL - cholesterol plasma levels . The effects of fibrates on lipid metabolism are entirely due to their capacity to activate Q07869 and to induce the over expression of genes containing a PPRE in their promoter . Fibrates decrease triglyceride concentrations by increasing the beta - oxidation of fatty acids in the liver and by decreasing triglyceride - VLDL synthesis . Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C - III transcription , respectively . Fibrates could decrease triglycerides partly by inducing apo A - V over - expression . These molecules increase HDL - cholesterol by increasing apo A - I and apo A - II transcription . Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism .", "P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK49___ ) in castrated male and female mice subjected to ___MASK49___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK49___ in mice CPs .", "Excessive fructose intake causes 1 , 25 -( OH )( 2 ) D ( 3 )- dependent inhibition of intestinal and renal calcium transport in growing rats . We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca ( 2 +) transport and in levels of 1 , 25 -( OH ) 2D3 , the active form of vitamin D . Since sufficient Ca ( 2 +) absorption is essential for skeletal growth , our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children . We tested the hypothesis that 1 , 25 -( OH ) 2D3 mediates the inhibitory effect of excessive fructose intake on active Ca ( 2 +) transport . First , compared with those fed glucose or starch , growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca ( 2 +) transport rate as well as in expression of intestinal and renal Ca ( 2 +) transporters that was tightly associated with decreases in circulating levels of 1 , 25 -( OH ) 2D3 , bone length , and total bone ash weight but not with serum parathyroid hormone ( PTH ) . Dietary fructose increased the expression of 24 - hydroxylase ( Q07973 ) and decreased that of 1α - hydroxylase ( O15528 ) , suggesting that fructose might enhance the renal catabolism and impair the synthesis , respectively , of 1 , 25 -( OH ) 2D3 . Serum Q9GZV9 , which is secreted by osteocytes and inhibits O15528 expression , was upregulated , suggesting a potential role of bone in mediating the fructose effects on 1 , 25 -( OH ) 2D3 synthesis . Second , 1 , 25 -( OH ) 2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca ( 2 +) transporter expression . The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca ( 2 +) transporters is a reduction in serum levels of 1 , 25 -( OH ) 2D3 . This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca ( 2 +) and vitamin D deficiency .", "Vitamin D and the regulation of placental inflammation . The vitamin D - activating enzyme 1α - hydroxylase ( O15528 ) and vitamin D receptor ( P11473 ) support anti - inflammatory responses to vitamin D in many tissues . Given the high basal expression of O15528 and P11473 in trophoblastic cells from the placenta , we hypothesized that anti - inflammatory effects of vitamin D may be particularly important in this organ . Pregnant wild type ( WT ) mice i . p . injected with LPS showed elevated expression of mouse Cyp27b1 ( 4 - fold ) and P11473 ( 6 - fold ) . Similar results were also obtained after ex vivo treatment of WT placentas with LPS . To assess the functional impact of this , we carried out ex vivo studies using placentas -/- for fetal ( trophoblastic ) Cyp27b1 or P11473 . Vehicle - treated -/- placentas showed increased expression of IFN - γ and decreased expression of P22301 relative to +/+ placentas . LPS - treated -/- placentas showed increased expression of O60603 , IFN - γ , and P05231 . Array analyses identified other inflammatory factors that are dysregulated in Cyp27b1 (-/-) versus Cyp27b1 (+/+) placentas after LPS challenge . Data highlighted enhanced expression of P05112 , P40933 , and Q14116 , as well as several chemokines and their receptors , in Cyp27b1 (-/-) placentas . Similar results for P05231 expression were observed with placentas -/- for trophoblastic P11473 . Finally , ex vivo treatment of WT placentas with the substrate for Cyp27b1 , 25 - hydroxyvitamin D ( 3 ) , suppressed LPS - induced expression of P05231 and the chemokine Ccl11 . These data indicate that fetal ( trophoblastic ) vitamin D plays a pivotal role in controlling placental inflammation . In humans , this may be a key factor in placental responses to infection and associated adverse outcomes of pregnancy .", "DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK61___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .", "Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .", "___MASK88___ : kinetic and dynamic profile in the treatment of pain . ___MASK88___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK88___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK88___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK88___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .", "Autosomal - dominant hypophosphatemic rickets ( P30518 ) mutations stabilize Q9GZV9 . BACKGROUND : The gene for the renal phosphate wasting disorder autosomal - dominant hypophosphatemic rickets ( P30518 ) is Q9GZV9 , which encodes a secreted protein related to the fibroblast growth factors ( FGFs ) . We previously detected missense mutations R176Q , R179W , and R179Q in Q9GZV9 from P30518 kindreds . The mutations replace R residues within a subtilisin - like proprotein convertase ( Q969E3 ) cleavage site 176RHTR - 179 ( RXXR motif ) . The goal of these studies was to determine if the P30518 mutations lead to protease resistance of Q9GZV9 . METHODS : The P30518 mutations were introduced into human Q9GZV9 cDNA clones with or without an N - terminal FLAG tag by site - directed mutagenesis and were transiently transfected into HEK293 cells . Protein expression was determined by Western analyses . RESULTS : Antibodies directed toward the C - terminal portion of Q9GZV9 revealed that the native Q9GZV9 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media ; however , the three mutated proteins were detected only as the 32 kD band . An N - terminal FLAG - tagged native Q9GZV9 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody , whereas the R176Q mutant resolved primarily as the 36 kD protein species . Cleavage of Q9GZV9 was not enhanced by extracellular incubation of Q9GZV9 with HEK293 cells . Native and mutant FGF - 23s bound heparin . CONCLUSIONS : Q9GZV9 proteins containing the P30518 mutations are secreted , and produce polypeptides less sensitive to protease cleavage than wild - type Q9GZV9 . Therefore , the P30518 mutations may protect Q9GZV9 from proteolysis , thereby potentially elevating circulating concentrations of Q9GZV9 and leading to phosphate wasting in P30518 patients .", "Modulation of the P22301 / IL - 12 cytokine circuit by interferon - beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis . IFN - beta has been shown to be effective in the treatment of multiple sclerosis ( MS ) . However , the primary mechanism by which IFN - beta mediates its therapeutic effect remains unclear . Recent studies indicate that under defined conditions , IFN - beta may downregulate DC expression of IL - 12 . We and others have shown that IFN - beta may also downregulate P22301 . In light of the recently proposed paradigm that an P22301 / IL - 12 immunoregulatory circuit controls susceptibility to autoimmune disease , we examined the effect of IFN - beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis ( EAE ) , an animal model sharing many features with MS . SWXJ mice were immunized with the immunodominant p139 - 151 determinant of myelin proteolipid protein ( PLP ) , and at onset of EAE were treated every other day with IFN - beta . After eight weeks of treatment , we assessed autoreactivity and observed no significant IFN - beta effect on splenocyte proliferation or splenocyte production of P01579 , P60568 , P05112 , or P05113 in response to the priming determinant used to initiate disease . However , in IFN - beta treated mice , the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of P22301 and a concurrent decreased production of IL - 12 . Moreover , the in vivo modulation of the P22301 / IL - 12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading . Our results indicate that IFN - beta induces a reciprocal modulation of the P22301 / IL - 12 cytokine circuit in vivo . This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self - priming thereby inhibiting the progression of disease associated with epitope spreading .", "Block of Q12809 channels by berberine : mechanisms of voltage - and state - dependence probed with site - directed mutant channels . DB04115 prolongs the duration of cardiac action potentials without affecting resting membrane potential or action potential amplitude . Controversy exists regarding whether berberine exerts this action by preferential block of different components of the delayed rectifying potassium current , I ( Kr ) and I ( Ks ) . Here we have studied the effects of berberine on hERG ( I ( Kr ) ) and P51787 / P15382 ( I ( Ks ) ) channels expressed in P29320 - 293 cells and Xenopus oocytes . In P29320 - 293 cells , the IC50 for berberine was 3 . 1 +/- 0 . 5 microM on hERG compared with 11 +/- 4 % decreases on P51787 / P15382 channels by 100 microM berberine . Likewise in oocytes , hERG channels were more sensitive to block by berberine ( IC50 = 80 +/- 5 microM ) compared with P51787 / P15382 channels ( approximately 20 % block at 300 microM ) . hERG block was markedly increased by membrane depolarization . Mutation to Ala of Y652 or F656 located on the S6 domain , or V625 located at the base of the pore helix of hERG decreased sensitivity to block by berberine . An inactivation - deficient mutant hERG channel ( G628C / S631C ) was also blocked by berberine . Together these findings indicate that berberine preferentially blocks the open state of hERG channels by interacting with specific residues that were previously reported to be important for binding of more potent antagonists .", "The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .", "[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK75___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .", "A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK8___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .", "Clonal differences in expression of 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase , of 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase , and of the vitamin D receptor in human colon carcinoma cells : effects of epidermal growth factor and 1alpha , 25 - dihydroxyvitamin D ( 3 ) . Human colon carcinoma cells express 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase ( O15528 ) and thus produce the vitamin D receptor ( P11473 ) ligand 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 - D3 ) , which can be metabolized by 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase ( Q07973 ) . Expression of P11473 , O15528 , and Q07973 determines the efficacy of the antimitotic action of 1 , 25 - D3 and is distinctly related to the degree of differentiation of cancerous lesions . In the present study we addressed the question of whether the effects of epidermal growth factor ( P01133 ) and of 1 , 25 - D3 on P11473 , O15528 , and Q07973 gene expression in human colon carcinoma cell lines also depend on the degree of cellular differentiation . We were able to show that slowly dividing , highly differentiated Caco - 2 / 15 cells responded in a dose - dependent manner to both P01133 and 1 , 25 - D3 by up - regulation of P11473 and O15528 expression , whereas in highly proliferative , less differentiated cell lines , such as Caco - 2 / AQ and COGA - 1A and - 1E , negative regulation was observed . Q07973 mRNA was inducible in all clones by 1 , 25 - D3 but not by P01133 . From the observed clonal differences in the regulatory effects of P01133 and 1 , 25 - D3 on P11473 and O15528 gene expression we suggest that P11473 - mediated growth inhibition by 1 , 25 - D3 would be efficient only in highly differentiated carcinomas even when under mitogenic stimulation by P01133 .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK80___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 gene activity is DB00136 itself , which down - regulates the gene . The down - regulation of the O15528 gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 - binding regions in the distal promoter , 2 . 6 and 3 . 2 kb upstream from the TSS , that bind vitamin D receptor - retinoid X receptor complexes . Since the down regulation of the O15528 gene is tissue - and cell - type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non - permissive to the phenomenon of DB00136 - mediated down - regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 gene is repressed in P29320 - 293 but not in MCF - 7 cells .", "Role of NF - kappaB in the regulation of cytochrome P450 enzymes . Nuclear factor kappa B ( NF - kappaB ) is an important transcription factor that regulates a wide spectrum of genes including cytochrome P450 ( CYP ) , the most important family of drug metabolizing enzymes . Therefore , in this review , we addressed the potential role of NF - kappaB in CYP regulation . We proposed three mechanisms by which NF - kappaB can regulate CYP expression and activity . First , NF - kappaB can directly regulate the expression of P04798 , CYP2B1 / 2 , CYP2C11 , CYP2D5 , P05181 , P24462 , and O15528 through binding to the promoter region of these genes . Second , NF - kappaB indirectly regulates the transcription of CYP genes through mutual repression with some nuclear receptors that are involved in CYP regulation such as P35869 , CAR , GR , O75469 , RXR , Q07869 , Q96RI1 , and LXR . Finally , NF - kappaB can regulate CYP activity at post - transcriptional level by inducing heme oxygenase or by affecting the CYP protein stability . In addition , increased inflammatory mediators , oxidative stress , and subsequent NF - kappaB activation have been demonstrated in many conditions such as inflammatory bowel diseases , rheumatoid arthritis , psychological stress , diabetes , aging , cancer , renal diseases , and congestive heart failure . Meanwhile , there is a significant alteration of CYP expression and activity in these diseases . Therefore , we propose that NF - kappaB could be one of the links between inflammation , oxidative stress , and CYP regulation in these diseases . In conclusion , NF - kappaB plays a crucial role in the regulation of CYP through several mechanisms and this role can explain the altered CYP regulation in many conditions ." ]

[ "___MASK17___", "___MASK36___", "___MASK49___", "___MASK61___", "___MASK75___", "___MASK80___", "___MASK82___", "___MASK88___", "___MASK8___" ]

[ "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK96___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "Investigation of P25116 - type thrombin receptors in rat glioma P13671 cells with a novel monoclonal anti - P25116 antibody ( Mab COR7 - 6H9 ) . Rat glioma P13671 cells have been demonstrated to be a suitable model in the investigation of P25116 - type thrombin receptors in brain . However , anti - P25116 antibodies , which should be very helpful tools in studying P25116 in rat cells , have not been available up until now . Therefore , we prepared a monoclonal anti - thrombin receptor antibody ( Mab COR7 - 6H9 ) directed against the peptide sequence GRAVYLNKSRFPPMPPPPFISEDASG in the N - terminus below the thrombin cleavage site of the rat P25116 - type thrombin receptor . Using this antibody , we demonstrated the presence of P25116 binding sites on the plasma membrane of rat glioma P13671 cells both with confocal laser fluorescence and with scanning electron microscopy . In addition , Mab COR7 - 6H9 was shown to block P25116 - mediated transmembranal signaling as demonstrated by measurement of free intracellular calcium and cyclic AMP . This novel anti - P25116 antibody is therefore likely to be a very helpful tool in studying P25116 - type thrombin receptors in rat brain .", "Immunogenicity of a recombinant Mycobacterium bovis bacille Calmette - Guèrin expressing malarial and tuberculosis epitopes . Recombinant Mycobacterium bovis bacille Calmette - Guèrin ( rBCG ) expressing the malarial epitopes P25116 ( II ) EBA and ( Q8TBE9 ) 3 as well as two T cell epitopes of the M . tuberculosis ESAT - 6 antigen , generated in favour of mycobacterium codon usage elicited specific immune response against these epitopes . Immunised Balb / c mice demonstrated an increase in almost all of the IgG subclasses against both malarial epitopes and enhanced splenocyte proliferative response against the malarial epitopes as well as selected peptides of ESAT - 6 . Furthermore , flow cytometric analyses showed elevated numbers of P01730 + lymphocytes expressing P01579 and P60568 against the ESAT - 6 peptides , suggesting a specific Th1 - mediated response . This study demonstrated that expressing malarial and TB epitopes in a single rBCG construct induced appropriate humoral and cellular immune response against immunogenic epitopes from both organisms .", "P25116 antagonists : current state of evidence . DB09030 ( P35240 530348 ) and atopaxar ( E5555 ) are oral protease - activated receptor - 1 ( P25116 ) antagonists with high bioavailability . They inhibits thrombin induced platelet aggregation by competitively inhibiting P25116 . We systematically evaluated the evidence for the efficacy and safety of all P25116 antagonists as well as for the individual drugs vorapaxar and atopaxar in different databases - PubMed , EMBASE , Scopus , and Cochrane register of Controlled Clinical Trials ( CENTRAL ). We selected randomized controlled trials of P25116 antagonists that reported on cardiovascular mortality as a clinical outcome . The random - effects Mantel - Haenszel model was used to evaluate the effect of P25116 antagonists on cardiovascular mortality . Seven trials were selected ( N = 42 , 355 ) for analysis . P25116 antagonists as a class , as well as individually , were associated with a non - significant numerically lower risk of cardiovascular mortality than that seen with agents used in the control group ; RR , 0 . 93 ; 95 % CI , 0 . 83 - 1 . 04 ; P = 0 . 20 ) . No heterogeneity was noted . However , P25116 antagonists also appeared to increase the risk of bleeding significantly . P25116 antagonists appear to be associated with some reduction in the risk of cardiovascular mortality ; however the significantly higher bleeding risk noted with P25116 antagonists appear to mandate a very careful selection of patients that may benefit without a substantially increased risk of bleeds .", "Thrombin induces osteoprotegerin synthesis via phosphatidylinositol 3 '- kinase / mammalian target of rapamycin pathway in human periodontal ligament cells . BACKGROUND AND OBJECTIVE : Thrombin influences the biological behavior of periodontal ligament cells and plays multiple roles in the early stages of bone healing . O00300 ( O00300 ) is one of the key molecules that regulate bone homeostasis and prevent osteoclastogenesis . The purpose of this study was to evaluate the biological effects of thrombin on O00300 synthesis in human periodontal ligament ( Q96IR7 ) cells in vitro . MATERIAL AND METHODS : Cells were treated with various concentrations ( 0 . 001 , 0 . 01 and 0 . 1 U / mL ) of thrombin . The mRNA expression and protein synthesis of O00300 , as well as of receptor activator of nuclear factor kappaB ligand ( O14788 ) , were determined by reverse transcriptase - polymerase chain reaction ( RT - PCR ) and Western blot analysis , respectively . The influence of thrombin on O00300 synthesis and its signaling pathway were investigated using inhibitors . RESULTS : Thrombin profoundly induces protein synthesis of O00300 at 0 . 1 U / mL . The inductive effect was inhibited by cycloheximide , but not by indomethacin . The phosphatidylinositol 3 '- kinase ( PI3K ) inhibitor , LY294002 , and the mammalian target of rapamycin ( P42345 ) inhibitor , rapamycin , exerted an inhibitory effect on the thrombin - induced O00300 synthesis . In addition , the effect was inhibited by protease - activated receptor ( PAR ) - 1 antagonist . Activation of phospho - Akt ( p - Akt ) was observed and the effect was abolished by LY294002 . CONCLUSION : Thrombin induces O00300 synthesis in Q96IR7 cells post - transcriptionally , possibly through P25116 . The regulation was through the PI3K / Akt and P42345 pathway . This finding suggests that thrombin may play a significant role in alveolar bone repair and homeostasis of periodontal tissue , partly through the O00300 / O14788 system .", "DB09030 : first global approval . DB09030 [ DB09030 (®) ( US ) ] , an orally active protease - activated receptor - 1 ( P25116 ) receptor antagonist , has been developed by Merck & Co for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction ( MI ) or peripheral arterial disease ( PAD ) . DB09030 has received its first global approval for this indication in the US . This article summarizes the milestones in the development of vorapaxar leading to this first approval for the reduction of thrombotic cardiovascular events in patients with a prior MI or PAD .", "DB09030 : a novel protease - activated receptor - 1 inhibitor . INTRODUCTION : Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences . AREAS COVERED : Only 20 % relative risk ( ∼ 2 % absolute risk ) reduction associated with newer P2Y ( 12 ) receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet - mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy . Therefore , inhibition of the thrombin - protease - activated receptor ( PAR ) - 1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients . There are two major P25116 blockers are under investigations - vorapaxar and atopaxar . In preclinical and Phase I - II studies , inhibition of thrombin - mediated platelet activation by a P25116 inhibitor , in general , has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding . However , intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns . EXPERT OPINION : At this time , the specific role of P25116 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome , both during the acute setting and as a long - term therapeutic agent , is not clear . Although the P25116 inhibitors are associated with less bleeding , its effectiveness as an antithrombotic agent and also side effects are major concerns . Future large - scale trials with goals addressing these concerns are needed to define the specific role of P25116 receptor inhibitor .", "DB09030 expands antiplatelet options . Which patients may benefit from thrombin receptor antagonism ? DB09030 is the first substance of a new class of antiplatelet drugs that has been tested in large clinical trials . The protease - activated receptor 1 ( P25116 ) antagonist inhibits thrombin - induced platelet activation to prevent atherothrombosis . In the phase 3 trials TRACER ( acute coronary syndrome ) and TRA 2P - TIMI 50 ( stable atherosclerosis ) reducing ischemic events with vorapaxar came at the cost of bleeding . TRACER compared vorapaxar to placebo in 12 , 944 patients who had non - ST - segment elevation acute coronary syndromes on top of contemporary treatment including dual antiplatelet therapy ( aspirin and clopidogrel ) . DB09030 reduced ischemic events non - significantly , but increased bleeding significantly , therefore not justifying triple antiplatelet therapy in this setting . Follow - up was stopped early because of bleeding . TRA 2P - TIMI 50 examined 26 , 449 patients who had a history of myocardial infarction , ischemic stroke , or peripheral arterial disease . DB09030 reduced ischemic events and increased bleeding both significantly . Recruitment of patients with prior stroke was stopped early . Net clinical outcome and subgroup analyses suggested that vorapaxar could be beneficial for patients with prior myocardial infarction - but no history of stroke .", "Pharmacokinetics of the novel P25116 antagonist vorapaxar in patients with hepatic impairment . PURPOSE : To determine whether hepatic impairment has an effect on the pharmacokinetics ( PK ) of vorapaxar or M20 , its main pharmacologically active metabolite . METHODS : This was an open - label study in which a single 40 - mg oral dose of vorapaxar was administered to patients with mild ( n = 6 ) , moderate ( n = 6 ) , and severe ( n = 4 ) hepatic impairment and healthy controls ( n = 16 ) matched for age , gender , weight , and height . Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose . RESULTS : Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls . Group mean values for vorapaxar C ( max ) and AUC ( tf ) were 206 - 279 ng / mL and 14 , 200 - 18 , 200 ng · h / mL , respectively , with the lowest values observed in patients with severe impairment . DB09030 median T ( max ) and mean t ( 1 / 2 ) values were 1 . 00 - 1 . 75 h and 298 - 366 h , respectively . There was no apparent correlation between vorapaxar or M20 exposure or t ( 1 / 2 ) values and disease severity . DB09030 was generally well tolerated ; one serious adverse event ( gastrointestinal bleeding secondary to ruptured esophageal varices ) was reported in a patient with severe hepatic impairment . CONCLUSIONS : Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20 . No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment . Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment , administration of vorapaxar to such patients is not recommended given their bleeding diathesis .", "No differences in the pharmacodynamics and pharmacokinetics of the thrombin receptor antagonist vorapaxar between healthy Japanese and Caucasian subjects . BACKGROUND : DB09030 , a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease , is a potent , orally bioavailable thrombin receptor antagonist selective for the protease - activated receptor 1 ( P25116 ) . METHODS : Since race / ethnicity may affect the safety , efficacy and dosage of drugs , this study was conducted to evaluate potential differences in the pharmacodynamics , pharmacokinetics and safety of vorapaxar after single ( 5 , 10 , 20 , or 40 mg ) or multiple ( 0 . 5 , 1 , or 2 . 5 mg once daily ) doses in healthy Japanese and matched ( gender , age , height , and weight ) Caucasian volunteers . RESULTS : DB09030 was well tolerated in both Japanese and Caucasian subjects . Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial / ethnic groups were similar . In both racial groups , complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40 mg and was consistently achieved and maintained with a 2 . 5 mg daily maintenance dose . CONCLUSION : There were no substantial differences in the safety , pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects .", "___MASK30___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK30___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK30___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK30___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .", "Pharmacodynamics and pharmacokinetics of the novel P25116 antagonist vorapaxar ( formerly P35240 530348 ) in healthy subjects . PURPOSE : The aim of our study was to evaluate the pharmacology of vorapaxar ( P35240 530348 ) , an oral P25116 antagonist , in healthy volunteers . METHODS AND RESULTS : In two randomized , placebo - controlled studies , subjects received either single ascending doses of vorapaxar ( 0 . 25 , 1 , 5 , 10 , 20 , or 40 mg ; n = 50 ) , multiple ascending doses of vorapaxar ( 1 , 3 , or 5 mg / day for 28 days ; n = 36 ) , a loading dose ( 10 or 20 mg ) followed by daily maintenance doses ( 1 mg ) for 6 days ( n = 12 ) , or placebo . Single 20 - and 40 - mg doses of vorapaxar completely inhibited thrombin receptor activating peptide ( TRAP ) - induced platelet aggregation ( > 80 % inhibition ) at 1 h and sustained this level of inhibition for ≥ 72 h . Multiple doses yielded complete inhibition on Day 1 ( 5 mg / day ) and Day 7 ( 1 and 3 mg / day ) . Adverse events were generally mild , transient , and unrelated to dose . CONCLUSION : DB09030 provided rapid and sustained dose - related inhibition of platelet aggregation without affecting bleeding or clotting times .", "Activation of proteinase - activated receptor - 1 inhibits neurally evoked chloride secretion in the mouse colon in vitro . The proteinase - activated thrombin receptor - 1 ( P25116 ) belongs to a unique family of G protein - coupled receptors activated by proteolytic cleavage . We studied the effect of P25116 activation in the regulation of ion transport in mouse colon in vitro . Expression of P25116 in mouse colon was assessed by RT - PCR and immunohistochemistry . To study the role of P25116 activation in chloride secretion , mouse colon was mounted in Ussing chambers . Changes in short - circuit current ( Isc ) were measured in tissues exposed to either thrombin , saline , the P25116 - activating peptide TFLLR - NH2 , or the inactive reverse peptide RLLFT - NH2 , before electrical field stimulation ( O43281 ) . Experiments were repeated in the presence of either a P25116 antagonist or in P25116 - deficient mice to assess receptor specificity . In addition , studies were conducted in the presence of chloride - free buffer or the muscarinic antagonist atropine to assess chloride dependency and the role of cholinergic neurons in the P25116 - induced effect . P25116 mRNA was expressed in full - thickness specimens and mucosal scrapings of mouse colon . P25116 immunoreactivity was found on epithelial cells and on neurons in submucosal ganglia where it was colocalized with both P01282 and neuropeptide Y . After P25116 activation by thrombin or TFLLR - NH2 , secretory responses to O43281 but not those to forskolin or carbachol were significantly reduced . The reduction in the response to O43281 was not observed in the presence of the P25116 antagonist , in P25116 - deficient mice , when chloride was excluded from the bathing medium , or when atropine was present . P25116 is expressed in submucosal ganglia in the mouse colon and its activation leads to a decrease in neurally evoked epithelial chloride secretion .", "Colocalization of thrombin , P05121 , and vitronectin in the atherosclerotic vessel wall : A potential regulatory mechanism of thrombin activity by P05121 / vitronectin complexes . The serine protease thrombin is a mitogen for vascular smooth muscle cells . To that end , thrombin cleaves the surface - exposed , protease - activated receptor type 1 ( P25116 ) , resulting in signal transduction and ultimately , proliferation of these cells . Regulation of thrombin activity in the human atherosclerotic vessel wall has not been studied in great detail , conceivably because the traditional plasma thrombin inhibitor , anti - thrombin III , is not encountered at this location . By using immunofluorescence confocal microscopy , we demonstrate that the antigens of thrombin , plasminogen activator inhibitor 1 ( P05121 ) , and vitronectin ( Vn ) colocalize in human neointimal atherosclerotic arterial tissue . Furthermore , it is shown by in situ reverse zymography that these specimens harbor the active form of P05121 , which is the only configuration of P05121 capable of complexing with Vn and inhibiting serine proteases , eg , thrombin . Two different criteria were used to establish that neointimal atherosclerotic material contains active alpha - thrombin , namely , its ability to bind to the thrombin inhibitor hirudin and to convert the thrombin - specific chromogenic substrate S2238 . The latter activity could be fully prevented by preincubation with the thrombin - specific inhibitor , phenyl - prolyl - arginyl - chloromethyl ketone . The thrombin concentration measured by conversion of the chromogenic substrate was 7 to 12 nmol / L in the vascular specimens studied . This concentration range suffices to activate the P25116 receptor on vascular smooth muscle cells and to cause neointimal proliferation . It is concluded that the human atherosclerotic arterial vessel wall provides conditions that favor a regulatory mechanism of thrombin activity by P05121 / Vn complexes .", "___MASK46___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .", "Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK32___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .", "Molecular insights and therapeutic targets for blood - brain barrier disruption in ischemic stroke : critical role of matrix metalloproteinases and tissue - type plasminogen activator . Blood - brain barrier ( BBB ) disruption , mediated through matrix metalloproteinases ( MMPs ) and other mechanisms , is a critical event during ischemic stroke . Tissue plasminogen activator ( tPA ) is the only FDA - approved thrombolytic therapy for acute ischemic stroke , but the efficacy and safety of its therapeutic application are limited by narrow treatment time windows and side effects . Thus , there is a pressing need to develop combinational therapy that could offset tPA side effects and improve efficacy in clinical practice . Recent experimental studies indicate that tPA has previously unidentified functions in the brain beyond its well - established thrombolytic activity , which might contribute to tPA - related side effects through MMPs ( mainly P14780 ) and several signaling pathways involved in P01130 - related protein ( Q14764 ) , activated protein C ( P25054 ) and protease - activated receptor 1 ( P25116 ) , platelet - derived growth factor C ( Q9NRA1 ) , and N - methyl - d - aspartate ( DB01221 ) receptor . Therapeutic targeting of MMPs and / or tPA - related signaling pathways might offer promising new approaches to combination therapies for ischemic stroke . This review provides an overview of the relationship between structural components and function of the BBB / neurovascular unit with respect to ischemic stroke . We discuss how MMPs and tPA contribute to BBB disruption during ischemic stroke and highlight recent findings of molecular signaling pathways involved in neurotoxicity of tPA therapy .", "DB09030 , an oral P25116 receptor antagonist , does not affect the pharmacokinetics and pharmacodynamics of warfarin . PURPOSE : DB09030 is an orally active protease - activated receptor 1 ( P25116 ) antagonist that inhibits thrombin - induced platelet aggregation . This open - label study assessed the pharmacokinetics and pharmacodynamics of single - dose warfarin in the presence / absence of multiple - dose vorapaxar in 12 healthy men . METHODS : Subjects received two treatments separated by ≥ 7 - day washout : Treatment A warfarin 25 mg ( Day 1 ) ; Treatment B vorapaxar 2 . 5 mg / day on Days 1 - 6 and vorapaxar 40 mg coadministered with warfarin 25 mg ( Day 7 ) . R - warfarin , S - warfarin , and prothrombin time ( PT ) were assayed predose and up to 120 h postdose . RESULTS : The geometric mean ratio ( GMR ) as a percentage ( warfarin + vorapaxar / warfarin ) was calculated . The GMR ( 90 % CIs ) estimates of C ( max ) were 105 ( 99 , 111 ) and 105 ( 99 , 112 ) for R - and S - warfarin , respectively . The GMR ( 90 % CIs ) estimates of AUC ( 0 -∞) were 108 ( 101 , 116 ) and 105 ( 96 , 115 ) for R - and S - warfarin , respectively . The GMR ( 95 % CIs ) estimates of AUC ( 0 - 120 h ) for PT and INR were 97 ( 95 , 98 ) and 96 ( 94 , 98 ) , respectively . CONCLUSION : Results of this study indicate that vorapaxar has no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin , suggesting that the coadministration of these two drugs or vorapaxar coadministered with other P11712 / P33261 substrates is unlikely to cause a clinically significant pharmacokinetic drug interaction .", "Safety of the novel protease - activated receptor - 1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke . BACKGROUND : DB09030 , formerly P35240 530348 , is a novel , orally active , potent thrombin receptor inhibitor selective for the protease - activated receptor - 1 ( P25116 ) . Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events , particularly myocardial infarction , without increasing bleeding risk . The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin . METHODS : Ninety patients with previous ischemic stroke ( ≥ 14 days to < 1 year before randomization ) were randomized to receive vorapaxar ( 1 or 2 . 5 mg ) or placebo once daily for 60 days . All patients received aspirin ( 75 - 150 mg / day ) . The primary endpoint was overall incidence of adverse events during the protocol - defined treatment phase ( 60 days ) . RESULTS : Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events , including serious adverse events . None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo . Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar . CONCLUSIONS : DB09030 used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke .", "P37840 activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease - activated receptor - 1 . The mutation or overexpression of alpha - synuclein protein plays a pivotal role in the pathogenesis of Parkinson ' s disease . In our preliminary experiments , we found that alpha - synuclein induced the expression of matrix metalloproteinases ( MMPs ) ( P03956 , - 3 , - 8 , and - 9 ) in rat primary cultured microglia . Thus , the current study was undertaken to determine the roles of MMPs in alpha - synuclein - induced microglial activation . The inhibition of P08254 , - 8 , or - 9 significantly reduced NO and reactive oxygen species levels and suppressed the expression of P01375 and IL - 1beta . Notably , P22894 inhibitor suppressed P01375 production more efficaciously than P08254 or P14780 inhibitors . Inhibition of P08254 or - 9 also suppressed the activities of MAPK , NF - kappaB , and AP - 1 . Previously , protease - activated receptor - 1 ( P25116 ) has been associated with the actions of MMPs , and thus , we further investigated the role of P25116 in alpha - synuclein - induced inflammatory reactions . A P25116 - specific inhibitor and a P25116 antagonist significantly suppressed cytokine levels , and NO and reactive oxygen species production in alpha - synuclein - treated microglia . Subsequent P25116 cleavage assay revealed that P08254 , - 8 , and - 9 , but not alpha - synuclein , cleaved the synthetic peptide containing conventional P25116 cleavage sites . These results suggest that MMPs secreted by alpha - synuclein - stimulated microglia activate P25116 and amplify microglial inflammatory signals in an autocrine or paracrine manner . Furthermore , our findings suggest that modulation of the activities of MMPs and / or P25116 may provide a new therapeutic strategy for Parkinson ' s disease .", "Clinical potential of vorapaxar in cardiovascular risk reduction in patients with atherosclerosis . DB09030 ( ZONTIVITY ™ , formerly known as P35240 530348 ) is a specific , orally active antagonist of the protease - activated receptor - 1 ( P25116 ) on platelets . It inhibits thrombin - induced platelet activation by binding to the ectodomain of P25116 . After animal studies and Phase II studies showed that vorapaxar sufficiently inhibits platelet activation without significantly increasing bleeding complications , safety and efficacy of vorapaxar were assessed in two large multicenter trials in patients with coronary artery disease and atherosclerosis . The Thrombin - Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndromes ( TRACER ) trial investigated safety and efficacy of vorapaxar in patients with an acute coronary syndrome without ST - segment elevation . The Trial to Assess the Effects of DB09030 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis - Thrombolysis In Myocardial Infarction 50 ( TRA 2 ° P - TIMI 50 ) investigated atherothrombotic events in patients with stable atherosclerosis . Results of both studies suggested that vorapaxar given in addition to standard antiplatelet therapy can reduce atherothrombotic events , but increases the risk of mild and moderate bleeding complications . This review article summarizes the main results of TRACER and TRA 2 ° P - TIMI 50 and suggests patient cohorts that might benefit from treatment with vorapaxar in addition to standard antiplatelet therapy .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "Store - operated Ca2 + entry ( SOCE ) induced by protease - activated receptor - 1 mediates Q13586 protein phosphorylation to inhibit SOCE in endothelial cells through AMP - activated protein kinase and p38β mitogen - activated protein kinase . The Ca ( 2 +) sensor Q13586 is crucial for activation of store - operated Ca ( 2 +) entry ( SOCE ) through transient receptor potential canonical and Orai channels . Q13586 phosphorylation serves as an \" off switch \" for SOCE . However , the signaling pathway for Q13586 phosphorylation is unknown . Here , we show that SOCE activates AMP - activated protein kinase ( AMPK ) ; its effector p38β mitogen - activated protein kinase ( p38β MAPK ) phosphorylates Q13586 , thus inhibiting SOCE in human lung microvascular endothelial cells . Activation of AMPK using 5 - aminoimidazole - 4 - carboxamide - 1 - β - d - ribofuranoside ( AICAR ) resulted in Q13586 phosphorylation on serine residues and prevented protease - activated receptor - 1 ( P25116 ) - induced Ca ( 2 +) entry . Furthermore , AICAR pretreatment blocked P25116 - induced increase in the permeability of mouse lung microvessels . Activation of SOCE with thrombin caused phosphorylation of isoform α1 but not α2 of the AMPK catalytic subunit . Moreover , knockdown of AMPKα1 augmented SOCE induced by thrombin . Interestingly , SB203580 , a selective inhibitor of p38 MAPK , blocked Q13586 phosphorylation and led to sustained Q13586 - puncta formation and Ca ( 2 +) entry . Of the three p38 MAPK isoforms expressed in endothelial cells , p38β knockdown prevented P25116 - mediated Q13586 phosphorylation and potentiated SOCE . In addition , inhibition of the SOCE downstream target P62158 kinase kinase β ( CaMKKβ ) or knockdown of AMPKα1 suppressed P25116 - mediated phosphorylation of p38β and hence Q13586 . Thus , our findings demonstrate that SOCE activates CaMKKβ - AMPKα1 - p38β MAPK signaling to phosphorylate Q13586 , thereby suppressing endothelial SOCE and permeability responses .", "Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK85___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .", "___MASK82___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK82___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK82___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .", "P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK29___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .", "___MASK34___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .", "Cleavage of protease - activated receptors on an immortalized oral epithelial cell line by Porphyromonas gingivalis gingipains . Porphyromonas gingivalis activates protease - activated receptors ( PARs ) on oral keratinocytes , resulting in downstream signalling for an innate immune response . Activation depends on P . gingivalis gingipains , but could be confounded by lipopolysaccharide signalling through Toll - like receptors . We therefore hypothesized that P . gingivalis cleaves oral keratinocyte PARs in an DB00125 - ( Rgp ) or Lys - ( Kgp ) gingipain - specific manner to upregulate pro - inflammatory cytokines . Immortalized human oral keratinocytes ( O14746 - 2 ) were incubated with wild - type P . gingivalis ( ATCC 33277 ) or strains from a panel of isogenic gingipain deletion mutants : Kgp - deficient ( Q9H4A3 129 ) ; Rgp - deficient ( Q9H4A3 133 ) ; or Kgp - and Rgp - deficient ( Q9H4A3 136 ) . After incubation with P . gingivalis , keratinocytes were probed with specific antibodies against the N - terminus of P25116 and P55085 . Using flow cytometry and immunofluorescence , receptor cleavage was marked by loss of specific antibody binding to the respective PARs . O14746 - 2 cells constitutively expressed high levels of P25116 and P55085 , and lower levels of PAR - 3 . P . gingivalis ATCC 33277 cleaved P25116 and P55085 in a dose - dependent manner , while the receptors were unaffected by the protease - negative double mutant ( Q9H4A3 136 ) at all m . o . i . tested . The single Kgp - negative mutant preferentially cleaved P25116 , whereas the Rgp - negative mutant cleaved P55085 . Wild - type or Kgp - negative mutant cleavage of P25116 upregulated expression of IL - 1alpha , IL - 1beta , P05231 and P01375 ; the Rgp - negative mutant did not modulate these cytokines . Selective cleavage of P25116 on oral epithelial cells by P . gingivalis Rgp therefore upregulates expression of pro - inflammatory cytokines .", "Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK80___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK80___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly ." ]

[ "___MASK29___", "___MASK30___", "___MASK32___", "___MASK34___", "___MASK46___", "___MASK80___", "___MASK82___", "___MASK85___", "___MASK96___" ]

[ "DB00360 regulation of P29474 redox function . DB00360 ( BH4 ) is an essential cofactor of nitric oxide synthase ( NOS ) . In the cardiovascular system , endothelial NOS ( P29474 ) has a major role in maintaining vascular tone and endothelial function , as well as in mediating many other vascular protective properties . Evidence from humans and animals have demonstrated that decreased BH4 bioavailability , with subsequent uncoupling of P29474 , has significant effects on the pathogenesis of endothelial dysfunction , which is a hallmark of vascular injury in cardiovascular disorders , including hypertension , hyperlipidemia , and diabetes . In this review , we discuss the synthesis of BH4 , its molecular mechanisms regulating P29474 coupling , the pathophysiologic roles of decreased BH4 bioavailability in cardiovascular diseases , and the potential therapeutic application of BH4 in clinics .", "Inhibition of suicidal erythrocyte death by nitric oxide . DB00435 ( NO ) is known to counteract apoptosis by S - nitrosylation of protein thiol groups . NO is generated and stored in erythrocytes , which may undergo eryptosis , a suicidal cell death similar to apoptosis of nucleated cells . Eryptosis is triggered by increased cytosolic Ca2 + activity and / or ceramide and characterized by cell shrinkage and phosphatidylserine exposure at the cell surface . The present study explored whether nitric oxide could interfere with the machinery underlying eryptosis . To this end , erythrocyte phosphatidylserine exposure ( annexin V - binding ) and cell volume ( forward scatter ) were determined by flow cytometry . The Ca2 + ionophore ionomycin ( 0 . 1 microM ) increased cytosolic Ca2 + activity , triggered annexin binding , and decreased forward scatter . The annexin binding and decrease of forward scatter but not the increase of cytosolic Ca2 + activity were reversed by the NO - donor nitroprusside ( 1 microM ) and papanonoate ( 100 microM ) . Higher concentrations of nitroprusside ( 0 . 1 and 1 mM ) stimulated eryptosis . DB09341 depletion , exposure to P13671 - ceramide ( 3 microM ) , hypertonic ( addition of 550 mM sucrose ) , and isotonic ( replacement of Cl - with gluconate ) cell shrinkage all triggered annexin V binding , effects all reversed by nitroprusside ( 1 microM ) . Dibutyryl - cGMP ( 1 mM ) blunted the ionomycin - but not the ceramide - induced annexin V binding . Ionomycin decreased protein nitrosylation and thioredoxin activity , effects reversed by the NO - donor papanonoate . Clearance of erythrocytes from circulating blood was significantly faster in P29474 knockout mice than in their wild - type littermates . In conclusion , nitric oxide participates in the regulation of erythrocyte survival , an effect partially mimicked by cGMP and paralleled by alterations of protein nitrosylation and thioredoxin activity .", "Sinusoidal endothelial cells as an early target for hepatic toxicants . Recent studies demonstrate that the hepatic sinusoidal endothelial cells ( SEC ) are a sensitive direct target for early toxicity to acetaminophen ( paracetamol , DB00316 ) and this toxicity is exacerbated following a single and multiple week - end type alcoholic binge ( s ) . SEC become swollen and begin to lose the ability to endocytose FITC - Q2LD37 , a ligand for the scavenger receptor , as early as 30 minutes after the administration of DB00316 . Gaps through the SEC appear to be formed by the destruction and / or coalescence of fenestrae and are seen as early as 2 hrs after the administration of DB00316 which is prior to any evidence of injury to parenchymal cells . The gaps permit red blood cells to penetrate into the Space of Disse . Subsequently , the sinusoid may collapse or disintegrate reducing blood flow . The gaps are larger and more frequent in ethanol binged animals subsequently treated with DB00316 . Similar gaps are seen in the early stages of hepatic venoocclusive disease . Administration of a NO donor or a P08253 and P14780 inhibitor minimizes endothelial injury and red blood cell penetration into the Space of Disse . The injury is exacerbated when an inhibitor of P29474 is administered and minimized when P35228 is inhibited suggesting a protective role for constitutive NO derived from SEC . Both NO and MMPs are known to affect the cytoskeleton of SEC which in turn affects the formation and maintenance of the fenestrae .", "Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK52___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK52___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .", "Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .", "[ The role of matrix metalloproteinases and their inhibitors in pathogenesis of pancreatic pseudocysts ] . The investigation was conducted in 47 patients , operated on for pancreatic pseudocysts ( PP ) . Activity of matrix metalloproteinases ( P14780 ) and content of their tissue inhibitor ( P16035 ) were determined in the blood serum for estimation of inflammatory factors , hypoxia severity and state of the pancreatic tissue reconstruction . High activity of P14780 and P16035 in presence of PP types I and II was noted in patients , what , probably , is caused by compensation reaction , directed towards inhibition of the collagen system destruction ( predominantly of collagen type IV ) and prevention of further reconstruction of pancreatic connective tissue . While progressing of pancreatic fibrosis the P14780 activity and the P16035 level have lowered in comparison with these indices while its absence . In PP type III the P14780 activity was by 83 . 6 % higher , than in a control group , but , by 51 . 4 and 35 . 1 % lower , than in PP types I and IV . In all the patients endothelial dysfunction with endothelial injury was observed , witnessed by significant rising of the P15692 content in the blood serum . It have created favorable conditions for pancreatic tissue remodeling while parenchymal defect have been constituted by tissue , owing lower level of organization , including a cicatricial one . In cases of cellular repeated affection more activation of pancreatic stellate cells and enhancement of production of extracellular matrix component were noted .", "Obesity and breast cancer : the roles of peroxisome proliferator - activated receptor - γ and plasminogen activator inhibitor - 1 . Breast cancer is the most prominent cancer among females in the United States . There are a number of risk factors associated with development of breast cancer , including consumption of a high - fat diet and obesity . P00747 activator inhibitor - 1 ( P05121 ) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer . As a key mediator of adipogenesis and regulator of adipokine production , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) is involved in P05121 expression from adipose tissue . We summarize the current knowledge linking Q07869 - γ and P05121 expression to high - fat diet and obesity in the risk of breast cancer .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .", "Janus - faced role of endothelial NO synthase in vascular disease : uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal . Endothelial NO synthase ( P29474 ) is the predominant enzyme responsible for vascular NO synthesis . A functional P29474 transfers electrons from NADPH to its heme center , where L - arginine is oxidized to L - citrulline and NO . Common conditions predisposing to atherosclerosis , such as hypertension , hypercholesterolemia , diabetes mellitus and smoking , are associated with enhanced production of reactive oxygen species ( ROS ) and reduced amounts of bioactive NO in the vessel wall . NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology . NADPH oxidase - derived superoxide avidly interacts with P29474 - derived NO to form peroxynitrite ( ONOO (-) ) , which oxidizes the essential NOS cofactor ( 6R -) DB00360 ( BH ( 4 ) ) . As a consequence , oxygen reduction uncouples from NO synthesis , thereby rendering NOS to a superoxide - producing pro - atherosclerotic enzyme . Supplementation with BH ( 4 ) corrects P29474 dysfunction in several animal models and in patients . Administration of high local doses of the antioxidant L - ascorbic acid ( vitamin C ) improves endothelial function , whereas large - scale clinical trials do not support a strong role for oral vitamin C and / or E in reducing cardiovascular disease . Statins , angiotensin - converting enzyme inhibitors and AT1 receptor blockers have the potential of reducing vascular oxidative stress . Finally , novel approaches are being tested to block pathways leading to oxidative stress ( e . g . protein kinase C ) or to upregulate antioxidant enzymes .", "P41597 - mediated antiinflammatory effects of endothelial tetrahydrobiopterin inhibit vascular injury - induced accelerated atherosclerosis . BACKGROUND : Vascular injury results in loss of endothelial nitric oxide ( NO ) , production of reactive oxygen species ( ROS ) , and the initiation of an inflammatory response . Both NO and ROS modulate inflammation through redox - sensitive pathways . DB00360 ( BH4 ) is an essential cofactor for endothelial nitric oxide synthase ( P29474 ) that regulates enzymatic synthesis of either nitric oxide or ROS . We hypothesized that endothelial BH4 is an important regulator of inflammation and vascular remodeling . METHODS AND RESULTS : Endothelium - targeted overexpression of P30793 ( P30793 ) , the rate limiting enzyme in BH4 synthesis , increased levels of tetrahydrobiopterin ( BH4 ) , reduced endothelial superoxide , improved P29474 coupling , and reduced vein graft atherosclerosis in transgenic P30793 / ApoE - KO mice compared to ApoE - KO controls . Immunohistochemistry using anti - MAC - 3 and MAC - 1 antibody staining revealed a marked reduction in vein graft macrophage content , as did RT - PCR expression of macrophage marker P34810 mRNA levels in P30793 / ApoE - KO mice . When we investigated the potential mediators of this reduction , we discovered that mRNA and protein levels of P13500 ( P13500 ) but not RANTES ( P13501 ) were significantly reduced in P30793 / ApoE - KO aortic tissue . Consistent with this finding we found a decrease in P41597 - mediated , but not P51681 - mediated , chemotaxis in vascular tissue and plasma samples from P30793 / ApoE - KO animals . CONCLUSIONS : Increased endothelial BH4 reduces vein graft neointimal hyperplasia and atherosclerosis through a reduction in vascular inflammation . These findings highlight the importance of P13500 / P41597 signaling in the response to vascular injury and identify novel pathways linking endothelial BH4 to inflammation and vascular remodeling .", "The role of tetrahydrobiopterin in superoxide generation from P29474 : enzymology and physiological implications . DB00360 ( BH4 ) is a ubiquitous pteridine metabolite that serves as a NOS cofactor . Recently , we showed that BH4 efficiently inhibits superoxide generation from the heme group at the oxygenase domain of P29474 . This role indicates that BH4 acts as a redox switch in the catalytic mechanism of the enzyme , which may have important consequences in the physiology of the endothelium . Here the mechanism by which BH4 inhibits superoxide release from P29474 and the \" uncoupling \" effects of oxidized BH4 metabolites are presented . The implications of the disparate actions of fully reduced and oxidized BH4 metabolites in the control of P29474 biochemistry are discussed in the light of clinical data indicating that BH4 levels are important in the regulation of superoxide levels and of endothelial reactivity .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "The P29474 cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis . In cirrhosis , intrahepatic endothelial dysfunction is one of the mechanisms involved in the increased resistance to portal blood flow and therefore in the development of portal hypertension . Endothelial nitric oxide synthase ( P29474 ) uncoupling due to deficiency of tetrahydrobiopterin ( BH4 ) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions . We examined whether P29474 uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis . Basal levels of tetrahydrobiopterin and guanosine triphosphate ( GTP ) - cyclohydrolase ( BH4 rate - limiting enzyme ) expression and activity were determined in liver homogenates of control and rats with CCl4 cirrhosis . Thereafter , rats were treated with tetrahydrobiopterin , and P29474 activity , NO bioavailability , assessed with a functional assay , and the vasodilator response to acetylcholine ( endothelial function ) were evaluated . Livers with cirrhosis showed reduced BH4 levels and decreased GTP - cyclohydrolase activity and expression , which were associated with impaired vasorelaxation to acetylcholine . DB00360 supplementation increased BH4 hepatic levels and P29474 activity and significantly improved the vasodilator response to acetylcholine in rats with cirrhosis . In conclusion , the impaired response to acetylcholine of livers with cirrhosis is modulated by a reduced availability of the P29474 cofactor , tetrahydrobiopterin . DB00360 supplementation improved the endothelial dysfunction of cirrhotic livers .", "[ Molecular mechanism of cardiovascular damage induced by aldosterone ] . Although the pro - inflammatory and pro - fibrotic actions of aldosterone on the vasculature have been reported , the effects and molecular mechanisms of aldosterone on endothelial function are yet to be determined . We investigated how aldosterone regulates endothelial nitric oxide synthase ( P29474 ) function in human umbilical vein endothelial cells ( HUVECs ) . HUVECs were incubated for 16 hrs with 10 (- 7 ) mol / l of aldosterone . The concentration of reactive oxygen species ( ROS ) was estimated by measuring DCF chemiluminescence . Signal transduction was estimated by Western immunoblots . Realtime RT - PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase - 1 ( P30793 ) and components of NAD ( P ) H oxidase . In order to eliminate the possible effect of the glucocorticoid receptor ( GR ) , and to emphasize the role of mineralocorticoid receptor ( MR ) , we used GR siRNA and knocked down GR expression in several experiments . NO output was estimated by intracellular cGMP concentration . ROS production increased significantly in aldosterone - treated HUVEC , but was abolished by pre - treatment with eplerenone . Transcripts of p47 ( phox ) were increased by aldosterone treatment . Vascular endothelial growth factor ( P15692 ) - induced P29474 DB00133 1177 but not Akt DB00133 473 phosphorylation levels were reduced significantly by pretreatment with aldosterone . Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of P29474 DB00133 1177 in aldosterone - treated cells , suggesting that protein phosphatase ( PP ) 2A was upregulated by aldosterone via MR . The decrease in NO output caused by aldosterone pretreatment was reversed significantly by either DB00360 ( BH ( 4 ) ) , P30793 overexpression , or p47 ( phox ) knockdown . These results suggest that aldosterone inhibits P29474 function through bimodal mechanisms of BH ( 4 ) deficiency and PP2A activation .", "Targeting endothelial and myocardial dysfunction with tetrahydrobiopterin . DB00360 ( BH ( 4 ) ) is an essential cofactor for aromatic amino acid hydroxylases and for all three nitric oxide synthase ( NOS ) isoforms . It also has a protective role in the cell as an antioxidant and scavenger of reactive nitrogen and oxygen species . Experimental studies in humans and animals demonstrate that decreased BH ( 4 )- bioavailability , with subsequent uncoupling of endothelial NOS ( P29474 ) plays an important role in the pathogenesis of endothelial dysfunction , hypertension , ischemia - reperfusion injury , and pathologic cardiac remodeling . Synthetic BH ( 4 ) is clinically approved for the treatment of phenylketonuria , and experimental studies support its capacity for ameliorating cardiovascular pathophysiologies . To date , however , the translation of these studies to human patients remains limited , and early results have been mixed . In this review , we discuss the pathophysiologic role of decreased BH ( 4 ) bioavailability , molecular mechanisms regulating its metabolism , and its potential therapeutic use as well as pitfalls as an NOS - modulating drug . This article is part of a special issue entitled '' Key Signaling Molecules in Hypertrophy and Heart Failure . ''", "The role of tetrahydrobiopterin and dihydrobiopterin in ischemia / reperfusion injury when given at reperfusion . Reduced nitric oxide ( NO ) bioavailability and increased oxidative stress are major factors mediating ischemia / reperfusion ( I / R ) injury . DB00360 ( BH ( 4 ) ) is an essential cofactor of endothelial NO synthase ( P29474 ) to produce NO , whereas dihydrobiopterin ( BH ( 2 ) ) can shift the P29474 product profile from NO to superoxide , which is further converted to hydrogen peroxide ( H ( 2 ) O ( 2 ) ) and cause I / R injury . The effects of BH ( 4 ) and BH ( 2 ) on oxidative stress and postreperfused cardiac functions were examined in ex vivo myocardial and in vivo femoral I ( 20 min ) / R ( 45 min ) models . In femoral I / R , BH ( 4 ) increased NO and decreased H ( 2 ) O ( 2 ) releases relative to saline control , and these effects correlated with improved postreperfused cardiac function . By contrast , BH ( 2 ) decreased NO release relative to the saline control , but increased H ( 2 ) O ( 2 ) release similar to the saline control , and these effects correlated with compromised postreperfused cardiac function . In conclusion , these results suggest that promoting P29474 coupling to produce NO and decrease H ( 2 ) O ( 2 ) may be a key mechanism to restore postreperfused organ function during early reperfusion .", "Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP - cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE - knockout mice . OBJECTIVE : Increased production of reactive oxygen species and loss of endothelial nitric oxide ( NO ) bioactivity are key features of vascular disease states such as atherosclerosis . DB00360 ( BH4 ) is a required cofactor for NO synthesis by endothelial nitric oxide synthase ( P29474 ) ; pharmacologic studies suggest that reduced BH4 availability may be an important mediator of endothelial dysfunction in atherosclerosis . We aimed to investigate the importance of endothelial BH4 availability in atherosclerosis using a transgenic mouse model with endothelial - targeted overexpression of the rate - limiting enzyme in BH4 synthesis , GTP - cyclohydrolase I ( GTPCH ) . METHODS AND RESULTS : Transgenic mice were crossed into an ApoE knockout ( ApoE - KO ) background and fed a high - fat diet for 16 weeks . Compared with ApoE - KO controls , transgenic mice ( ApoE - KO / P30793 - P01266 ) had higher aortic BH4 levels , reduced endothelial superoxide production and P29474 uncoupling , increased cGMP levels , and preserved NO - mediated endothelium dependent vasorelaxations . Furthermore , aortic root atherosclerotic plaque was significantly reduced in ApoE - KO / P30793 - P01266 mice compared with ApoE - KO controls . CONCLUSIONS : These findings indicate that BH4 availability is a critical determinant of P29474 regulation in atherosclerosis and is a rational therapeutic target to restore NO - mediated endothelial function and reduce disease progression .", "P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK94___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .", "Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .", "DB00360 , a cofactor for NOS , improves endothelial dysfunction during chronic alcohol consumption . We sought to investigate mechanisms that may account for impaired nitric oxide synthase ( NOS ) - dependent dilatation of cerebral arterioles during alcohol consumption . Our goals were to examine 1 ) the effect of exogenous application of a cofactor for NOS , i . e . , tetrahydrobiopterin ( BH4 ) on the reactivity of pial arterioles during alcohol consumption ; and 2 ) endothelial NOS ( P29474 ) protein in nonalcohol - fed and alcohol - fed rats . Sprague - Dawley rats were fed liquid diets with or without alcohol for 2 - 3 mo . We measured in vivo diameter of pial arterioles in response to NOS - dependent agonists ( ACh and ADP ) and a NOS - independent agonist ( nitroglycerin ) before and during application of BH4 . Blood vessels were then harvested for Western blot analysis of P29474 protein . In nonalcohol - fed rats , ACh and ADP produced vasodilatation , which was impaired in alcohol - fed rats . Vasodilatation to nitroglycerin was similar in both groups of rats . Application of BH4 did not alter vasodilatation in nonalcohol - fed rats but improved impaired vasodilatation in alcohol - fed rats . Also , P29474 protein in cerebral cortex microvessels , the basilar artery , and aorta was not different between nonalcohol - fed and alcohol - fed rats . Thus impaired NOS - dependent vasodilatation during alcohol consumption does not appear to be related to an alteration in P29474 protein but may be related to a deficiency and / or alteration in the utilization of BH4 .", "Q07869 - α Agonist Fenofibrate Upregulates DB00360 Level through Increasing the Expression of DB02857 5 '- Triphosphate Cyclohydrolase - I in Human Umbilical Vein Endothelial Cells . DB00360 ( BH4 ) is an essential cofactor for endothelial nitric oxide ( NO ) synthase . DB02857 5 '- triphosphate cyclohydrolase - I ( GTPCH - I ) is a key limiting enzyme for BH4 synthesis . In the present in vitro study , we investigated whether peroxisome proliferator - activated receptor α ( Q07869 - α ) agonist fenofibrate could recouple P29474 by reversing low - expression of intracellular BH4 in endothelial cells and discussed the potential mechanisms . After human umbilical vein endothelial cells ( HUVECs ) were treated with lipopolysaccharide ( LPS ) for 24 hours , the levels of cellular P29474 , BH4 and cell supernatant NO were significantly reduced compared to control group . And the fluorescence intensity of intracellular ROS was significantly increased . But pretreated with fenofibrate ( 10 umol / L ) for 2 hours before cells were induced by LPS , the levels of P29474 , NO , and BH4 were significantly raised compared to LPS treatment alone . ROS production was markedly reduced in fenofibrate group than LPS group . In addition , our results showed that the level of intracellular GTPCH - I detected by western blot was increased in a concentration - dependent manner after being treated with fenofibrate . These results suggested that fenofibrate might help protect endothelial function and against atherosclerosis by increasing level of BH4 and decreasing production of ROS through upregulating the level of intracellular GTPCH - I .", "P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .", "DB00360 and P29474 dimer / monomer ratio -- a clue to P29474 uncoupling in diabetes ?", "Acute erythropoietin cardioprotection is mediated by endothelial response . Increasing evidence indicates that high levels of serum erythropoietin ( Epo ) can lessen ischemia - reperfusion injury in the heart and multiple cardiac cell types have been suggested to play a role in this Epo effect . To clarify the mechanisms underlying this cardioprotection , we explored Epo treatment of coronary artery endothelial cells and Epo cardioprotection in a Mus musculus model with Epo receptor expression restricted to hematopoietic and endothelial cells ( ΔEpoR ) . Epo stimulation of coronary artery endothelial cells upregulated endothelial nitric oxide synthase ( P29474 ) activity in vitro and in vivo , and enhanced nitric oxide ( NO ) production that was determined directly by real - time measurements of gaseous NO release . Epo stimulated phosphoinositide 3 - kinase ( PI3K ) / protein kinase B ( AKT ) and mitogen - activated protein kinase kinase ( MEK ) / extracellular signal regulated kinase ( P29323 ) signaling pathways , and inhibition of PI3K , but not MEK activity , blocked Epo - induced NO production . To verify the potential of this Epo effect in cardioprotection in vivo , ΔEpoR - mice with Epo response in heart restricted to endothelium were treated with Epo . These mice exhibited a similar increase in P29474 phosphorylation in coronary artery endothelium as that found in wild type ( WT ) mice . In addition , in both WT - and ΔEpoR - mice , exogenous Epo treatment prior to myocardial ischemia provided comparable protection . These data provide the first evidence that endothelial cell response to Epo is sufficient to achieve an acute cardioprotective effect . The immediate response of coronary artery endothelial cells to Epo stimulation by NO production may be a critical mechanism underlying this Epo cardioprotection .", "The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase : an EPR spin trapping study . Augmentation of superoxide levels has been linked to impaired relaxation in hypertension , diabetes and hypercholesterolaemia . Purified endothelial nitric oxide synthase ( P29474 ) generates superoxide under limited availability of DB00360 ( BH ( 4 ) ) . Thus alterations in endothelial BH ( 4 ) levels have been postulated to stimulate superoxide production from P29474 . This possibility was examined by determining the concentration - dependent effects of BH ( 4 ) , and its analogues , on superoxide formation by P29474 . Superoxide was quantified by EPR spin trapping , which is the only available technique to quantify superoxide from P29474 . Using 5 - ethoxycarbonyl - 5 - methyl - pyrroline N - oxide , we show that only fully reduced BH ( 4 ) diminished superoxide release from P29474 , with efficiency BH ( 4 ) > 6 - methyl - BH ( 4 ) > 5 - methyl - BH ( 4 ) . In contrast , partially oxidized BH ( 4 ) analogues , 7 , 8 - dihydrobiopterin ( 7 , 8 - BH ( 2 ) ) and sepiapterin had no effect . Neither l - arginine nor N ( G )- nitro - l - arginine methyl ester ( l - NAME ) abolished superoxide formation . Together , BH ( 4 ) and l - arginine stimulated . NO production at maximal rates of 148 nmol / min per mg of protein . These results indicate that BH ( 4 ) acts as a \" redox switch \" , decreasing superoxide release and enhancing . NO formation . This role was verified by adding 7 , 8 - BH ( 2 ) or sepiapterin to fully active P29474 . Both 7 , 8 - BH ( 2 ) and sepiapterin enhanced superoxide release while inhibiting DB00435 formation . Collectively , these results indicate that the ratio between oxidized and reduced BH ( 4 ) metabolites tightly regulates superoxide formation from P29474 . The pathological significance of this scenario is discussed .", "P30793 gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells : effects on nitric oxide synthase activity , protein levels and dimerisation . OBJECTIVES : DB00360 ( BH4 ) is an essential cofactor for endothelial nitric oxide synthase ( P29474 ) activity . BH4 levels are regulated by de novo biosynthesis ; the rate - limiting enzyme is P30793 ( GTPCH ) . BH4 activates and promotes homodimerisation of purified P29474 protein , but the intracellular mechanisms underlying BH4 - mediated P29474 regulation in endothelial cells remain less clear . We aimed to investigate the role of BH4 levels in intracellular P29474 regulation , by targeting the BH4 synthetic pathway as a novel strategy to modulate intracellular BH4 levels . METHODS : We constructed a recombinant adenovirus , AdGCH , encoding human GTPCH . We infected human endothelial cells with AdGCH , investigated the changes in intracellular biopterin levels , and determined the effects on P29474 enzymatic activity , protein levels and dimerisation . RESULTS : GTPCH gene transfer in EAhy926 endothelial cells increased BH4 > 10 - fold compared with controls ( cells alone or control adenovirus infection ) , and greatly enhanced NO production in a dose - dependent , P29474 - specific manner . We found that P29474 was principally monomeric in control cells , whereas GTPCH gene transfer resulted in a striking increase in P29474 homodimerisation . Furthermore , the total amounts of both native P29474 protein and a recombinant P29474 - GFP fusion protein were significantly increased following GTPCH gene transfer . CONCLUSIONS : These findings suggest that GTPCH gene transfer is a valid approach to increase BH4 levels in human endothelial cells , and provide new evidence for the relative importance of different mechanisms underlying BH4 - mediated P29474 regulation in intact human endothelial cells . Additionally , these observations suggest that GTPCH may be a rational target to augment endothelial BH4 and normalise P29474 activity in endothelial dysfunction states .", "Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension . DB00360 is a critical cofactor for the NO synthases , and in its absence these enzymes become \" uncoupled , \" producing reactive oxygen species ( ROSs ) rather than NO . In aortas of mice with deoxycorticosterone acetate - salt ( DOCA - salt ) hypertension , ROS production from NO synthase is markedly increased , and tetrahydrobiopterin oxidation is evident . Using mice deficient in the NADPH oxidase subunit p47 ( phox ) and mice lacking either the endothelial or neuronal NO synthase , we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase ( P29474 ) . This decreases NO production and increases ROS production from P29474 . Treatment of mice with oral tetrahydrobiopterin reduces vascular ROS production , increases NO production as determined by electron spin resonance measurements of nitrosyl hemoglobin , and blunts the increase in blood pressure due to DOCA - salt hypertension . Endothelium - dependent vasodilation is only minimally altered in vessels of mice with DOCA - salt hypertension but seems to be mediated by hydrogen peroxide released from uncoupled P29474 , since it is inhibited by catalase . DB00360 oxidation may represent an important abnormality in hypertension . Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease .", "Pulmonary hypertension in the newborn P30793 - deficient mouse . DB00360 ( BH4 ) is a regulator of endothelial nitric oxide synthase ( P29474 ) activity . Deficient levels result in P29474 uncoupling , with a shift from nitric oxide to superoxide generation . The hph - 1 mutant mouse has deficient P30793 ( GTPCH1 ) activity , resulting in low BH4 tissue content . The adult hph - 1 mouse has pulmonary hypertension , but whether such condition is present from birth is not known . Thus , we evaluated newborn animals ' pulmonary arterial medial thickness , biopterin content ( BH4 + BH2 ) , H ( 2 ) O ( 2 ) and P29474 , right ventricle - to - left ventricle + septum ( RV / LV + septum ) ratio , near - resistance pulmonary artery agonist - induced force , and endothelium - dependent and - independent relaxation . The lung biopterin content was inversely related to age for both types , but significantly lower in hph - 1 mice , compared to wild - type animals . As judged by the RV / LV + septum ratio , newborn hph - 1 mice have pulmonary hypertension and , after a 2 - week 13 % oxygen exposure , the ratios were similar in both types . The pulmonary arterial agonist - induced force was reduced ( P < 0 . 01 ) in hph - 1 animals and no type - dependent difference in endothelium - dependent or - independent vasorelaxation was observed . Compared to wild - type mice , the lung H ( 2 ) O ( 2 ) content was increased , whereas the P29474 expression was decreased ( P < 0 . 01 ) in hph - 1 animals . The pulmonary arterial medial thickness , a surrogate marker of vascular remodeling , was increased ( P < 0 . 01 ) in hph - 1 compared to wild - type mice . In conclusion , our data suggest that pulmonary hypertension is present from birth in the GTPCH1 - deficient mice , not as a result of impaired vasodilation , but secondary to vascular remodeling .", "Joint effects of P29474 gene T - 786C and P00325 Arg47His polymorphisms on the risk of premature coronary artery disease . INTRODUCTION : Both T - 786C mutation in endothelial nitric oxide synthase ( P29474 ) gene and alcohol dehydrogenase ( DB00067 ) gene polymorphism such as P00326 gamma1 / gamma2 have been reportedly associated with coronary artery disease ( CAD ) . Since P00325 Arg47His polymorphism is common in Asian population , the aim of this present study was to assess the interaction between P29474 gene T - 786C and P00325 Arg47His polymorphisms on premature CAD risk . MATERIALS AND METHODS : Hospital - based case - control study was conducted with 167 premature CAD and 235 late - onset CAD patients . Polymerase chain reaction restriction fragment length polymorphism was used to detect the polymorphisms . Multivariate logistic regression model was performed to adjust the potential confounders and estimate odds ratios ( ORs ) with 95 % confidence intervals ( CIs ) . Synergy index ( S ) was the measure to assess the interaction as departure from additivity . RESULTS : After the adjustment for the potential confounders , and compared with the carriers of TT and DB00125 / DB00125 as the reference , the ORs with 95 % CIs in parentheses of premature CAD were that 1 . 13 ( 0 . 19 - 6 . 59 ) for CT or CC and DB00125 / DB00125 carriers ; 2 . 24 ( 0 . 77 - 6 . 49 ) for TT and DB00125 / DB00117 or DB00117 / DB00117 carriers ; 4 . 18 ( 1 . 32 - 13 . 22 ) for CT or CC and DB00125 / DB00117 or DB00117 / DB00117 carriers , respectively . Based on those ORs , S was 2 . 32 ( 95 % CI : 0 . 37 - 14 . 72 ) . CONCLUSIONS : The mutant genotypes of P29474 gene T - 786C mutation and the fast form of P00325 Arg47His polymorphism had an additive interaction on the risk of premature CAD in Chinese population . Further investigations with big sample size are necessary for confirming this additive interaction .", "DB00360 as another EDRF in man . Endotoxin and inflammatory cytokines downregulate expression of constitutive nitric oxide synthase ( P29474 ) in human vascular endothelial cells with concomitant increase of tetrahydrobiopterin synthesis in these cells and parallel upregulation of inducible NOS expression in smooth muscle cells , indicating compartmentalized nitric oxide ( NO ) production under septic conditions in man . In this report the compartmentalization has been further studied using dual chamber cell cultures with inflammatory activated human endothelial cells . We show that endothelial cells secrete BH4 vectorially into the basal direction thereby providing underlining smooth muscle cells with the cofactor necessary for NO production . Furthermore , by laser Doppler velocimetry we show that intraarterial infusion of BH4 induces strong vasodilatation in man . Consumption of L - arginine and production of cyclic GMP increased and therefore imply NO as second messenger . Thus the discovery of an endothelium - derived factor regulating NOS activity would reconcile the concept of an inflammatory EDRF that is not NO itself but results in NO - dependent vasodilatation in man .", "DB09140 metabolism by endothelial nitric - oxide synthase . Nitric - oxide synthase ( NOS ) catalyzes both coupled and uncoupled reactions that generate nitric oxide and reactive oxygen species . DB09140 is often the overlooked substrate , and the oxygen metabolism catalyzed by NOS has been poorly defined . In this paper we focus on the oxygen stoichiometry and effects of substrate / cofactor binding on the endothelial NOS isoform ( P29474 ) . In the presence of both L - arginine and tetrahydrobiopterin , P29474 is highly coupled ( > 90 % ) , and the measured stoichiometry of O ( 2 )/ NADPH is very close to the theoretical value . We report for the first time that the presence of L - arginine stimulates oxygen uptake by P29474 . The fact that nonhydrolyzable L - arginine analogs are not stimulatory indicates that the occurrence of the coupled reaction , rather than the accelerated uncoupled reaction , is responsible for the L - arginine - dependent stimulation . The presence of DB00360 quenched the uncoupled reactions and resulted in much less reactive oxygen species formation , whereas the presence of redox - incompetent 7 , 8 - dihydrobiopterin demonstrates little quenching effect . These results reveal different mechanisms for oxygen metabolism for P29474 as opposed to P29475 and , perhaps , partially explain their functional differences .", "Glucocorticoids inhibit tetrahydrobiopterin - dependent endothelial function . DB00360 ( BH4 ) acts as an important co - factor for endothelial nitric oxide synthase ( P29474 ) . Glucocorticoids have been shown to inhibit expression of the rate - limiting enzyme for tetrahydrobiopterin synthesis , GTP cyclohydrolase , in other cell types . We hypothesized that endothelium - dependent vasodilator responses would be blunted in rats made hypertensive with dexamethasone . Further , we hypothesized that treatment of rat vascular segments with dexamethasone would result in attenuation of endothelial function accompanied by decreased GTP cyclohydrolase expression . We report that endothelium - dependent relaxation responses to the calcium ionophore A23187 are reduced in aortic rings from dexamethasone - hypertensive rats compared with sham values . Dexamethasone incubation abolishes contraction to Nomega - nitro - L - arginine ( DB04223 , 10 (- 5 ) M ) in endothelium - intact aortic rings , and inhibits expression of GTP cyclohydrolase . We conclude that inhibition of BH4 synthesis by glucocorticoid regulation of GTP cyclohydrolase expression may contribute to reduced endothelium - dependent vasodilation characteristic of glucocorticoid - induced hypertension .", "Relationship between tetrahydrobiopterin and portal hypertension in patients with chronic liver disease . DB00360 ( BH4 ) is an essential cofactor in NO synthesis by endothelial nitric oxide synthase ( P29474 ) enzymes . It has been previously suggested that reduced intrahepatic BH4 results in a decrease in intrahepatic NO and contributes to increased hepatic vascular resistance and portal pressure in animal models of cirrhosis . The main aim of the present study was to evaluate the relationship between BH4 and portal hypertension ( PHT ) . One hundred ninety - three consecutive patients with chronic liver disease were included in the study . Liver biopsy , measurement of BH4 and hepatic venous pressure gradient ( HVPG ) were performed . Hepatic fibrosis was classified using the Laennec fibrosis scoring system . BH4 levels were determined in homogenized liver tissues of patients using a high performance liquid chromatography ( HPLC ) system . Statistical analysis was performed to evaluate the relationship between BH4 and HVPG , grade of hepatic fibrosis , clinical stage of cirrhosis , Child - Pugh class . A positive relationship between HVPG and hepatic fibrosis grade , clinical stage of cirrhosis and Child - Pugh class was observed . However , the BH4 level showed no significant correlation with HVPG or clinical features of cirrhosis . BH4 concentration in liver tissue has little relation to the severity of portal hypertension in patients with chronic liver disease .", "DB00360 prevents endothelial dysfunction and restores adiponectin levels in rats . Oxidative stress induces endothelial dysfunction and hypoadiponectinemia . We previously reported that supplementation with tetrahydrobiopterin ( BH4 ) , one of the most potent naturally occurring reducing agents and an essential cofactor of enzymatic NO synthase ( NOS ) , ameliorates endothelial dysfunction and reverses hypoadiponectinemia as a result of oxidative stress in rats . To further confirm this hypothesis , we investigated the effects of treatment with BH4 on endothelium - dependent relaxation and adiponectin levels during oxidative stress in fructose - fed rats , which provide an animal model for the metabolic syndrome . Ingestion of a fructose diet for 8 weeks significantly impaired endothelium - dependent arterial relaxation in aortic strips and decreased plasma adiponectin levels , as well as adiponectin mRNA levels within adipose tissue . However , oral supplementation with BH4 ( 10 mg / kg day ) over the final 4 weeks leads to a significant partial reversal of impaired endothelium - dependent arterial relaxation , as well as normalization of plasma adiponectin and fat adiponectin mRNA levels . Moreover , BH4 treatment of the fructose - fed rats significantly reduced the lipid peroxidation content of aorta , heart , liver , and kidney tissues , which were increased in fructose - fed rats . This effect of BH4 treatment may be due to its function as a cofactor for P29474 , as well as its anti - oxidative effects . Thus , BH4 might show promise for the treatment of oxidative stress - induced disorders , including the metabolic syndrome .", "Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity . Although the proinflammatory and profibrotic actions of aldosterone ( Aldo ) on the vasculature have been reported , the effects and molecular mechanisms of Aldo on endothelial function are yet to be determined . We investigated how Aldo regulates endothelial NO synthase ( P29474 ) function in human umbilical vein endothelial cells ( HUVECs ) . HUVECs were incubated for 16 hours with Aldo 10 (- 7 ) mol / L . The concentration of reactive oxygen species was estimated by measuring 2 ', 7 '- dichlorodihydrofluorescein diacetate chemiluminescence . Signal transduction was estimated by Western immunoblots . Real - time RT - PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase - 1 and components of reduced nicotinamide - adenine dinucleotide phosphate oxidase . To eliminate the possible effect of the glucocorticoid receptor ( GR ) and to emphasize the role of mineralocorticoid receptor , we used GR small interfering RNA and knocked down GR expression in several experiments . NO output was estimated by intracellular cGMP concentration . Reactive oxygen species production increased significantly in Aldo - treated HUVECs but was abolished by pretreatment with eplerenone . Transcripts of p47 ( phox ) were increased by Aldo treatment . Vascular endothelial growth factor - induced P29474 DB00133 1177 but not Akt DB00133 473 phosphorylation levels were reduced significantly by pretreatment with Aldo . Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of P29474 DB00133 1177 in Aldo - treated cells , suggesting that protein phosphatase 2A was upregulated by Aldo via mineralocorticoid receptor . The decrease in NO output caused by Aldo pretreatment was reversed significantly by DB00360 , GTP cyclohydrolase - 1 overexpression , or p47 ( phox ) knockdown . These results suggest that Aldo inhibits P29474 function through bimodal mechanisms of DB00360 deficiency and protein phosphatase 2A activation .", "DB00360 : a critical cofactor for P29474 and a strategy in the treatment of endothelial dysfunction ?", "Functional comparison of the endothelial nitric oxide synthase Glu298Asp polymorphic variants in human endothelial cells . The G894T endothelial nitric oxide synthase ( P29474 ) polymorphism results in a DB00142 to DB00128 substitution at position 298 . This position is located externally on the protein and as the regulation of P29474 is dependent on its subcellular localization and interaction with modulatory proteins , we aimed to address whether the substitution of DB00128 at 298 had any effect on these mechanisms . Initially , we developed a novel method to accurately determine molar quantities of each variant by expressing them as green fluorescent protein ( GFP ) fusion proteins and using recombinant adenoviruses to facilitate transient infection of human microvascular endothelial cells . DB00815 - polyacrylamide gel electrophoresis and Western blotting of eNOSAsp revealed a 135 - kDa proteolytic fragment which was not present with eNOSGlu . This proteolysis was prevented by using LDS buffer confirming that this differential cleavage is an artefact of sample preparation and unlikely to occur intracellularly . DB00435 was measured following stimulation with calcium ionophore or oestrogen in the presence of varying sepiapterin concentrations . GFP fluorescence was used to quantify the amount of fusion protein and calculate intracellular specific activity . There was no significant difference in intracellular specific activity between DB00142 and DB00128 P29474 in response to calcium ionophore or oestrogen . DB00360 supplementation increased P29474 activity of both variants in an identical manner . The presence of the GFP also facilitated the visualization of the variants by confocal microscopy and demonstrated that both localized to the plasma membrane and the Golgi . These findings demonstrate that the DB00128 substitution at 298 does not have a major effect in modulating P29474 activity in vivo .", "[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK45___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .", "Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK45___ and Tissue P00747 Activator in Occluded Arteries .", "DB00360 , but not L - arginine , decreases NO synthase uncoupling in cells expressing high levels of endothelial NO synthase . Endothelial NO synthase ( P29474 ) produces superoxide when depleted of ( 6R ) - 5 , 6 , 7 , 8 - tetrahydro - L - biopterin ( BH4 ) and L - arginine by uncoupling the electron flow from NO production . High expression of P29474 has been reported to have beneficial effects in atherosclerotic arteries after relatively short periods of time . However , sustained high expression of P29474 may have disadvantageous vascular effects because of uncoupling . We investigated NO and reactive oxygen species ( ROS ) production in a microvascular endothelial cell line ( bEnd . 3 ) with sustained high P29474 expression and absent inducible NOS and neuronal NOS expression using 4 , 5 - diaminofluorescein diacetate and diacetyldichlorofluorescein as probes , respectively . Unstimulated cells produced both NO and ROS . After stimulation with vascular endothelial growth factor ( P15692 ) , NO and ROS production increased . P15692 - induced ROS production was even further increased by the addition of extra L - arginine . Nomega - nitro - L - arginine methyl ester decreased ROS production . These findings strongly suggest that P29474 is a source of ROS in these cells . Although BH4 levels were increased as compared with another endothelial cell line , P29474 levels were > 2 orders of magnitude higher . The addition of BH4 resulted in increased NO production and decreased generation of ROS , indicating that bEnd . 3 cells produce ROS through P29474 uncoupling because of relative BH4 deficiency . Nevertheless , P29474 - dependent ROS production was not completely abolished by the addition of BH4 , suggesting intrinsic superoxide production by P29474 . This study indicates that potentially beneficial sustained increases in P29474 expression and activity could lead to P29474 uncoupling and superoxide production as a consequence . Therefore , sustained increases of P29474 or P15692 activity should be accompanied by concomitant supplementation of BH4 .", "[ Moclobemide ( ___MASK77___ ) , the first P21397 - inhibitor : really something new ? ] .", "Toona sinensis ( leaf extracts ) inhibit vascular endothelial growth factor ( P15692 ) - induced angiogenesis in vascular endothelial cells . AIM OF THE STUDY : Toona sinensis is well known as a traditional Chinese medicine ; also , it has been shown to exhibit anticancer and anti - inflammatory effects . This study was aimed at evaluating the anti - angiogenesis effect of the aqueous extracts of Toona sinensis ( TS extracts ) or gallic acid , a major component of TS extracts , against both P15692 - induced EA . hy 926 and human umbilical vein endothelial cells ( HUVECs ) . MATERIALS AND METHODS : Anti - proliferative activity of TS extracts or gallic acid , was determined against EA . hy 926 and HUVECs by trypan blue exclusion method . Invasion , tube formation and chick chorioallantoic membrane assay were carried out to determine the in vitro and in vivo anti - angiogenic effects . RESULTS : Non - cytotoxic concentration of TS extracts ( 50 - 100μg / mL ) and gallic acid ( 5μg / mL ) inhibited the proliferation of P15692 - stimulated EA . hy 926 and HUVECs . Inhibitory effects of TS extracts and gallic acid on angiogenesis were assessed by P15692 - induced migration / invasion and capillary - like tube formation by EA . hy 926 and HUVECs . Additionally , gelatin zymography assays showed that TS extracts and gallic acid suppressed the activity of metalloproteinase ( MMP ) - 9 and P08253 activated by P15692 . In vivo , TS extracts and gallic acid strongly suppressed neovessel formation in the chorioallantoic membrane of chick embryos . Flow cytometry analyses and Western blot demonstrated that treatment with TS extracts and gallic acid induced G ( 0 )/ G ( 1 ) arrest in P15692 - stimulated EA . hy 926 cells via a reduction in the amounts of cyclin D1 , cyclin E , P11802 , hyperphosphorylated retinoblastoma protein ( P06400 ) , P35968 , and P29474 . CONCLUSIONS : These results support an anti - angiogenic activity of Toona sinensis that may contribute critically to its cancer and inflammation chemopreventive potentials .", "Cell - autonomous role of endothelial P30793 and tetrahydrobiopterin in blood pressure regulation . DB00360 ( BH4 ) is an essential cofactor for endothelial nitric oxide synthase ( P29474 ) function and NO generation . Augmentation of BH4 levels can prevent P29474 uncoupling and can improve endothelial dysfunction in vascular disease states . However , the physiological requirement for de novo endothelial cell BH4 biosynthesis in P29474 function remains unclear . We generated a novel mouse model with endothelial cell - specific deletion of P30793 , encoding P30793 , an essential enzyme for BH4 biosynthesis , to test the cell - autonomous requirement for endothelial BH4 biosynthesis in vivo . Mice with a floxed P30793 allele ( P30793 ( fl / fl ) ) were crossed with Tie2cre mice to delete P30793 in endothelial cells . P30793 ( fl / fl ) Tie2cre mice demonstrated virtually absent endothelial NO bioactivity and significantly greater O2 ( •- ) production . P30793 ( fl / fl ) Tie2cre aortas and mesenteric arteries had enhanced vasoconstriction to phenylephrine and impaired endothelium - dependent vasodilatations to acetylcholine and SLIGRL . Endothelium - dependent vasodilatations in P30793 ( fl / fl ) Tie2cre aortas were , in part , mediated by P29474 - derived hydrogen peroxide ( H2O2 ) , which mediated vasodilatation through soluble guanylate cyclase . Ex vivo supplementation of aortic rings with the BH4 analogue sepiapterin restored normal endothelial function and abolished P29474 - derived H2O2 production in P30793 ( fl / fl ) Tie2cre aortas . P30793 ( fl / fl ) Tie2cre mice had higher systemic blood pressure than wild - type littermates , which was normalized by NOS inhibitor , NG - nitro - L - arginine methyl ester . Taken together , these studies reveal an endothelial cell - autonomous requirement for P30793 and BH4 in regulation of vascular tone and blood pressure and identify endothelial cell BH4 as a pivotal regulator of NO versus H2O2 as alternative P29474 - derived endothelial - derived relaxing factors .", "The potential role of PD0332991 ( ___MASK88___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK88___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .", "Cluster analysis of risk factor genetic polymorphisms in Alzheimer ' s disease . Multiple genetic variants may contribute to the risk of developing Alzheimer ' s disease . We have analyzed polymorphisms in 9 genes to determine whether particular combinations would contribute to this risk . The genes were P02649 , LDLr , P01034 , P07339 , P01375 , P56817 , P10636 , Q8IWL8 , P29474 , and Q12800 . Three risk groups for the disease were identified . Risk group I was younger , was heterozygous for the P01034 ( GA ) , CTSD2936 ( AG ) , P01375 - 308 ( AG ) genetic variants . Risk group II was older , was homozygous for the - 427 P02649 promoter polymorphism ( TT ) , and heterozygous for the P10636 deletion and for the Q8IWL8 variant ( QR ) . Group III had both the youngest and oldest subjects , were heterozygous for the - 863 ( AC ) and - 1031 ( CT ) P01375 promoter polymorphisms . All three groups carried the P02649 4 allele and were heterozygous for both P56817 polymorphisms . The control groups were carriers of the P02649 3 allele and were homozygous for the P56817 genetic variants .", "Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK39___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .", "Effect of chronic ___MASK7___ treatment on the prostate of C57Bl / 6 mice . ___MASK7___ is a potent and selective inhibitor of phosphodiesterase - 5 ( O76074 ) and is considered first - line therapy for erectile dysfunction . Nowadays , ___MASK7___ is used extensively throughout the world on patients with pulmonary hypertension . However , few studies have evaluated the possible side effects of chronic ___MASK7___ treatment on the male reproductive system , specifically in the prostate . In the present study , it was demonstrated via morphological and ultrastructural analysis that chronic treatment with ___MASK7___ induced an enhancement of the glandular activity of the prostate . In addition , mice treated with ___MASK7___ showed a significant increase in testosterone serum levels . However , no statistically significant differences were observed in nitric oxide serum levels , or in sGC , P29474 , PSA and TGF - β prostatic expression . In conclusion , the present study suggests that chronic use of ___MASK7___ does not cause evident prostatic damage , and therefore , can be used pharmacologically to treat a variety of disorders .", "The inhibition of the constitutive bovine endothelial nitric oxide synthase by imidazole and indazole agents . DB00155 formation by the Ca2 + P62158 - dependent nitric oxide synthase of bovine endothelium is inhibited reversibly by 7 - nitroindazole , 1 - phenylimidazole , and imidazole . As measured at 0 . 67 microM ( 6R ) - DB00360 ( BH4 ) , IC50 values of 0 . 8 , 200 , and 50 microM were determined for 7 - nitroindazole , 1 - phenylimidazole , and imidazole , respectively . Increasing concentrations of added BH4 cofactor increased the IC50 values for 7 - nitroindazole and 1 - phenylimidazole but did not alter the IC50 value for imidazole . 7 - nitroindazole inhibited citrulline formation by the endothelial P29474 noncompetitively versus arginine substrate but competitively versus BH4 with a Ki value of 0 . 8 microM . 1 - Phenylimidazole inhibited citrulline formation by the endothelial P29474 competitively versus both arginine substrate and BH4 with a Ki value of 50 microM . Imidazole inhibited citrulline formation competitively versus arginine substrate but noncompetitively versus BH4 with a Ki value of 50 microM . Neither 7 - nitroindazole , 1 - phenylimidazole , nor imidazole inhibited the cytochrome c reductase activity of endothelial P29474 at concentrations up to 5000 - fold higher than their Ki values for inhibition of citrulline formation . By comparison with the previously determined kinetic properties of the other nitric oxide synthase isoforms , these observations establish that 1 - phenylimidazole displays marked specificity for inhibiting the inducible nitric oxide synthase isoform and , since 7 - nitroindazole has been reported not to elevate blood pressure ( McCall et al . , 1991 , Br . J . Pharmacol . 102 , 234 - 238 ) , fails to confirm the expected insensitivity of the constitutive endothelial nitric oxide synthase to inhibition by 7 - nitroindazole .", "Quantitative regulation of intracellular endothelial nitric - oxide synthase ( P29474 ) coupling by both tetrahydrobiopterin - P29474 stoichiometry and biopterin redox status : insights from cells with tet - regulated P30793 expression . DB00360 ( BH4 ) is a critical determinant of endothelial nitric - oxide synthase ( P29474 ) activity . In the absence of BH4 , P29474 becomes \" uncoupled \" and generates superoxide rather than NO . However , the stoichiometry of intracellular BH4 / P29474 interactions is not well defined , and it is unclear whether intracellular BH4 deficiency alone is sufficient to induce P29474 uncoupling . To address these questions , we developed novel cell lines with tet - regulated expression of human P30793 ( GTPCH ) , the rate - limiting enzyme in BH4 synthesis , to selectively induce intracellular BH4 deficiency by incubation with doxycycline . These cells were stably co - transfected to express a human P29474 - green fluorescent protein fusion protein , selecting clones expressing either low ( P30793 / P29474 - LOW ) or high ( P30793 / P29474 - HIGH ) levels . DB00254 abolished GTPCH mRNA expression and GTPCH protein , leading to markedly diminished total biopterin levels and a decreased ratio of BH4 to oxidized biopterins in cells expressing P29474 . Intracellular BH4 deficiency induced superoxide generation from P29474 , as assessed by N - nitro - L - arginine methyl ester inhibitable 2 - hydroxyethidium generation , and attenuated NO production . Quantitative analysis of cellular BH4 versus superoxide production between P30793 / P29474 - LOW and P30793 / P29474 - HIGH cells revealed a striking linear relationship between P29474 protein and cellular BH4 stoichiometry , with P29474 uncoupling at P29474 : BH4 molar ratio > 1 . Furthermore , increasing the intracellular BH2 concentration in the presence of a constant P29474 : BH4 ratio was sufficient to induce P29474 - dependent superoxide production . This specific , reductionist approach in a cell - based system reveals that P29474 : BH4 reaction stoichiometry together with the intracellular BH4 : BH2 ratio , rather than absolute concentrations of BH4 , are the key determinants of P29474 uncoupling , even in the absence of exogenous oxidative stress .", "Therapeutic effect of enhancing endothelial nitric oxide synthase ( P29474 ) expression and preventing P29474 uncoupling . DB00435 ( NO ) produced by the endothelium is an important protective molecule in the vasculature . It is generated by the enzyme endothelial NO synthase ( P29474 ) . Similar to all NOS isoforms , functional P29474 transfers electrons from nicotinamide adenine dinucleotide phosphate ( NADPH ) , via the flavins flavin adenine dinucleotide and flavin mononucleotide in the carboxy - terminal reductase domain , to the heme in the amino - terminal oxygenase domain . Here , the substrate L - arginine is oxidized to L - citrulline and NO . Cardiovascular risk factors such as diabetes mellitus , hypertension , hypercholesterolaemia or cigarette smoking reduce bioactive NO . These risk factors lead to an enhanced production of reactive oxygen species ( ROS ) in the vessel wall . NADPH oxidases represent major sources of this ROS and have been found upregulated in the presence of cardiovascular risk factors . NADPH - oxidase - derived superoxide avidly reacts with P29474 - derived NO to form peroxynitrite ( ONOO (-) ) . The essential NOS cofactor ( 6R -) DB00360 ( BH ( 4 ) ) is highly sensitive to oxidation by this ONOO (-) . In BH ( 4 ) deficiency , oxygen reduction uncouples from NO synthesis , thereby converting NOS to a superoxide - producing enzyme . Among conventional drugs , compounds interfering with the renin - angiotensin - aldosterone system and statins can reduce vascular oxidative stress and increase bioactive NO . In recent years , we have identified a number of small molecules that have the potential to prevent P29474 uncoupling and , at the same time , enhance P29474 expression . These include the protein kinase C inhibitor midostaurin , the pentacyclic triterpenoids ursolic acid and betulinic acid , the P29474 enhancing compounds AVE9488 and AVE3085 , and the polyphenolic phytoalexin trans - resveratrol . Such compounds enhance NO production from P29474 also under pathophysiological conditions and may thus have therapeutic potential .", "Endothelial cell superoxide anion radical generation is not dependent on endothelial nitric oxide synthase - serine 1179 phosphorylation and endothelial nitric oxide synthase dimer / monomer distribution . DB00360 ( BH4 ) and heat shock protein 90 ( hsp90 ) have been anticipated to regulate endothelial nitric oxide synthase ( P29474 ) - dependent superoxide anion radical ( O2 *- ) generation in endothelial cells . It is not known , however , whether hsp90 and BH4 increase O2 *- in a synergistic manner , or whether this increase is a consequence of downstream changes in P29474 phosphorylation on serine 1179 ( P29474 - S1179 ) and changes in dimer / monomer distribution . Here O2 *- production from purified BH4 - free P29474 and P29474 : hsp90 complexes determined by spin - trapping methodology showed that hsp90 neither inhibits O2 *- nor alters the requirement of BH4 to inhibit radical release from P29474 . In endothelial cells , O2 *- detection with the novel high - performance liquid chromatography assay of 2 - hydroxyethidium showed that inhibition of hsp90 did not increase O2 *- , while a significant increase in O2 *- was detected in BH4 - depleted cells . DB03758 , a hsp90 inhibitor , disrupted P29474 : hsp90 association , decreased P29474 - S1179 , but increased biopterin production in a dose - dependent fashion . These changes were followed by an increase in P29474 activity , demonstrating that high biopterin levels offset inhibition of P29474 phosphorylation and diminished interaction with hsp90 . In contrast , depletion of biopterin did not affect hsp90 levels or interaction with P29474 or P29474 dimer / monomer ratio in bovine aorta endothelial cells ( BAECs ) . We conclude that low BH4 but not inhibition of hsp90 increases O2 *- in BAECs by mechanism ( s ) that unlikely involve phosphorylation to P29474 - S1179 or P29474 monomerization .", "___MASK76___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .", "Bi - modal dose - dependent cardiac response to tetrahydrobiopterin in pressure - overload induced hypertrophy and heart failure . The exogenous administration of tetrahydrobiopterin ( BH4 ) , an essential cofactor of nitric oxide synthase ( NOS ) , has been shown to reduce left ventricular hypertrophy , fibrosis , and cardiac dysfunction in mice with pre - established heart disease induced by pressure - overload . In this setting , BH4 re - coupled endothelial NOS ( P29474 ) , with subsequent reduction of NOS - dependent oxidative stress and reversal of maladaptive remodeling . However , recent studies suggest the effective BH4 dosing may be narrower than previously thought , potentially due to its oxidation upon oral consumption . Accordingly , we assessed the dose response of daily oral synthetic sapropterin dihydrochloride ( 6 - R - l - erythro - DB00360 , DB00360 ) on pre - established pressure - overload cardiac disease . Mice ( n = 64 ) were administered 0 - 400mg / kg / d BH4 by ingesting small pre - made pellets ( consumed over 15 - 30 min ) . In a dose range of 36 - 200mg / kg / d , DB00360 suppressed cardiac chamber remodeling , hypertrophy , fibrosis , and oxidative stress with pressure - overload . However , at both lower and higher doses , BH4 had less or no ameliorative effects . The effective doses correlated with a higher myocardial BH4 / BH2 ratio . However , BH2 rose linearly with dose , and at the 400mg / kg / d , this lowered the BH4 / BH2 ratio back toward control . These results expose a potential limitation for the clinical use of BH4 , as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals . This article is part of a special issue entitled '' Key Signaling Molecules in Hypertrophy and Heart Failure . ''", "DB04540 attenuates linoleic acid - induced endothelial cell activation . Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis . Even though very low or high levels of cholesterol can compromise cellular functions , cholesterol is a critical membrane component and may protect the vascular endothelium from oxidative stress and polyunsaturated fatty acid - mediated inflammatory responses . We have previously shown that the parent omega - 6 fatty acid linoleic acid can markedly activate vascular endothelial cells . We now propose that membrane cholesterol can modify and inhibit linoleic acid - mediated endothelial cell dysfunction . To test this hypothesis , pulmonary artery endothelial cells were incubated with cholesterol ( 0 to 100 micromol / L ) for 24 hours and then treated with 90 micromol / L of linoleic acid ( 18 : 2n - 6 ) for 6 to 24 hours . In control cells , treatment with linoleic acid reduced intracellular glutathione levels and induced the DNA binding activity of nuclear factor - kappaB ( NF - kappaB ) leading to the upregulation of interleukin - 6 ( P05231 ) . In addition , the expression of endothelial nitric oxide synthase ( P29474 ) was altered , with linoleic acid increasing P29474 activity . In contrast , enrichment with cholesterol enhanced glutathione levels and reduced the linoleic acid - induced activation of NF - kappaBand the production of P05231 . Prior exposure to 50 micromol / L cholesterol also prevented the fatty acid - induced increase in P29474 activation . DB04540 loading activated peroxisome proliferator - activated receptor - gamma ( P37231 ) , a nuclear receptor that can decrease inflammatory responses . Furthermore , the P37231 agonist thiazolidinedione markedly downregulated the NF - kappaB activation mediated by linoleic acid . Our data suggest that signaling pathways linked to endothelial cell activation by prooxidant and proinflammatory insults may be influenced by cellular cholesterol levels .", "Gene expression profiles of adipose tissue of obese rats after central administration of neuropeptide Y - Q15761 antisense oligodeoxynucleotides by cDNA microarrays . To investigate the gene expression profiles of adipose tissue of obese rats after central administration of neuropeptide Y - Q15761 antisense oligodeoxynucleotides ( ODNs ) , Q15761 antisense , mismatched ODNs or vehicle was intracerebroventricularly injected and cDNA microarrays were undertaken . Central administration of Q15761 antisense ODNs decreased food intake , body weight and serum insulin compared with both vehicle and mismatched ODNs . The average area of adipocytes both at retroperitoneal and epididymal adipose tissue were fall in antisense group while only the weight of the retroperitoneal fat pats was reduced in antisense group . cDNA microarrays containing 18 , 000 genes / Ests were used to investigate gene expression of adipose tissue . Autoradiographic analysis showed that 404 , 81 , and 34 genes were differently expressed over twofold , threefold , and fivefold , respectively . The analysis of gene expression profiles indicated that 332 genes were up - regulated and 187 genes were down - regulated in response to Q15761 antisense ODNs treatment . Different clusters of genes associated with apoptosis , signal transduction , energy metabolism , lipid metabolism , etc . , such as P51114 , Q8WV24 , Q7L5Y9 , P27986 , P13598 , Q00169 , P62158 , Q13557 , P61925 , P14416 , O95258 , CKB , P22760 , P38571 , O15254 , O60427 , were concerned . Analysis of differentially expressed genes will help to understand the effects of Q15761 antisense ODNs therapy .", "DB00360 alters superoxide and nitric oxide release in prehypertensive rats . Constitutive nitric oxide synthase ( P29474 ) with insufficient cofactor ( 6R ) - DB00360 ( H4B ) may generate damaging superoxide ( O2 - ) . This study was designed to determine whether P29474 - dependent generation of O2 - occurs in spontaneously hypertensive rats ( SHR ) before the onset of hypertension . Aortas from 4 - wk - old SHR and Wistar - Kyoto rats were used . P29474 was stimulated by calcium ionophore A23187 . In situ measurements of nitric oxide and hydrogen peroxide by electrochemical sensors and O2 - production by chemiluminescence method were performed . Isometric tension was continuously recorded . H4B by high performance liquid chromatography and [ 3H ] citrulline assay were determined in homogenized tissue . The A23187 - stimulated production of O2 - and its superoxide dismutase product hydrogen peroxide were significantly higher , whereas nitric oxide release was reduced in SHR aortas , with opposite results in the presence of exogenous H4B . Furthermore , NG - monomethyl - L - arginine inhibited the generation of P29474 - dependent O2 - by approximately 70 % . Natural H4B levels were similar in both strains ; however , equivalent P29474 activity required additional H4B in SHR . The endothelium - dependent relaxations to A23187 were significantly inhibited by catalase , and enhanced by superoxide dismutase , only in SHR ; however , these enzymes had no effect in the presence of H4B . Thus , dysfunctional P29474 may be a source of O2 - in prehypertensive SHR and contribute to the development of hypertension and its vascular complications .", "DB00435 synthases : regulation and function . DB00435 ( NO ) , the smallest signalling molecule known , is produced by three isoforms of NO synthase ( NOS ; EC 1 . 14 . 13 . 39 ) . They all utilize l - arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide - adenine - dinucleotide phosphate ( NADPH ) , flavin adenine dinucleotide ( DB03147 ) , flavin mononucleotide ( Q68DA7 ) , and ( 6R -) DB00360 ( BH ( 4 ) ) . All NOS bind calmodulin and contain haem . P29475 ( P29475 , NOS I ) is constitutively expressed in central and peripheral neurons and some other cell types . Its functions include synaptic plasticity in the central nervous system ( CNS ) , central regulation of blood pressure , smooth muscle relaxation , and vasodilatation via peripheral nitrergic nerves . Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection . Phosphodiesterase 5 inhibitors ( sildenafil , vardenafil , and tadalafil ) require at least a residual P29475 activity for their action . P35228 ( NOS II ) can be expressed in many cell types in response to lipopolysaccharide , cytokines , or other agents . P35228 generates large amounts of NO that have cytostatic effects on parasitic target cells . P35228 contributes to the pathophysiology of inflammatory diseases and septic shock . P29474 ( P29474 , NOS III ) is mostly expressed in endothelial cells . It keeps blood vessels dilated , controls blood pressure , and has numerous other vasoprotective and anti - atherosclerotic effects . Many cardiovascular risk factors lead to oxidative stress , P29474 uncoupling , and endothelial dysfunction in the vasculature . Pharmacologically , vascular oxidative stress can be reduced and P29474 functionality restored with renin - and angiotensin - converting enzyme - inhibitors , with angiotensin receptor blockers , and with statins .", "Effects of tetrahydrobiopterin oral treatment in hypoxia - induced pulmonary hypertension in rat . Endothelial nitric oxide synthase ( P29474 ) plays a major role in maintaining pulmonary vascular homeostasis . DB00360 ( BH4 ) , an essential cofactor that stabilizes the dimerization of P29474 and balances nitric oxide ( NO ) and superoxide production , may have therapeutic potential in pulmonary hypertension . In the isolated perfused lung , we demonstrated a direct effect of exogenous administration of BH4 on pulmonary NO production , leading to acute vasorelaxation during the plateau phase of hypoxia - induced pulmonary vasoconstriction . In the chronic hypoxia - induced pulmonary hypertension rat model , chronic BH4 oral administration attenuated the pressor response to hypoxia ( mean pulmonary artery pressure ± standard error of the mean , 31 . 8 ± 0 . 5 mmHg at 100 mg / kg / day ; placebo group , 36 . 3 ± 0 . 6 mmHg ; P < 0 . 05 ) . During telemetric monitoring , right ventricular systolic pressure was reduced by approximately 50 % after 1 week of BH4 treatment at 100 mg / kg / day . BH4 at 100 mg / kg / day reduced right ventricular hypertrophy ( from 0 . 55 ± 0 . 01 to 0 . 50 ± 0 . 01 ; P < 0 . 05 ) and pulmonary vascular muscularization ( from 79 . 2 % ± 2 % to 65 . 2 % ± 3 % ; P < 0 . 01 ) . BH4 treatment enhanced lung P29474 activity and reduced superoxide production , with a net increase in cyclic guanosine monophosphate levels . BH4 is effective in attenuating pulmonary hypertension in the hypoxic rat model when given as a rescue therapy .", "Impairment of endothelial - myocardial interaction increases the susceptibility of cardiomyocytes to ischemia / reperfusion injury . Endothelial - myocardial interactions may be critically important for ischemia / reperfusion injury . DB00360 ( BH4 ) is a required cofactor for nitric oxide ( NO ) production by endothelial NO synthase ( P29474 ) . Hyperglycemia ( HG ) leads to significant increases in oxidative stress , oxidizing BH4 to enzymatically incompetent dihydrobiopterin . How alterations in endothelial BH4 content impact myocardial ischemia / reperfusion injury remains elusive . The aim of this study was to examine the effect of endothelial - myocardial interaction on ischemia / reperfusion injury , with an emphasis on the role of endothelial BH4 content . Langendorff - perfused mouse hearts were treated by triton X - 100 to produce endothelial dysfunction and subsequently subjected to 30 min of ischemia followed by 2 h of reperfusion . The recovery of left ventricular systolic and diastolic function during reperfusion was impaired in triton X - 100 treated hearts compared with vehicle - treated hearts . Cardiomyocytes ( CMs ) were co - cultured with endothelial cells ( ECs ) and subsequently subjected to 2 h of hypoxia followed by 2 h of reoxygenation . Addition of ECs to CMs at a ratio of 1 ∶ 3 significantly increased NO production and decreased lactate dehydrogenase activity compared with CMs alone . This EC - derived protection was abolished by HG . The addition of 100 µM sepiapterin ( a BH4 precursor ) or overexpression of P30793 ( the rate - limiting enzyme for BH4 biosynthesis ) in ECs by gene trasfer enhanced endothelial BH4 levels , the ratio of P29474 dimer / monomer , P29474 phosphorylation , and NO production and decreased lactate dehydrogenase activity in the presence of HG . These results demonstrate that increased BH4 content in ECs by either pharmacological or genetic approaches reduces myocardial damage during hypoxia / reoxygenation in the presence of HG . Maintaining sufficient endothelial BH4 is crucial for cardioprotection against hypoxia / reoxygenation injury .", "Interactions of peroxynitrite , tetrahydrobiopterin , ascorbic acid , and thiols : implications for uncoupling endothelial nitric - oxide synthase . DB00360 ( BH4 ) serves as a critical co - factor for the endothelial nitric - oxide synthase ( P29474 ) . A deficiency of BH4 results in P29474 uncoupling , which is associated with increased superoxide and decreased NO * production . BH4 has been suggested to be a target for oxidation by peroxynitrite ( ONOO - ) , and ascorbate has been shown to preserve BH4 levels and enhance endothelial NO * production ; however , the mechanisms underlying these processes remain poorly defined . To gain further insight into these interactions , the reaction of ONOO - with BH4 was studied using electron spin resonance and the spin probe 1 - hydroxy - 3 - carboxy - 2 , 2 , 5 - tetramethyl - pyrrolidine . ONOO - reacted with BH4 6 - 10 times faster than with ascorbate or thiols . The immediate product of the reaction between ONOO - and BH4 was the trihydrobiopterin radical ( BH3 . ) , which was reduced back to BH4 by ascorbate , whereas thiols were not efficient in recycling of BH4 . Uncoupling of P29474 caused by peroxynitrite was investigated in cultured bovine aortic endothelial cells ( BAECs ) by measuring superoxide and NO * using spin probe 1 - hydroxy - 3 - methoxycarbonyl - 2 , 2 , 5 , 5 - tetramethyl - pyrrolidine and the NO *- spin trap iron - diethyldithiocarbamate . Bolus ONOO - , the ONOO - donor 3 - morpholinosydnonimine , and an inhibitor of BH4 synthesis ( 2 , 4 - diamino - 6 - hydroxypyrimidine ) uncoupled P29474 , increasing superoxide and decreasing NO * production . Exogenous BH4 supplementation restored endothelial NO * production . Treatment of BAECs with both BH4 and ascorbate prior to ONOO - prevented uncoupling of P29474 by ONOO - . This study demonstrates that endothelial BH4 is a crucial target for oxidation by ONOO - and that the BH4 reaction rate constant exceeds those of thiols or ascorbate . We confirmed that ONOO - uncouples P29474 by oxidation of tetrahydrobiopterin and that ascorbate does not fully protect BH4 from oxidation but recycles BH3 . radical back to BH4 .", "Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK16___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .", "Sense p16 and antisense Q03405 bicistronic construct inhibits angiogenesis and induces glioma cell death . High - grade gliomas comprise the most malignant type of primary brain tumor and are relatively frequent in adults . Recent studies have indicated that the loss of p16 , an inhibitor of P11802 , promotes the acquisition of malignant characteristics in gliomas . A correlation between overexpression of urokinase - type plasminogen activator receptor ( Q03405 ) and glioblastoma invasion has also been established . Moreover , Q03405 / integrin binding has been shown to initiate or potentiate integrin signaling through focal adhesion kinase and / or src kinases . Our previous studies demonstrated that downregulation of Q03405 expression and restoration of p16 regress glioma growth in nude mice and downregulate alphavbeta3 integrin receptor expression . Here , we show the effect of a bicistronic construct on alphavbeta5 integrin receptor expression , angiogenesis and the biochemical pathway that causes glioma cell death . The U251 glioblastoma and a glioblastoma xenograft cell line transduced with a recombinant replication - defective adenovirus vector containing the cDNA of wild - type p16 and antisense RNA of Q03405 significantly inhibited human mammary epithelial cell capillary formation and vascular endothelial growth factor ( P15692 ) expression . Inactivation of anti - apoptotic molecules such as Akt , PARP , activation of caspases and accumulation of heteroduplex chromosomal DNA in pre - P55008 phase of the cell cycle was demonstrated by Western blotting , caspase activity assay and FACS analysis . Nuclear DNA fragmentation upon induction of apoptosis was scored using the TUNEL assay . Significant downregulation of alphavbeta5 integrin receptor expression was also confirmed by FACS analysis , immunoprecipitation and RT - PCR . Taken together , the results demonstrate that the sense p16 and anti - sense Q03405 bicistronic construct significantly inhibits angiogenesis , induces apoptosis by deregulation of the PI3K - Akt pathway and downregulates alphavbeta5 integrin receptor expression .", "DB00360 : pleiotropic roles in cardiovascular pathophysiology . DB00360 ( BH4 ) functions as a cofactor in several important enzyme systems . Substantial evidence implicates BH4 as a key regulator of endothelial nitric oxide synthase ( P29474 ) in the setting of endothelial dysfunction and atherosclerosis . Investigators have now taken early steps in addressing the potential of BH4 as a therapeutic strategy . However , it has become more apparent that the role of BH4 in other enzymatic pathways , including other NOS isoforms and the aromatic amino acid hydroxylases , may have a bearing on important aspects of cardiovascular homeostasis . Together with P29474 , these enzymes may play key roles in diverse cardiovascular disease states such as ischaemia - reperfusion injury , cardiac hypertrophy , cardiac autonomic function and pulmonary hypertension . This review provides an overview of the role of BH4 in cardiovascular pathophysiology ." ]

[ "___MASK16___", "___MASK39___", "___MASK45___", "___MASK52___", "___MASK76___", "___MASK77___", "___MASK7___", "___MASK88___", "___MASK94___" ]

[ "P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK87___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .", "Immunomodulatory drugs inhibit expression of cyclooxygenase - 2 from P01375 , IL - 1beta , and LPS - stimulated human PBMC in a partially P22301 - dependent manner . Immunomodulatory drugs ( IMiDs ) are potent inhibitors of P01375 and IL - 1beta and elevators of P22301 production in LPS - stimulated human PBMC . They are currently in clinical trials for various diseases , including multiple myeloma , myelodysplastic syndrome , and melanoma . In the present study , we have investigated the effects of thalidomide , DB00480 and CC - 4047 on the expression of P35354 by stimulated PBMC . Our results show that thalidomide and IMiDs inhibited the expression of P35354 but not the P23219 protein in LPS - P01375 and IL - 1beta stimulated PBMC and shortened the half - life of P35354 mRNA in a dose - dependent manner . They also inhibited the synthesis of prostaglandin E2 from LPS - stimulated PBMC . While anti - P01375 or IL - 1beta neutralizing antibodies had no effect on P35354 expression , anti - P22301 neutralizing antibody elevated the expression of P35354 mRNA , and protein from treated PBMC . These data suggest that the anti - inflammatory and anti - tumor effects of IMiDs may be due in part to elevation of P22301 production and its subsequent inhibition of P35354 expression .", "Bresol inhibits phosphodiesterase 4 gene expression and modulates the levels of select mediators of inflammation in human monocytic cells . Bresol - a poly - herbal formulation , has been reported to be effective against bronchial asthma and allergic rhinitis in children . In vivo studies have supported the anti - histaminic and anti - anaphylactic action of bresol . However , the mechanism of action of bresol in modulation of inflammation has not been studied at the cellular and molecular level . The present study was aimed to elucidate the mechanism ( s ) of action of bresol at the cellular and molecular levels , using human monocyte leukemia cells . The effects of bresol on phosphodiesterase 4B ( Q07343 ) gene expression were analyzed using human monocytic U937 leukemia cells . The ability of bresol to stimulate DB02527 formation in these cells , as well as its effects on mediators of inflammation like tumor necrosis factor - α ( TNFα ) , nitric oxide ( NO ) , and cycloxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated U937 cells , were also studied . The results here indicated that bresol exhibited potential anti - inflammatory properties by inhibiting LPS - induced Q07343 gene expression in the cells . Bresol also dose dependently activated DB02527 formation , and inhibited TNFα , NO , as well as P35354 formation in the LPS - stimulated cells . Based upon the results , we concluded that the reported anti - inflammatory activity of bresol might be attributed to its abilities to inhibit Q07343 and thus elevate DB02527 levels in human monocytes . The anti - inflammatory effects of bresol might also be a result of the capacity of bresol to modulate the formation of TNFα , NO , and P35354 in monocytes .", "O14788 promotes migration and invasion of hepatocellular carcinoma cells via NF - κB - mediated epithelial - mesenchymal transition . BACKGROUND : Metastasis accounts for the most deaths in patients with hepatocellular carcinoma ( HCC ) . Receptor activator of nuclear factor kappa B ligand ( O14788 ) is associated with cancer metastasis , while its role in HCC remains largely unknown . METHODS : Immunohistochemistry was performed to determine the expression of Q9Y6Q6 in HCC tissue ( n = 398 ) . Quantitative real - time polymerase chain reaction ( qRT - PCR ) and Western blot were used to examine the expression of Q9Y6Q6 , P12830 , P19022 , vimentin , Snail , Slug , Twist and MMPs in HCC cells . Wound healing and Transwell assays were used to evaluate cell migration and invasion ability . RESULTS : We found that expression of Q9Y6Q6 , the receptor of O14788 , was significantly higher in HCC tumor tissues than in peritumor liver tissues ( p < 0 . 001 ) . Constitutive expression of Q9Y6Q6 was detected in HCC cell lines , which can be up - regulated when HCC cells were stimulated with O14788 . Notably , in vitro experiments showed that activation of O14788 - Q9Y6Q6 axis significantly promoted migration and invasion ability of HCC cells . In addition , O14788 stimulation increased the expression levels of P19022 , Snail , and Twist , while decreased the expression of P12830 , with concomitant activation of NF - κB signaling pathway . Moreover , administration of the NF - κB inhibitor attenuated O14788 - induced migration , invasion and epithelial - mesenchymal transition of HCC cells . CONCLUSIONS : O14788 could potentiate migration and invasion ability of Q9Y6Q6 - positive HCC cells through NF - κB pathway - mediated epithelial - mesenchymal transition , which means that O14788 - Q9Y6Q6 axis could be a potential target for HCC therapy .", "Molecular mechanisms of the inhibitory effects of bovine lactoferrin on lipopolysaccharide - mediated osteoclastogenesis . P02788 ( LF ) is an important modulator of the immune response and inflammation . It has also been implicated in the regulation of bone tissue . In our previous study we demonstrated that bovine LF ( bLF ) reduces LPS - induced bone resorption through a reduction of P01375 - α production in vivo . However , it was not known how bLF inhibits LPS - mediated P01375 - α and O14788 ( receptor activator of nuclear factor κB ligand ) production in osteoblasts . In this study we show that bLF impairs LPS - mediated P01375 - α and O14788 production . bLF inhibited LPS - mediated osteoclastogenesis via osteoblasts in a co - culture system . Furthermore , bLF pretreatment inhibited LPS - induced NFκB DNA binding activity as well as IκBα and IKKβ ( IκB kinase β ) phosphorylation . Q96HU1 kinase activation was also inhibited by bLF pretreatment . However , bLF pretreatment failed to block the degradation of P51617 ( interleukin - 1 receptor - associated kinase 1 ) , which is an essential event after its activation . Remarkably , we found that bLF pretreatment inhibited LPS - mediated Lys - 63 - linked polyubiquitination of Q9Y4K3 ( Q9Y4K3 ) . We also found that bLF is mainly endocytosed through Q07954 ( lipoprotein receptor - related protein - 1 ) and intracellular distributed bLF binds to endogenous Q9Y4K3 . In addition , bLF inhibited IL - 1β - and flagellin - induced Q9Y4K3 - dependent activation of the NFκB signaling pathway . Collectively , our findings demonstrate that bLF inhibits NFκB and Q96HU1 kinase activation , which play critical roles in chronic inflammatory disease by interfering with the Q9Y4K3 polyubiquitination process . Thus , bLF could be a potent therapeutic agent for inflammatory diseases associated with bone destruction , such as periodontitis and rheumatoid arthritis .", "Serotonin and fluoxetine modulate bone cell function in vitro . Recent studies have proposed a role for serotonin and its transporter in regulation of bone cell function . In the present study , we examined the in vitro effects of serotonin and the serotonin transporter inhibitor fluoxetine \" DB00472 \" on osteoblasts and osteoclasts . Human mononuclear cells were differentiated into osteoclasts in the presence of serotonin or fluoxetine . Both compounds affected the total number of differentiated osteoclasts as well as bone resorption in a bell - shaped manner . RT - PCR on the human osteoclasts demonstrated several serotonin receptors , the serotonin transporter , and the rate - limiting enzyme in serotonin synthesis , tryptophan hydroxylase 1 ( Tph1 ) . Tph1 expression was also found in murine osteoblasts and osteoclasts , indicating an ability to produce serotonin . In murine pre - osteoclasts ( RAW264 . 7 ) , serotonin as well as fluoxetine affected proliferation and NFkappaB activity in a biphasic manner . Proliferation of human DB05914 ( O60682 ) and primary osteoblasts ( NHO ) , and 5 - Q13049 receptor expression was enhanced by serotonin . DB00472 stimulated proliferation of O60682 and murine preosteoblasts ( MC3T3 - E1 ) in nM concentrations , microM concentrations were inhibitory . The effect of fluoxetine seemed direct , probably through 5 - HT2 receptors . Serotonin - induced proliferation of MC3T3 - E1 cells was inhibited by the PKC inhibitor ( GF109203 ) and was also markedly reduced when antagonists of the serotonin receptors P41595 / C or 5 - Q13049 / C were added . Serotonin increased osteoprotegerin ( O00300 ) and decreased receptor activator of NF - kappaB ligand ( O14788 ) secretion from osteoblasts , suggesting a role in osteoblast - induced inhibition of osteoclast differentiation , whereas fluoxetine had the opposite effect . This study further describes possible mechanisms by which serotonin and the serotonin transporter can affect bone cell function .", "Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK18___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .", "Immunohistochemical analysis of low - grade and high - grade prostate carcinoma : relative changes of parathyroid hormone - related protein and its parathyroid hormone 1 receptor , osteoprotegerin and receptor activator of nuclear factor - kB ligand . AIM : To investigate multiple bone cytokines produced by prostate carcinoma ( PCa ) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis . METHODS : A total of 47 cases of PCa undergoing radical prostatectomy or transurethral prostatic resection at our institution ( Fundación Jiménez Díaz ( Grupo Capio ) , Madrid , Spain ) between January 1991 and June 1998 were identified as low - grade ( < or = 4 ; n = 22 ) or high - grade ( > or = 7 , excluding 7 ( 3 + 4 ) cases ; n = 25 ) PCa according to Gleason grade . PCa specimens were immunostained for : parathyroid hormone ( PTH ) - related protein ( P12272 ) , the Q03431 , osteoprotegerin and receptor activator of nuclear factor - kappa B ligand ( O14788 ) , as well as Ki67 ( a proliferation marker ) and P28906 ( an angiogenesis marker ) . RESULTS : PCa samples showed an increased immunostaining for both osteoprotegerin and O14788 , associated with tumour grade and P12272 positivity , in the tumoral epithelium . Using a score value of 4 - corresponding to moderate staining - as cut - off , the best sensitivity value was for P12272 ( with C - terminal antiserum P13671 ; 100 % ) ; wheras the best specificity value was for O14788 ( 95 % ) . CONCLUSIONS : All the evaluated factors are overexpressed mainly in the high - grade tumours . Our findings indicate that , in most patients with PCa ( with Ki67 values between 1 % and 9 % ) , sequential determination of C - terminal P12272 and O14788 immunoreactivities is a useful approach to discriminate low - grade and high - grade tumours .", "Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK85___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .", "O00300 in sputum is a potential biomarker in P48444 . BACKGROUND : P48444 is characterized by chronic airflow limitation and inflammation of the respiratory tract . Several inflammatory biomarkers have been evaluated in P48444 but are poorly related to disease severity and progression . O00300 ( O00300 ) is a glycoprotein mediator that is expressed in the lung and macrophages , so we have studied its concentration in induced sputum and macrophages of patients with P48444 . METHODS : O00300 was measured by enzyme - linked immunosorbent assay in induced sputum of patients with P48444 and control subjects . RESULTS : O00300 concentrations in induced sputum of patients with P48444 ( 18 . 7 ± 18 . 6 ng / mL , n = 39 ) were significantly higher than those of healthy smokers ( 8 . 1 ± 5 . 6 ng / mL , n = 15 ) , healthy nonsmokers ( 3 . 5 ± 3 . 8 ng / mL , n = 14 ) , or patients with asthma ( 8 . 0 ± 5 . 4 ng / mL , n = 18 ) . Sputum O00300 levels in P48444 negatively correlated with Q99581 ( 1 ) and positively correlated with residual volume to total lung capacity ratio ( RV / TLC ) ( r = 0 . 55 , P < . 05 ) , transfer factor of the lung for carbon monoxide ( r = - 0 . 53 , P < . 05 ) , and carbon monoxide transfer coefficient ( r = - 0 . 61 , P < . 01 ) . By contrast , sputum P10145 concentrations were related to disease severity but not to RV / TLC or gas diffusion . Airway macrophages and neutrophils were positive for O00300 by immunocytochemistry in sputum and peripheral lung tissue . O00300 induced matrix metalloproteinase - 9 release from sputum macrophages in vitro . CONCLUSIONS : Sputum O00300 may be a useful biomarker to monitor parenchymal destruction in P48444 .", "The attenuation of experimental lung metastasis by a bile acid acylated - heparin derivative . The inhibitory efficacies of new bile acid acylated - heparin derivative ( heparin - DOCA ) were evaluated on experimental lung metastasis . We evaluated the effect of heparin - DOCA on intercellular interactions including those between B16F10 and thrombin - activated platelets and P01375 - activated HUVECs , and between B16F10 and immobilized mouse P16109 . In addition , the inhibitory effects of heparin - DOCA on adhesion and invasion of B16F10 to Matrigel were studied . In an animal mouse study , the blood clot formation and the retention of red fluorescence protein ( RFP ) - B16F10 in lungs were assessed after heparin - DOCA and RFP - B16F10 intravenous administration . Furthermore , we investigated the anti - metastatic effect of heparin - DOCA against lung metastasis induced by B16F10 and SCC7 . ___MASK69___ - DOCA inhibited intercellular interactions between B16F10 and activated platelets or activated HUVECs by blocking P - and P16581 - mediated interactions . Moreover , it reduced adhesion and invasion of B16F10 to Q13201 , thereby affecting the reduction of early retention of B16F10 in the lung . ___MASK69___ - DOCA attenuated lung colony formation on the surfaces and in interior of the lung , and attenuated metastasis by B16F10 and SCC7 . These results suggest that heparin - DOCA may have potentials as therapeutic agent that prevents tumor metastasis and progression .", "___MASK69___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK69___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK69___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .", "DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .", "Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK9___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "The anti - tumor effect of HDAC inhibition in a human pancreas cancer model is significantly improved by the simultaneous inhibition of cyclooxygenase 2 . Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide , with no satisfactory treatment to date . In this study , we tested whether the combined inhibition of cyclooxygenase - 2 ( P35354 ) and class I histone deacetylase ( HDAC ) may results in a better control of pancreatic ductal adenocarcinoma . The impact of the concomitant HDAC and P35354 inhibition on cell growth , apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC - 3 , PANC - 1 or CFPAC - 1 cells treated with chemical inhibitors ( ___MASK21___ , MS - 275 and celecoxib ) or Q13547 / 2 / 3 / 7 siRNA . To test the potential antitumoral activity of this combination in vivo , we have developed and characterized , a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma . The combination of Q13547 / 3 and P35354 inhibition significantly impaired proliferation of BxPC - 3 cells in vitro and stalled entirely the BxPC - 3 cells tumor growth onto the chorioallantoic membrane in vivo . The combination was more effective than either drug used alone . Consistently , we showed that both Q13547 and O15379 inhibition induced the expression of P35354 via the NF - kB pathway . Our data demonstrate , for the first time in a Pancreatic Ductal Adenocarcinoma ( PDAC ) model , a significant action of HDAC and P35354 inhibitors on cancer cell growth , which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients .", "DB00480 inhibits osteoclastogenesis , survival factors and bone - remodeling markers in multiple myeloma . Osteolytic bone disease in multiple myeloma ( MM ) is caused by enhanced osteoclast ( OCL ) activation and inhibition of osteoblast function . DB00480 and bortezomib have shown promising response rates in relapsed and newly diagnosed MM , and bortezomib has recently been reported to inhibit OCLs . We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib . Both drugs decreased alpha V beta 3 - integrin , tartrate - resistant acid phosphatase - positive cells and bone resorption on dentin disks . In addition , both agents decreased receptor activator of nuclear factor - kappaB ligand ( O14788 ) secretion of bone marrow stromal cells ( BMSCs ) derived from MM patients . We identified PU . 1 and pERK as major targets of lenalidomide , and nuclear factor of activated T cells of bortezomib , resulting in inhibition of osteoclastogenesis . Furthermore , downregulation of cathepsin K , essential for resorption of the bone collagen matrix , was observed . We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein - alpha , B - cell activating factor and a proliferation - inducing ligand . Importantly , in serum from MM patients treated with lenalidomide , the essential bone - remodeling factor O14788 , as well as the O14788 / O00300 ratio , were significantly reduced , whereas osteoprotegerin ( O00300 ) was increased . We conclude that both agents specifically target key factors in osteoclastogenesis , and could directly affect the MM - OCL - BMSCs activation loop in osteolytic bone disease .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "___MASK82___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK82___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .", "O00300 inhibits calcification of vascular smooth muscle cell via down regulation of the Notch1 - P02753 - Jκ / Msx2 signaling pathway . OBJECTIVE : Vascular calcification is a common pathobiological process which occurs among the elder population and in patients with diabetes and chronic kidney disease . O00300 , a secreted glycoprotein that regulates bone mass , has recently emerged as an important regulator of the development of vascular calcification . However , the mechanism is not fully understood . The purpose of this study is to explore novel signaling mechanisms of osteoprotegerin in the osteoblastic differentiation in rat aortic vascular smooth muscle cells ( VSMCs ) . METHODS AND RESULTS : VSMCs were isolated from thoracic aorta of Sprague Dawley rats . Osteoblastic differentiation of VSMCs was induced by an osteogenic medium . We confirmed by Von Kossa staining and direct cellular calcium measurement that mineralization was significantly increased in VSMCs cultured in osteogenic medium ; consistent with an enhanced alkaline phosphatase activity . This osteoblastic differentiation in VSMCs was significantly reduced by the addition of osteoprotegerin in a dose responsive manner . Moreover , we identified , by real - time qPCR and western blotting , that expression of Notch1 and P02753 - Jκ were significantly up - regulated in VSMCs cultured in osteogenic medium at both the mRNA and protein levels , these effects were dose - dependently abolished by the treatment of osteoprotegerin . Furthermore , we identified that Msx2 , a downstream target of the Notch1 / P02753 - Jκ signaling , was markedly down - regulated by the treatment of osteoprotegerin . CONCLUSION : O00300 inhibits vascular calcification through the down regulation of the Notch1 - P02753 - Jκ signaling pathway .", "The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer . It is now well established that cancer cells exhibit a number of genetic defects in the machinery that governs programmed cell death and that sabotage of apoptosis is one of the principal factors aiding in the evolution of the carcinogenic phenotype . A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer , whereby promoter hypermethylation silences genes essential for many processes including apoptosis . To date , studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast , colon and stomach , with only limited data available on prostate cancer . Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer . The most significant advances have involved the discovery of apoptotic gene targets of methylation , including Q6GPH4 , ( fragile histidine triad ( P49789 ) , cellular retinol binding protein 1 ( P09455 ) , decoy receptor 1 ( O14798 ) , decoy receptor 2 ( Q9UBN6 ) , target of methylation - induced silenceing 1 ( Q9ULZ3 ) , P01375 receptor superfamily , member 6 ( FAS ) , Reprimo ( Q9NS64 ) and P08151 pathogenesis - related 1 ( P48060 ) . These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers . We also introduce the concept of an ' apoptotic methylation signature ' for prostate cancer and evaluate its potential in a diagnostic , prognostic and therapeutic setting .", "Concomitant loss of p120 - catenin and β - catenin membrane expression and oral carcinoma progression with P12830 reduction . The binding of p120 - catenin and β - catenin to the cytoplasmic domain of P12830 establishes epithelial cell - cell adhesion . Reduction and loss of catenin expression degrades P12830 - mediated carcinoma cell - cell adhesion and causes carcinomas to progress into aggressive states . Since both catenins are differentially regulated and play distinct roles when they dissociate from P12830 , evaluation of their expression , subcellular localization and the correlation with P12830 expression are important subjects . However , the same analyses are not readily performed on squamous cell carcinomas in which P12830 expression determines the disease progression . In the present study , we examined expression and subcellular localization of p120 - catenin and β - catenin in oral carcinomas ( n = 67 ) and its implications in the carcinoma progression and P12830 expression using immunohitochemistry . At the invasive front , catenin - membrane - positive carcinoma cells were decreased in the dedifferentiated ( p120 - catenin , P < 0 . 05 ; β - catenin , P < 0 . 05 ) and invasive carcinomas ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 05 ) and with the P12830 staining ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 01 ) . Carcinoma cells with β - catenin cytoplasmic and / or nuclear staining were increased at the invasive front compared to the center of tumors ( P < 0 . 01 ) . Although the p120 - catenin isoform shift from three to one associates with carcinoma progression , it was not observed after TGF - β , P01133 or P01375 - α treatments . The total amount of p120 - catenin expression was decreased upon co - treatment of TGF - β with P01133 or P01375 - α . The above data indicate that catenin membrane staining is a primary determinant for P12830 - mediated cell - cell adhesion and progression of oral carcinomas . Furthermore , it suggests that loss of p120 - catenin expression and cytoplasmic localization of β - catenin fine - tune the carcinoma progression .", "Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK21___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .", "Inhibition of receptor activator of nuclear factor - κB ligand ( O14788 ) - induced osteoclast formation by pyrroloquinoline quinine ( PQQ ) . The effect of pyrroloquinoline quinine ( PQQ ) on receptor activator of nuclear factor - κB ligand ( O14788 ) - induced osteoclast formation was examined using RAW 264 . 7 macrophage - like cells . O14788 led to the formation of osteoclasts identified as tartrate - resistant acid phosphatase ( TRAP ) - positive multinucleated cells in the culture of RAW 264 . 7 cells . However , PQQ inhibited the appearance of osteoclasts and prevented the decrease of F4 / 80 macrophage maturation marker on O14788 - stimulated cells , suggesting a preventive action of PQQ on O14788 - induced osteoclast differentiation . PQQ inhibited the activation of nuclear factor of activated T cells ( O95644 ) , a key transcription factor of osteoclastogenesis , in O14788 - stimulated cells . On the other hand , PQQ did not inhibit the signaling pathway from Q9Y6Q6 / O14788 binding to O95644 activation , including NF - κB and mitogen - activated protein kinases ( MAPKs ) . PQQ augmented the expression of type I interferon receptor ( P17181 ) and enhanced the IFN - β - mediated janus kinase ( P23458 ) and signal transducer and activator of transcription ( P42224 ) expression . Moreover , PQQ reduced the expression level of c - Fos leading to the activation of O95644 . Taken together , PQQ was suggested to prevent O14788 - induced osteoclast formation via the inactivation of O95644 by reduced c - Fos expression . The reduced c - Fos expression might be mediated by the enhanced IFN - β signaling due to augmented P17181 expression .", "Structure of the human Q9H244 receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G - protein - coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 - like receptors and Q9H244 - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R -- including the prodrugs clopidogrel ( Plavix ) and prasugrel ( ___MASK9___ ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor -- have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half - life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2 . 6 Å resolution crystal structure of human P2Y12R in complex with a non - nucleotide reversible antagonist , AZD1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand - binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .", "Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK81___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK81___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .", "Q15077 nucleotide receptors activate NF - kappaB and increase survival of osteoclasts . Nucleotides , released from cells during inflammation and by mechanical stimulation , act through the P2 family of nucleotide receptors . Previous studies have demonstrated the expression of P47900 and P41231 receptors in osteoclasts . The aim of this study was to determine whether osteoclast P2Y receptors signal through NF - kappaB , a key transcription factor regulating osteoclastogenesis . Immunofluorescence was used to detect the p65 subunit of NF - kappaB , which upon activation translocates from the cytosol to nuclei . Low levels of NF - kappaB activation were observed in untreated rabbit osteoclasts and in those exposed to 2 - methylthio ADP ( P47900 agonist ) or DB00171 or UTP ( P41231 agonists ) . In contrast , UDP or INS48823 ( Q15077 agonists ) induced a significant increase in the number of cells exhibiting NF - kappaB activation , a process sensitive to the proteasome inhibitor lactacystin . In osteoclasts purified by micromanipulation , reverse transcription - PCR revealed the presence of P47900 , P41231 , and Q15077 receptor transcripts , and application of agonists for these receptors induced the transient rise of cytosolic calcium . Treatment of rat osteoclasts with UDP or INS48823 , but not 2 - methylthio ADP or UTP , increased osteoclast survival . O00300 ( a decoy receptor for Q9Y6Q6 ligand ) did not significantly alter the effects of UDP on NF - kappaB localization or osteoclast survival , consistent with a direct action . Moreover , SN50 ( cell - permeable peptide inhibitor of NF - kappaB ) suppressed the enhancement of cell survival induced by UDP and INS48823 . Our findings demonstrate the presence of functional Q15077 receptors in osteoclasts . Thus , nucleotides , following their release at sites of inflammation and mechanical stimulation , can act through Q15077 receptors to initiate NF - kappaB signaling and enhance osteoclast survival .", "Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK34___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .", "Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space ." ]

[ "___MASK18___", "___MASK21___", "___MASK34___", "___MASK69___", "___MASK81___", "___MASK82___", "___MASK85___", "___MASK87___", "___MASK9___" ]

[ "Improvement of chloride transport defect by gonadotropin - releasing hormone ( DB00644 ) in cystic fibrosis epithelial cells . Cystic fibrosis ( CF ) , the most common autosomal recessive disease in Caucasians , is due to mutations in the P13569 gene . F508del , the most frequent mutation in patients , impairs P13569 protein folding and biosynthesis . The F508del - P13569 protein is retained in the endoplasmic reticulum ( ER ) and its traffic to the plasma membrane is altered . Nevertheless , if it reaches the cell surface , it exhibits a Cl (-) channel function despite a short half - life . Pharmacological treatments may target the F508del - P13569 defect directly by binding to the mutant protein or indirectly by altering cellular proteostasis , and promote its plasma membrane targeting and stability . We previously showed that annexine A5 ( AnxA5 ) directly binds to F508del - P13569 and , when overexpressed , promotes its membrane stability , leading to the restoration of some Cl (-) channel function in cells . Because Gonadotropin - Releasing Hormone ( DB00644 ) increases AnxA5 expression in some cells , we tested it in CF cells . We showed that human epithelial cells express DB00644 - receptors ( P30968 ) and that DB00644 induces an AnxA5 overexpression and an increased Cl (-) channel function in F508del - P13569 cells , due to an increased stability of the protein in the membranes . Beside the numerous physiological implications of the P30968 expression in epithelial cells , we propose that a topical use of DB00644 is a potential treatment in CF .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "Connexin36 knockout mice display increased sensitivity to pentylenetetrazol - induced seizure - like behaviors . OBJECTIVE : Large - scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions . To explore roles for connexin36 ( Q9UKL4 ) gap junctions in seizures , we examined the seizure threshold of connexin36 knockout ( Cx36KO ) mice using a pentylenetetrazol ( PTZ ) model . METHODS : Mice ( 2 - 3months old ) with Q9UKL4 wildtype ( WT ) or Cx36KO genotype were treated with vehicle or 10 - 40mg / kg of the convulsant PTZ by intraperitoneal injection . Seizure and seizure - like behaviors were scored by examination of video collected for 20min . Quantitative real - time PCR ( QPCR ) was performed to measure potential compensatory neuronal connexin ( Q8NFK1 , P35212 , P17302 and P36383 ) , pannexin ( Q96RD7 and Q96RD6 ) and gamma - aminobutyric acid type A ( GABA ( A ) ) receptor α1 subunit gene expression . RESULTS : Cx36KO animals exhibited considerably more severe seizures ; 40mg / kg of PTZ caused severe generalized ( ≥ grade III ) seizures in 78 % of KO , but just 5 % of WT mice . A lower dose of PTZ ( 20mg / kg ) induced grade II seizure - like behaviors in 40 % KO vs . 0 % of WT animals . There was no significant difference in either connexin , pannexin or GABA ( A ) α1 gene expression between WT and KO animals . CONCLUSION : Increased sensitivity of Cx36KO animals to PTZ - induced seizure suggests that Q9UKL4 gap junctional communication functions as a physiological anti - convulsant mechanism , and identifies the Q9UKL4 gap junction as a potential therapeutic target in epilepsy .", "Cloning and sequence analysis of a rapamycin - binding protein - encoding gene ( RBP1 ) from Candida albicans . ___MASK99___ ( Rm ) and FK506 are macrolide antifungal agents that exhibit potent immunosuppressive properties in higher eukaryotes which are mediated through interaction with specific receptor proteins ( FKBPs or RBPs , for FK506 - and Rm - binding proteins , respectively ) . These proteins possess peptidyl - prolyl cis - trans isomerase ( PPIase ) activity in vitro which is inhibited by the binding of Rm and FK506 . We previously isolated a gene encoding an P02753 from Saccharomyces cerevisiae , and demonstrated that null mutations in this gene ( called RBP1 ) result in a recessive Rm - resistant ( RmR ) phenotype . We now have cloned the Candida albicans RBP1 gene via complementation of the RmR phenotype in S . cerevisiae . The predicted C . albicans P02753 exhibits 61 % , 52 % and 49 % amino acid ( aa ) sequence identity with RBPs ( FKBPs ) from S . cerevisiae , Neurospora crassa and human cells ( P62942 ) , respectively . Furthermore , several of the aa residues identified as being important for drug binding in human P62942 are conserved within the C . albicans P02753 .", "Characterization of the human gonadotropin - releasing hormone receptor heterologously produced using the baculovirus / insect cell and the Semliki Forest virus systems . 1 . Two eukaryotic viral systems , the baculovirus / insect cell and the Semliki Forest virus systems , were tested for heterologous expression of human gonadotropin - releasing hormone receptor ( GnRHR ) cDNA . 2 . An unmodified as well as a c - myc epitope - tagged human P30968 was produced in two insect cell lines ( Spodoptera frugiperda , Trichoplusia ni ) after infection with the respective recombinant baculoviruses . In both insect cell lines , the receptor was identified by immunoblot analysis as a triplet of bands between 35 and 40 kDa . After deglycosylation of the receptor the molecular mass decreased to 35 kDa . The P30968 was localized in membrane compartments within the infected insect cells . However , only in membranes of infected Trichoplusia ni insect cells could approximately 2000 receptors per cell be detected . 3 . Production of the P30968 in BHK cells using the Semliki Forest virus system resulted in approximately 50 , 000 receptors per cell . A maximal yield of 0 . 42 pmol / mg membrane protein was obtained 24 hr after electroporation of BHK cells with in vitro synthesized RNA . Binding of the antagonist [ 125I ] DB00050 was saturable with a KD of 1 . 3 nM . The receptor produced in the BHK cells was further characterized by ligand displacement studies . The rank order of agonist and antagonist affinities was DB00050 > DB06825 > Antide > DB00644 .", "Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .", "Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK28___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .", "Thirteen type I loci from HSA4q , HSA6p , HSA7q and HSA12q were comparatively Q5TCZ1 - mapped in four river buffalo and sheep chromosomes . Thirteen goat BAC clones containing coding sequences from HSA7 , HSA12q , HSA4 and HSA6p were fluorescence in situ mapped to river buffalo ( Bubalus bubalis , BBU ) and sheep ( Ovis aries , OAR ) R - banded chromosomes . The following type I loci were mapped : P03999 to BBU8q32 and OAR4q32 , P35523 to BBU8q34 and OAR4q34 , P17936 to BBU8q24 and OAR4q27 , KRT to BBU4q21 and OAR 3q21 , P01579 to BBU4q23 and OAR3q23 , IGF1 to BBU4q31 and OAR3q31 , P30968 to BBU7q32 and OAR6q32 , P55157 to BBU7q21 and OAR6q15 , P35913 to BBU7q36 and OAR6q36 , BF to BBU2p22 and OAR20q22 , P05305 to BBU2p24 and OAR20q24 , P08263 to BBU2p22 and OAR20q22 , OLADRB ( MHC ) to BBU2p22 and OAR20q22 . All mapped loci appeared to be located on homologous chromosomes and chromosome bands in both bovids . Comparison between gene orders in bovid ( BBU and OAR ) and human ( HSA ) chromosomes revealed complex rearrangements , especially between BBU7 / OAR6 and HSA4 , as well as between BBU2p / OAR20 and HSA6p .", "Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK53___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .", "[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK49___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .", "The localization of oxytocin , vasopressin , somatostatin and luteinizing hormone releasing hormone in the rat neurohypophysis . The hypothalamic hormones arginine - vasopressin ( AVP ) , oxytocin ( P01178 ) , somatostatin ( Q8TE85 ) , and luteinizing hormone - releasing hormone ( P01148 ) were localized in the rat neurohypophysis by the use of semithin serial sections and the unlabeled antibody enzyme method . Clusters of AVP fibres are present within the central region of the neural lobe , clusters of P01178 fibres mainly in the peripheral part . The AVP fibres enter bilaterally into the neural lobe . The results call into question previous reports on the presence of AVP on receptors in the pars intermedia cells , since incubation with anti - AVP resulted in similar staining in the pars intermedia of the Wistar and homozygous Brattleboro rat , a mutant strain deficient in AVP . The same intermediate lobe cells are stained after incubation of serial sections with anti - AVP and anti - alpha - melanocyte - stimulating hormone ( alpha - MSH ) . This staining of anti - AVP could be removed by solid phase absorption to alpha - MSH and is thus most probably due to cross reaction with alpha - MSH . Q8TE85 fibres appear to be present in the peripheral parts of the proximal neurohypophysial stalk and mainly lateral in its more distal parts . In the neural lobe they rapidly decrease in number , although some fibres continue into the distal part of the neural lobe , running bilaterally and situated adjacent to the pars intermedia . The Q8TE85 staining within magnocellular elements , which has been reported in the literature , can most probably be explained by cross reaction of anti - Q8TE85 with neurophysins . P01148 fibres are very scarce in the neurohypophysial stalk and absent in the neural lobe .", "DB00644 analogues reduce the proliferation of endometrial stromal cells but not endometriotic cells . AIMS : We investigated the potential of gonadotropin - releasing hormone ( DB00644 ) agonists and DB00644 antagonists to inhibit cell proliferation in endometriotic and endometrial stromal cells . METHODS : Twenty patients with ovarian endometriomas and 18 patients with uterine fibromas were recruited . Endometriotic and endometrial stromal cells were obtained from the ovarian chocolate cyst linings and the eutopic endometria of premenopausal women with uterine fibromas , respectively . RESULTS : DB00644 agonist or antagonist treatment attenuated tumor necrosis factor ( P01375 ) - α - induced cell proliferation in the endometrial stromal cells , whereas endometriotic stromal cells did not respond to treatment . The endometriotic stromal cells exhibited a decreased expression of the type I P30968 compared with the endometrial stromal cells . DB00644 agonists or antagonists did not repress P01375 - α - induced P10145 production in endometriotic stromal cells . CONCLUSION : DB00644 agonists and antagonists have similar effects in slowing the growth of endometrial stromal cells . Endometriotic stromal cells resist the antiproliferative effect of DB00644 agonists and antagonists .", "Expression of type I P01148 receptor and in vivo and in vitro P01148 - I effects in corpora lutea of pseudopregnant rabbits . The expression of type I P01148 receptor ( P30968 - I ) and the direct role of P01148 - I on corpora lutea ( CL ) function were studied in the pseudopregnant rabbit model . Immunohistochemistry evidenced P30968 - I and P01148 - I in luteal cells at early ( day 4 pseudopregnancy ) - , mid ( day 9 ) - , and late ( day 13 ) - luteal stages . Real - time RT - PCR and western blotting revealed P30968 - I mRNA and protein at the three luteal stages . DB06719 in vivo treatment at days 9 and 13 decreased plasma progesterone levels for 48 and 24 h respectively . In in vitro cultured CL , buserelin reduced progesterone secretion , increased prostaglandin F ( 2α ) ( P49763 ( 2α ) ) secretion and cyclo - oxygenase - 2 ( P35354 ) and nitric oxide synthase ( NOS ) activities at days 9 and 13 , and decreased PGE₂ at day 13 . Co - incubation with antagonists for P01148 - I ( antide ) , inositol 1 , 4 , 5 - trisphosphate ( IP₃ , 2 - amino - ethoxydiphenylborate ) , and diacylglycerol ( DAG , 1 - hexadecyl - 2 - acetyl glycerol ) or inhibitors for phospholipase C ( P98160 , compound 48 / 80 ) , and protein kinase C ( PKC , staurosporine ) counteracted the buserelin effects . DB06719 co - incubated with P36551 inhibitor ( acetylsalicylic acid ) increased progesterone and decreased P49763 ( 2α ) and NOS activity at days 9 and 13 , whereas co - incubation with NOS inhibitor ( DB04223 methyl ester ) increased progesterone at the same luteal stages . These results suggest that P30968 - I is constitutively expressed in rabbit CL independently of luteal stage , whereas P01148 - I down - regulates directly CL progesterone production via P49763 ( 2α ) at mid - and late - luteal stages of pseudopregnancy , utilizing its cognate type I receptor with a post - receptorial mechanism that involves P98160 , IP₃ , DAG , PKC , P35354 , and NOS .", "Genetic structure of candidate genes for litter size in Italian Large White pigs . The aim of this work was to verify whether polymorphisms in candidate genes for litter size segregate in Italian Large White ( ITLW ) pigs . We genotyped 120 sows that belonged to six different farms for 10 single nucleotide polymorphisms ( SNPs ) of 10 different genes . Polymorphisms in the chosen genes had already been associated with litter - size traits in other pig populations and were candidates for function and / or chromosomal location . The results indicated that the O14967 , pDAZL , and RFN4 SNPs were not segregating in the genotyped samples . The remaining seven markers were polymorphic with minor allele frequencies ranging from 0 . 10 ( AFP ) to 0 . 48 ( P02753 ) . Because of the observed genetic variabilities in the investigated loci , the polymorphisms in the AFP , O00238 , P02778 , Q92731 , P30968 , Q9Y2E5 , and P02753 genes can be considered suitable markers for association studies with litter - size traits in ITLW pigs .", "Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK35___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .", "Effects of gonadoliberin analogue triptorelin on the pituitary - testicular complex in neonatal rats . DB06825 , a synthetic analogue of neurohormone gonadoliberin ( gonadotropin - releasing hormone , DB00644 ) administered daily to rats on postnatal days 5 - 7 suppressed the expression of P30968 in the pituitary gland , but did not change functioning of the pituitary - testicular complex . Administration of triptorelin on postnatal days 12 - 14 ( i . e . during the formation of pulsatile pattern of DB00644 secretion and increasing levels of its mRNA receptor in the pituitary gland ) had no effect on receptor expression , but increased the levels of luteinizing hormone mRNA in the pituitary gland and the weight of testes . At that time , blood levels of testosterone were lowered , which indicated disturbed pulsatile pattern of DB00644 secretion .", "Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .", "Ontogeny of gene expression in the gonadotroph of the developing female rat . During the infantile period of the female rat ( 8 - 21 postnatal days [ P01160 ] of age ) , there is a dramatic increase in plasma DB00094 , which is thought to be important in initiating ovarian activity and , perhaps , the onset of puberty . To begin to understand the regulation of this DB00094 surge , we determined the ontogenetic development of LHbeta , FSHbeta , and P30968 ( P30968 ) mRNA levels in the pituitary gland throughout the infantile period of the female rat . Steady - state mRNA levels were determined by an external standard quantitative reverse transcriptase polymerase chain reaction assay . FSHbeta and P30968 mRNA levels increased to peak on P01160 12 ( p < 0 . 03 ) . LHbeta mRNA levels remained relatively constant until rising on P01160 18 . A DB00644 antagonist ( 10 - 100 microg / animal ) was administered daily from P01160 8 - 11 or P01160 11 - 13 , and animals were killed on P01160 12 or P01160 14 , respectively . FSHbeta , LHbeta , and P30968 mRNAs were not affected by DB00644 antagonist treatment . Plasma DB00094 was selectively reduced in the first group , whereas both plasma LH and DB00094 were suppressed in the second group . These data indicate that gene expression of LHbeta , FSHbeta , and P30968 are differentially regulated in the infantile female rat pituitary . DB00644 is involved in regulating the secretion of DB00094 and LH during the infantile period but not in regulating FSHbeta , LHbeta , or P30968 mRNA gene expression .", "Immunocytochemical demonstration of neuropeptides in the central nervous system of the roundworm , Ascaris suum ( Nematoda : Ascaroidea ) . The localization and distribution of neuropeptides in the central nervous system of the pig roundworm , Ascaris suum , have been determined by an indirect immunofluorescence technique in conjunction with confocal microscopy . Antisera to 25 vertebrate peptides and two invertebrate peptides were used to screen the worm for immunoreactivity ( IR ) . Immunostaining was obtained with antisera to pancreatic polypeptide ( PP ) , peptide YY ( P10082 ) , neuropeptide Y ( P01303 ) , gastrin , cholecystokinin ( CCK ) , DB05875 ( SP ) , atrial natriuretic peptide ( P01160 ) , salmon gonadotropin - releasing hormone ( SGnRH ) , mammalian gonadotropin - releasing hormone ( MGnRH ) , chromogranin A ( P01215 ) and FMRFamide . The most extensive patterns of IR occurred with antisera to P10082 , FMRFamide and gastrin . IR was evident in nerve cells and fibres in the ganglia associated with the anterior nerve ring and in the main nerve cords and their commissures ; IR to FMRFamide also occurred in the posterior nerve ring . Immunostaining for the other peptides was confined to the nerve cords , with the number of immunoreactive nerve fibres varying from peptide to peptide .", "Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK53___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .", "Chlorpromazine reduces the intercellular communication via gap junctions in mammalian cells . In the work presented herein , we evaluated the effect of chlorpromazine ( CPZ ) on gap junctions expressed by two mammalian cell types ; Gn - 11 cells ( cell line derived from mouse P01148 neurons ) and rat cortical astrocytes maintained in culture . We also attempted to elucidate possible mechanisms of action of CPZ effects on gap junctions . CPZ , in concentrations comparable with doses used to treat human diseases , was found to reduce the intercellular communication via gap junctions as evaluated with measurements of dye coupling ( Lucifer yellow ) . In both cell types , maximal inhibition of functional gap junctions was reached within about 1 h of treatment with CPZ , an recovery was almost complete at about 5 h after CPZ wash out . In both cell types , CPZ treatment increased the phosphorylation state of connexin43 ( P17302 ) , a gap junction protein subunit . Moreover , CPZ reduced the reactivity of P17302 ( immunofluorescence ) at cell interfaces and concomitantly increased its reactivity in intracellular vesicles , suggesting an increased retrieval from and / or reduced insertion into the plasma membrane . CPZ also caused cellular retraction reducing cell - cell contacts in a reversible manner . The reduction in contact area might destabilize existing gap junctions and abrogate formation of new ones . Moreover , the CPZ - induced reduction in gap junctional communication may depend on the connexins ( Cxs ) forming the junctions . If P17302 were the only connexin expressed , MAPK - dependent phosphorylation of this connexin would induce closure of gap junction channels .", "Large - scale association study for structural soundness and leg locomotion traits in the pig . BACKGROUND : Identification and culling of replacement gilts with poor skeletal conformation and feet and leg ( FL ) unsoundness is an approach used to reduce sow culling and mortality rates in breeding stock . Few candidate genes related to soundness traits have been identified in the pig . METHODS : In this study , 2066 commercial females were scored for 17 traits describing body conformation and FL structure , and were used for association analyses . Genotyping of 121 SNPs derived from 95 genes was implemented using Sequenom ' s MassARRAY system . RESULTS : Based on the association results from single trait and principal components using mixed linear model analyses and false discovery rate testing , it was observed that P02649 , P34820 , P30988 , P08123 , P20849 , DKFZ , P35555 and VDBP were very highly significantly ( P < 0 . 001 ) associated with body conformation traits . The genes P09917 , P34820 , P30988 , O00300 , P30559 and Q9UBV4 were very highly significantly ( P < 0 . 001 ) associated with FL structures , and P02649 , P30988 , P08123 , P30968 , Q14623 , P42898 and Q9UBV4 were highly significantly ( P < 0 . 01 ) associated with overall leg action . Strong linkage disequilibrium between P30988 and P08123 on SSC9 was detected , and haplotype - ACGACC - was highly significantly ( P < 0 . 01 ) associated with overall leg action and several important FL soundness traits . CONCLUSION : The present findings provide a comprehensive list of candidate genes for further use in fine mapping and biological functional analyses .", "P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .", "Immune senescence and cancer in elderly patients : results from an exploratory study . BACKGROUND : The challenge of immune senescence has never been addressed in elderly cancer patients . This study compares the thymic output and peripheral blood telomere length in ≥ 70year old cancer patients . PATIENTS AND METHODS : Fifty - two elderly cancer patients and 39 age - matched controls without personal history of cancer were enrolled . All patients underwent a Comprehensive Geriatric Assessment ( P01215 ) , from which a multidimensional prognostic index ( MPI ) score was calculated . Peripheral blood samples were studied for naïve and recent thymic emigrant ( RTE ) P01730 (+) and CD8 (+) cells by flow cytometry . T - cell receptor rearrangement excision circle ( TREC ) levels , telomere length and telomerase activity in peripheral blood cells were quantified by real - time PCR . RESULTS : The percentages of CD8 (+) naïve and CD8 (+) RTE cells and TREC levels were significantly lower in cancer patients than in controls ( p = 0 . 003 , p = 0 . 004 , p = 0 . 031 , respectively ) . Telomere lengths in peripheral blood cells were significantly shorter in cancer patients than in controls ( p = 0 . 046 ) and did not correlate with age in patients , whereas it did in controls ( r =- 0 . 354 , p = 0 . 031 ) . Short telomere ( ≤ median ) / low TREC ( ≤ median ) profile was associated with higher risk of cancer ( OR = 3 . 68 [ 95 % CI 1 . 22 - 11 . 11 ] ; p = 0 . 021 ) . Neither unfitness on P01215 nor MPI score were significantly related to thymic output or telomere length in either group . CONCLUSIONS : Immune senescence is significantly worse in elderly cancer patients than in age - matched controls . The low thymic output and the shorter telomeres in peripheral blood cells of cancer patients may reflect a pre - existing condition which facilitates the onset of malignancies in elderly people .", "The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK29___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .", "Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 - binding cassette transporters ( ABCs ) in one of the most drug - resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical - pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real - time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high - resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical - pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up - regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up - regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down - regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC .", "A de novo cystic fibrosis mutation : P01215 ( DB00125 ) to TGA ( stop ) at codon 851 of the P13569 gene .", "Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK99___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .", "Transcript and protein profiling identifies signaling , growth arrest , apoptosis , and NF - κB survival signatures following P01148 receptor activation . P01148 significantly inhibits proliferation of a proportion of cancer cell lines by activating P01148 receptor ( P30968 ) - G protein signaling . Therefore , manipulation of P30968 signaling may have an under - utilized role in treating certain breast and ovarian cancers . However , the precise signaling pathways necessary for the effect and the features of cellular responses remain poorly defined . We used transcriptomic and proteomic profiling approaches to characterize the effects of P30968 activation in sensitive cells ( HEK293 - P30968 , SCL60 ) in vitro and in vivo , compared to unresponsive HEK293 . Analyses of gene expression demonstrated a dynamic response to the P01148 superagonist DB06825 . Early and mid - phase changes ( 0 . 5 - 1 . 0 h ) comprised mainly transcription factors . Later changes ( 8 - 24 h ) included a P01148 target gene , P01215 , and up - or downregulation of transcripts encoding signaling and cell division machinery . Pathway analysis identified altered MAPK and cell cycle pathways , consistent with occurrence of G ( 2 )/ M arrest and apoptosis . Nuclear factor kappa B ( NF - κB ) pathway gene transcripts were differentially expressed between control and DB06825 - treated SCL60 cultures . Reverse - phase protein and phospho - proteomic array analyses profiled responses in cultured cells and SCL60 xenografts in vivo during DB06825 anti - proliferation . Increased phosphorylated NF - κB ( p65 ) occurred in SCL60 in vitro , and p - NF - κB and IκBε were higher in treated xenografts than controls after 4 days DB06825 . NF - κB inhibition enhanced the anti - proliferative effect of DB06825 in SCL60 cultures . This study reveals details of pathways interacting with intense P30968 signaling , identifies potential anti - proliferative target genes , and implicates the NF - κB survival pathway as a node for enhancing P01148 agonist - induced anti - proliferation .", "___MASK84___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .", "___MASK68___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK68___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK68___ is a promising pharmacological tool in the treatment of renal edema .", "Impact of aromatic residues within transmembrane helix 6 of the human gonadotropin - releasing hormone receptor upon agonist and antagonist binding . To investigate the impact of aromatic residues within transmembrane helix 6 ( TMH6 ) of the human gonadotropin - releasing hormone receptor ( P30968 ) on agonist and antagonist binding , residues Y ( 283 ) , Y ( 284 ) , W ( 289 ) , Y ( 290 ) , W ( 291 ) , and F ( 292 ) were exchanged to alanine and analyzed comprehensively in functional reporter gene and ligand binding assays . Whereas receptor mutants Y ( 283 ) A , Y ( 284 ) A , and W ( 291 ) A were capable of neither ligand binding nor signal transduction , mutants W ( 289 ) A , Y ( 290 ) A , and F ( 292 ) A were functional : the F ( 292 ) A mutant behaved like wild - type receptor , while mutants W ( 289 ) A and Y ( 290 ) A differentiated between agonistic and antagonistic ligands . On the basis of the high - resolution X - ray structure of bovine rhodopsin as well as available data on P30968 mutants , models for ligand - receptor interactions are proposed . The model for D - DB00150 ( 6 )- DB00644 ( DB06825 ) binding , representing a superagonistic ligand , is in full accordance to available data . Furthermore , new interactions are proposed : pGlu ( 1 ) interacts with N ( 212 ) in transmembrane helix 5 , DB00135 ( 5 ) with Y ( 290 ) , and D - DB00150 ( 6 ) with W ( 289 ) . The binding behavior of mutants W ( 289 ) A and Y ( 290 ) A corresponds to the proposed binding model for the antagonist DB00050 . In summary , our data as presented indicate that Y ( 290 ) plays a key function in agonist but not antagonist binding .", "Pharmacogenomics of methadone maintenance treatment . ___MASK40___ is the major opioid substitution therapy for opioid dependence . Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines . Nevertheless many genetic factors have been investigated including those affecting its metabolism ( P20813 - consistent results ) , efflux transport ( P - gp - inconsistent results ) , target μ - opioid receptor ( μ - opioid receptor - inconsistent results ) and a host of other receptors ( P14416 ) and signaling elements ( P48051 and P32121 ; not replicated ) . None by themselves have been able to substantially explain dosage variation ( the major but not sole end point ) . When multiple genes have been combined such as P08183 , P20813 , P35372 and P14416 a greater contribution to dosage variation was found but not as yet replicated . As stabilization of dosage needs to be made rapidly , it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed , which may or may not tailor to different ethnic groups and each country ' s policy towards an outcome that benefits all .", "Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic - pituitary - gonadal axis , including gonadotrophin - releasing hormone - I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor - 1 ( VIPR - 1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker - trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR - 1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR - 1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T - C1715301T haplotypes of VIPR - 1 and EN300 . H1H3 had the highest EN300 . Four PCR - RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C - G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3 - domain P62993 - like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR - 1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 .", "Differential neurotrophic regulation of sodium and calcium channels in an adult sympathetic neuron . Adult neuronal phenotype is maintained , at least in part , by the sensitivity of individual neurons to a specific selection of neurotrophic factors and the availability of such factors in the neurons ' environment . Nerve growth factor ( P01138 ) increases the functional expression of Na (+) channel currents ( I ( Na ) ) and both N - and L - type Ca ( 2 +) currents ( I ( Ca , N ) and I ( Ca , L ) ) in adult bullfrog sympathetic ganglion ( BFSG ) B - neurons . The effects of P01138 on I ( Ca ) involve the mitogen - activated protein kinase ( MAPK ) pathway . Prolonged exposure to the ganglionic neurotransmitter luteinizing hormone releasing hormone ( P01148 ) also increases I ( Ca , N ) but the transduction mechanism remains to be elucidated as does the transduction mechanism for P01138 regulation of Na (+) channels . We therefore exposed cultured BFSG B - neurons to chicken II P01148 ( 0 . 45 microM ; 6 - 9 days ) or to P01138 ( 200 ng / ml ; 9 - 10 days ) and used whole cell recording , immunoblot analysis , and ras or rap - 1 pulldown assays to study effects of various inhibitors and activators of transduction pathways . We found that 1 ) P01148 signals via ras - MAPK to increase I ( Ca , N ) , 2 ) this effect is mediated via protein kinase C - beta ( P05771 - IotaIota ) , 3 ) protein kinase A ( PKA ) is necessary but not sufficient to effect transduction , 4 ) P01138 signals via phosphatidylinositol 3 - kinase ( PI3K ) to increase I ( Na ) , and 5 ) long - term exposure to P01148 fails to affect I ( Na ) . Thus downstream signaling from P01148 has access to the ras - MAPK pathway but not to the PI3K pathway . This allows for differential retrograde and anterograde neurotrophic regulation of sodium and calcium channels in an adult sympathetic neuron .", "Systemic therapies for metastatic renal cell carcinoma in older adults . The introduction of targeted therapies has radically changed the treatment paradigm for metastatic renal cell carcinoma ( mRCC ) . However , multiple clinical dilemmas have emerged . For instance , limited data are available to juxtapose the safety and efficacy profile of targeted therapies between older and younger adults . Herein , pivotal trials of vascular endothelial growth factor ( P15692 ) - and mammalian target of rapamycin ( P42345 ) - directed therapies are assessed in the context of their implications in treating older adults with mRCC . In general , subset analyses from these pivotal studies suggest similar efficacy of targeted therapies amongst older adults . Aging is accompanied by a multitude of physiological changes , as well as an increased prevalence of co - morbidities . The age - related toxicity profiles of targeted agents for mRCC are detailed to provide a framework for the risks and benefits of these therapies in older adults . Ultimately , tools such as the Comprehensive Geriatric Assessment ( P01215 ) that account for physiological ( as opposed to chronological ) age may prove useful in the evaluation and treatment of older adults with mRCC ." ]

[ "___MASK28___", "___MASK29___", "___MASK35___", "___MASK40___", "___MASK49___", "___MASK53___", "___MASK68___", "___MASK84___", "___MASK99___" ]

[ "S - sulfhydration of Q02750 leads to P09874 activation and DNA damage repair . The repair of DNA damage is fundamental to normal cell development and replication . Hydrogen sulfide ( H2S ) is a novel gasotransmitter that has been reported to protect cellular aging . Here , we show that H2S attenuates DNA damage in human endothelial cells and fibroblasts by S - sulfhydrating Q02750 at cysteine 341 , which leads to P09874 activation . H2S - induced Q02750 S - sulfhydration facilitates the translocation of phosphorylated P27361 / 2 into nucleus , where it activates P09874 through direct interaction . Mutation of Q02750 cysteine 341 inhibits P29323 phosphorylation and P09874 activation . In the presence of H2S , activated P09874 recruits P18887 and P49916 to DNA breaks to mediate DNA damage repair , and cells are protected from senescence .", "Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK29___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK29___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK29___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK29___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK29___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK29___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK29___ .", "Is Q13304 a P2Y / leukotriene receptor ? examination of uracil nucleotides , nucleotide sugars , and cysteinyl leukotrienes as agonists of Q13304 . The orphan receptor Q13304 has been reported to be activated by UDP , UDP - sugars , and cysteinyl leukotrienes , and coupled to intracellular Ca ( 2 +) mobilization and inhibition of DB02527 accumulation , but other studies have reported either a different agonist profile or lack of agonist activity altogether . To determine if Q13304 is activated by uracil nucleotides and leukotrienes , the hemagglutinin - tagged receptor was expressed in five different cell lines and the signaling properties of the receptor were investigated . In P13671 , 1321N1 , or Chinese hamster ovary ( CHO ) cells stably expressing Q13304 , UDP , UDP - glucose , DB03501 , and cysteinyl leukotriene C4 ( LTC4 ) all failed to promote inhibition of forskolin - stimulated DB02527 accumulation , whereas both UDP and UDP - glucose promoted marked inhibition ( > 80 % ) of forskolin - stimulated DB02527 accumulation in P13671 and CHO cells expressing the Q15391 receptor . Likewise , none of these compounds promoted accumulation of inositol phosphates in COS - 7 or human embryonic kidney 293 cells transiently transfected with Q13304 alone or cotransfected with Gαq / i5 , which links Gi - coupled receptors to the Gq - regulated phospholipase C ( P98160 ) signaling pathway , or PLCε , which is activated by the Gα12 / 13 signaling pathway . Moreover , none of these compounds promoted internalization of Q13304 in 1321N1 - Q13304 cells . Consistent with previous reports , coexpression experiments of Q13304 with cysteinyl leukotriene receptor 1 ( Q9Y271 ) suggested that Q13304 acts as a negative regulator of Q9Y271 . Taken together , these data suggest that UDP , UDP - glucose , DB03501 , and LTC4 are not the cognate ligands of Q13304 .", "Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK79___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .", "Effects of ozone exposure mediated by BEAS - 2B cells on T cells activation : a possible link between environment and asthma . OBJECTIVE : To explore the possible link between ozone and asthma through analyzing Th1 / Th2 differentiation of T cells following incubation with conditioned medium from the BEAS - 2B cells exposed to ozone in vitro . METHOD : Bronchial epithelial cell line , BEAS - 2B , was cultured using an air - liquid interface culture system in a CO2 incubator and exposed to 0 or 0 . 16 or 0 . 25 mg / m3 of ozone for 8 h . The amounts of IL - 1β , P05231 and RANTES in the cell supernatant were detected . The cell culture supernatants were collected and used as conditioned medium in the next experiment . T cells from children recruited were incubated with conditioned medium for 12 h . Activation rate of Q07108 and Th1 / Th2 / Th17 differentiation were analyzed . RESULTS : BEAS - 2B cells exposed to different ozone concentrations showed morphological changes . Cells exposed to 0 . 16 and 0 . 25 mg / m3 ozone produced higher amounts of IL - 1β , P05231 and RANTES than that in the control group . Children with allergic asthma had upregulated expression of genes related with asthma , including P13500 , CCR4 , P19875 , Q9Y271 , Q99665 , Q14627 , Q13478 , P01584 , P10145 , P25025 and O75888 . Q07108 expression in T cells was significantly elevated irrespective of ozone exposure in children with allergic asthma . Following ozone exposure , in asthmatic children group , expression levels of cytokines of Th1 cells were collectively higher than those from Th2 cells . Ozone - exposed conditioned media could slightly increase all the Th1 , Th2 and Th17 cytokines in T cells from allergic asthmatic children . CONCLUSIONS : Our results suggested that Th1 cells activation might be predominant over Th2 activation upon ozone exposure in asthmatic children , which might help to clarify the mechanisms of asthma related to environmental factors like ozone .", "5 - Lipoxygenase mediates O14788 - induced osteoclast formation via the cysteinyl leukotriene receptor 1 . 5 - Lipoxygenase ( P09917 ) catalyzes the formation of two major groups of leukotrienes , leukotriene B4 and cysteinyl leukotrienes ( CysLTs ) , and it has been implicated as a promising drug target to treat various inflammatory diseases . However , its role in osteoclastogenesis has not been investigated . In this study , we used mouse bone marrow - derived macrophages ( BMMs ) to show that P09917 inhibitor suppresses O14788 - induced osteoclast formation . Inhibition of P09917 was associated with impaired activation of multiple signaling events downstream of Q9Y6Q6 , including P29323 and p38 phosphorylation , and IκB degradation , followed by a decrease in O95644 expression . Ectopic overexpression of a constitutively active form of O95644 partly rescued the antiosteoclastogenic effect of P09917 inhibitor . The knockdown of P09917 in BMMs also resulted in a significant reduction in O14788 - induced osteoclast formation , accompanied by decreased expression of O95644 . Similar effects were shown with CysLT receptor ( CysLTR ) 1 / 2 antagonist and small RNA for Q9Y271 in BMMs , indicating the involvement of CysLT and Q9Y271 in P09917 - mediated osteoclastogenesis . Finally , P09917 inhibitor suppressed LPS - induced osteoclast formation and bone loss in the in vivo mouse experiments , suggesting a potential therapeutic strategy for treating diseases involving bone destruction . Taken together , the results of this study demonstrate that P09917 is a key mediator of O14788 - induced osteoclast formation and possibly a novel therapeutic target for bone - resorption diseases .", "___MASK46___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK46___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK46___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .", "The potential role of PD0332991 ( ___MASK11___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK11___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .", "G - protein - coupled receptors and asthma endophenotypes : the cysteinyl leukotriene system in perspective . Genetic variation in specific G - protein coupled receptors ( GPCRs ) is associated with a spectrum of respiratory disease predispositions and drug response phenotypes . Although certain GPCR gene variants can be disease - causing through the expression of inactive , overactive , or constitutively active receptor proteins , many more GPCR gene variants confer risk for potentially deleterious endophenotypes . Endophenotypes are traits , such as bronchiole hyperactivity , atopy , and aspirin intolerant asthma , which have a strong genetic component and are risk factors for a variety of more complex outcomes that may include disease states . GPCR genes implicated in asthma endophenotypes include variants of the cysteinyl leukotriene receptors ( Q9Y271 and Q9NS75 ) , and prostaglandin D2 receptors ( Q13258 and Q9Y5Y4 ) , thromboxane A2 receptor ( P21731 ) , beta2 - adrenergic receptor ( P07550 ) , chemokine receptor 5 ( P51681 ) , and the G protein - coupled receptor associated with asthma ( Q6W5P4 ) . This review of the contribution of variability in these genes places the contribution of the cysteinyl leukotriene system to respiratory endophenotypes in perspective . The genetic variant ( s ) of receptors that are associated with endophenotypes are discussed in the context of the extent to which they contribute to a disease phenotype or altered drug efficacy .", "Effect of endothelin receptor antagonist ___MASK77___ on chronic hypoxia - induced inflammation and chemoafferent neuron adaptation in rat carotid body . Chronic hypoxia ( CH ) induces an inflammatory response in rat carotid body that is characterized by immune cell invasion and the expression of pro - inflammatory cytokines . In the present study , we have investigated the role of type - A endothelin ( P25101 ) receptors in the development of CH - induced inflammation . After 7 days of CH ( 380 Torr ) , double - label immunofluorescence studies demonstrated elevated levels of P25101 receptor and tyrosine hydroxylase ( TH ) in O ( 2 )- sensitive type I cells . Following CH , P25101 receptors were also expressed on resident and invasive P08575 + immune cells distributed in tissue surrounding chemosensory cell lobules . Immnofluorescence and quantitative PCR studies showed that concurrent treatment with the P25101 / B receptor antagonist , ___MASK77___ ( 200 mg / kg / day ) , blocked CH - induced ED - 1 + macrophage invasion and the upregulation of cytokines , including interleukin - 1β ( IL - 1β ) , interleukin - 6 ( P05231 ) , tumor necrosis factor α ( TNFα ) , and monocyte chemoattractant protein - 1 ( P13500 ) . Moreover , ___MASK77___ treatment blocked the CH - induced increases in expression of acid - sensitive ion channels ( ASICs ) in chemoafferent neurons in the petrosal ganglion ( PG ) . Our findings are consistent with the hypothesis that CH - induced inflammation involves the upregulation and release of ET - 1 from type I cells . ET - 1 may act in an autocrine / paracrine mechanism via P25101 receptors on chemosensory type I cells and immune cells to promote an inflammatory response .", "Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy . The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model . One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin ( 20 mg / kg per os ) . Three hours after indomethacin , the extent of macroscopically visible gastric damage was determined , and gastric LTB4 synthesis was determined . The compounds tested were PF - 5901 , A - 64077 , nordihydroguaiaretic acid , and L - 698 , 037 . Each compound produced dose - related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin - induced damage . The antioxidant properties of these compounds was assessed using an in vitro assay . There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin - induced gastric damage . In the second part of the study , the effects of intravenous , administration of LTD4 and LTB4 receptor antagonists on indomethacin - induced gastric epithelial damage ( measured by permeability to [ 51Cr ] DB00974 ) were assessed . The two Q9Y271 antagonists ( MK - 571 and DB00549 ) significantly reduced the permeability changes induced by indomethacin , while the two LTB4 antagonists ( SC - 41930 and LY - 255 , 283 ) were without significant effect . Despite the reduction of gastric epithelial injury , blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury . These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs . However , it remains unclear to what extent leukotrienes are involved in the initiation of the injury , as opposed to its amplification .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK3___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "Q9Y271 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin - intolerant asthma patients . OBJECTIVES : Leukotriene receptor antagonists ( LTRA ) , such as montelukast , have been used as a first - line treatment for patients with aspirin - intolerant asthma ( AIA ) . This study evaluated associations between the clinical requirement for LTRA and genetic polymorphisms of the P09917 , Q16873 , P35354 , Q9Y271 and P21731 genes in the arachidonic acid cascade in the long - term management of 89 AIA patients from a Korean population . METHODS : Asthma control status was monitored for 1 year with maintenance medications of inhaled corticosteroid and oral LTRA , and AIA patients were classified into three groups according to the mean montelukast dose required per month to maintain asthma control for 1 year : group I ( > or = 200 mg montelukast / month ; n = 37 ) , group II ( 5 - 150 mg / month ; n = 25 ) and group III ( < 5 mg / month ; n = 27 ) . Genetic polymorphisms in the arachidonic acid cascade were determined using a single - base extension method . RESULTS : We found that there was a significant difference in the genotype frequency of the Q9Y271 promoter polymorphism - 634C > T among the three groups ( p = 0 . 007 for group I vs group II , p = 0 . 017 for group I vs group III ) , while there were no significant associations between LTRA requirements and polymorphisms of the other genes . The patients with the variant genotype ( CT or TT ) of the - 634C = T Q9Y271 promoter polymorphism showed a higher expression level than those with the common genotype ( CC ) . CONCLUSION : These findings indicate that the Q9Y271 promoter polymorphism is a useful genetic marker for predicting LTRA requirements in the long - term management of AIA patients .", "Mobilization of Ph chromosome - negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate - induced complete cytogenetic remission . Imatinib mesylate ( IM , ___MASK55___ , Glivec ) can induce a high rate of complete cytogenetic response ( CCR ) in chronic myeloid leukaemia ( CML ) patients , although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction ( RT - PCR ) . It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant ( APBSCT ) . We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony - stimulating factor [ rHu - DB00099 ; 10 micro g / kg / d subcutaneously ( s . c . ) for at least 4 d ] alone , while continuing IM treatment . The median d 5 ( peak ) P28906 + count was 11 . 5 / microl ( range 0 - 108 / microl ) , and 43 / 58 ( 74 % ) patients underwent a median of two ( range 1 - 3 ) apheresis procedures . A median dose of 2 . 1 x 10 ( 6 )/ kg P28906 + cells ( range 0 . 1 - 6 . 5 x 10 ( 6 )/ kg ) was collected . Some 84 % of 31 collections analysed were negative for the Philadelphia ( Ph ) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue ( P11274 - P00519 ) translocation by cytogenetics or fluorescent in situ hybridization respectively . No toxicity was reported with the regimen . Overall , the target P28906 + dose ( 2 x 10 ( 6 )/ kg P28906 + ) was attained in 23 / 58 ( 40 % ) patients who entered the study . In summary , we have demonstrated that successful mobilization of Ph - P28906 + cells from IM - treated patients in CCR is possible using rHu - G - P04141 alone .", "Leukotriene D4 - induced increases in cytosolic calcium in THP - 1 cells : dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists . Agonist - induced changes in intracellular calcium ion concentration ( [ Ca ++] i ) were examined in human monocytic leukemia THP - 1 cells loaded with fura 2 / acetoxymethyl ester ( fura 2 / AM ) . Leukotriene ( LT ) D4 induced a concentration - dependent biphasic response consisting of a transient phase ( up to 5 - fold peak increase ) followed by a sustained phase , showing characteristics of a receptor - operated calcium channel . Homologous desensitization to LTD4 was observed . The responses to LTD4 were reduced by 80 to 90 % in calcium - free buffer . The responses to LTD4 in a calcium - free buffer were dependent upon the duration of prior exposure of the cells to a calcium - free environment . The response at 30 or 60 min after exposure to calcium - free buffer was greater than that at earlier time points ( time - dependent sensitization ) . Similar responses were obtained with THP - 1 cells exposed to DB00974 - containing buffer . It is speculated that such time - dependent sensitization is a result of changes at the receptor level . The responses to LTD4 were blocked by two specific LTD4 antagonists , MK - 0571 and DB00549 , in a concentration - dependent manner . When given after addition of LTD4 , MK - 0571 or DB00549 reversed the sustained phase of the LTD4 - induced response , suggesting that maintenance of the response requires persistent activation of the Q9Y271 . DB00549 was 5 to 10 times more potent than MK - 0571 ( IC50 values of 1 . 1 and 9 . 3 nM , respectively ) , in agreement with results from radioligand binding studies reported separately .", "Induction of granulocytic differentiation in myeloblasts by hydroquinone , a metabolite of benzene , involves the leukotriene D4 receptor . Chronic exposure of humans to benzene ( BZ ) , a Class I carcinogen , causes acute myelogenous leukemia , possibly via its bone marrow metabolite , hydroquinone ( HQ ) . The ability to alter cytokine - dependent growth and differentiation in hematopoietic stem or progenitor cells appears to be a property of agents with leukemogenic potential . We have previously reported that BZ and HQ specifically stimulate granulopoiesis in mice and cause granulocytic differentiation in normal murine interleukin ( IL ) - 3 - dependent , granulocyte colony - stimulating factor ( DB00099 ) - inducible 32D myeloblasts . BZ induces granulocytic differentiation by upregulating the production of leukotriene D4 ( LTD4 ) , an essential intracellular mediator of G - P04141 signaling . We report here that HQ ( 0 . 5 - 4 . 0 microM ) , as well as LTD4 ( 1 nM - 10 microM ) , causes a concentration - dependent induction of granulocytic differentiation in 32D myeloblasts . Unlike LTD4 , which induces terminal granulocytic differentiation , HQ undergoes a myeloperoxidase - dependent oxidation to bioreactive p - benzoquinone ( BQ ) , which induces differentiation predominantly to the myelocyte stage . Studies with the highly specific Q9Y271 antagonist , MK - 571 , suggest that BQ induces granulocytic differentiation in myeloblasts by activating the Q9Y271 , thus obviating the requirement for LTD4 . This was confirmed by the demonstration that HQ , in the presence of LTD4 , shifts the stage - specific pattern of terminal differentiation induced by LTD4 to the incomplete ( myelocyte ) profile induced by HQ . The inability of HQ to induce a complete program of terminal granulocytic differentiation in myeloblasts , as well as its ability to compete with induction by LTD4 , may have a bearing on the leukemogenic potential of BZ .", "The impact of biological agents interfering with receptor / ligand binding in the immune system . We herein discuss the impact of biological agents based on the ability of monoclonal antibodies to target specific molecules . This approach has given to clinical immunologists a spectrum of drugs able to manipulate the immune system . In the first session , we discuss drugs targeting T - cell function by : ( 1 ) targeting P10747 mediated costimulation ( DB01281 and DB06681 ) ; ( 2 ) interfering with interleukin - 2 receptor ( DB00074 and DB00111 ) ; ( 3 ) blocking cell adhesion and homing ( DB00092 , DB00095 , DB00108 ) . The second session is dedicated to drugs targeting cytokines or their receptors . The best known and largely experimented case is represented by drugs targeting tumor necrosis factor ( P01375 ) ( DB00065 , Adalilumab , Certolizumab ) or its p75 receptor ( DB00005 ) . However , newer products are now available to target other inflammatory cytokines including P05231 , P10145 , IL - 12 , P40933 , Q14116 , IL - 23 . These agents have the potential to become powerful tools in the control of several immune - mediated diseases , especially auto - immune and inflammatory ones . They traslate into reality the prediction that antibodies will eventually become \" magic bullets which seek their own target \" ( P . Ehrich , 1906 ) .", "Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK45___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK45___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK45___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK45___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK45___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .", "PPARgamma activation abolishes LDL - induced proliferation of human aortic smooth muscle cells via SOD - mediated down - regulation of superoxide . Native LDL would be a mitogenic and chemotactic stimulus of VSMC proliferation and differentiation in the atherosclerotic lesion where endothelial disruption occurred . In previous studies , our group investigated the molecular mechanisms by which LDL induces P10145 production and by which PPARalpha activation abolishes LDL effects in human aortic SMCs ( hAoSMCs ) . Herein is the first report of PPARgamma activation by troglitazone ( TG ) exerting its inhibitory effects on LDL - induced cell proliferation via generation not of H ( 2 ) O ( 2 ) , but of O2 (.-) , and the subsequent activation of Erk1 / 2 in hAoSMCs . Moreover , in this study TG abolished the LDL - accelerated G ( 1 )- S progression to control levels via down - regulation of active cyclinD1 / P11802 and cyclinE / P24941 complexes and up - regulation of P38936 ( Cip1 ) expression . TG exerted its anti - proliferative effects through the up - regulation of basal superoxide dismutase ( SOD ) expression . This data suggests that the regulation of O2 (.-) is located at the crossroads between LDL signaling and cell proliferation .", "O60760 is expressed in microglia in the developing postnatal mouse brain . O60760 ( O60760 ) is a P52209 ( 2 )- synthesizing enzyme and is expressed in antigen - presenting cells , mast cells , and other immunocompetent cells . We here report the O60760 expression in microglia and the migration pathway of microglia in the developing mouse brain as detected by O60760 immunohistochemistry . Expression of O60760 mRNA peaked at postnatal day ( P01160 ) 10 , decreased gradually thereafter , and reached a plateau at P01160 20 . The mRNAs for target molecules of P52209 ( 2 ) , i . e . , DP receptor ( DPR ) and Q9Y5Y4 receptor , showed developmental profiles overlapped to that of O60760 . Most of the O60760 (+) cells at P01160 10 had morphological characteristics of ameboid microglia and gave positive immunostaining with microglia - specific markers such as RCA - 1 , F4 / 80 , or ER - MP12 . These specific markers became less detectable later on , but O60760 was still expressed even in resting microglia . Thus , O60760 is a useful marker for investigation of microglial development . Spaciotemporal evaluation of microglial development and migration with O60760 immunostaining revealed the following three major possible migration pathways of microglia in the postnatal brain : from the lateral ventricle via subventricular zones to brain parenchyma ; from the leptomeninges around the cerebellopontine angle to the cerebellar white matter ; and from the overlying leptomeninges to the hippocampus , basal forebrain , and brainstem .", "___MASK48___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK48___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells ." ]

[ "___MASK11___", "___MASK29___", "___MASK3___", "___MASK45___", "___MASK46___", "___MASK48___", "___MASK55___", "___MASK77___", "___MASK79___" ]

[ "[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK39___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .", "Comparative study of the expression of DNA mismatch repair genes , the adenomatous polyposis coli gene and growth arrest DNA damage genes in melanoma recurrences and metastases . The main goal of this study was to examine the expression of DNA mismatch repair genes ( P40692 , P43246 , P54277 and P54278 ) , the adenomatous polyposis coli ( P25054 ) gene and growth arrest DNA damage inducible ( GADD ) genes ( O75807 , P24522 and P35638 ) in the different stages of melanoma recurrences and metastases , and to identify any mutual consistencies in their expression pattern . All the cases of primary melanoma examined showed a reduced expression of DNA repair genes . These results demonstrate that disturbances of DNA repair begin in the early stages of melanoma . No significant differences were found in the expression of these markers between cutaneous melanomas and their recurrences and metastases ( P > 0 . 05 ) . Eighteen significant correlations between markers were found in the primary melanomas , and 10 significant correlations were observed in the first recurrences of melanoma . In contrast , 27 statistically significant relationships were demonstrated in metastatic lymph nodes . The different correlations found in primary and metastatic tumours confirmed the hypothetical difference in marker interaction in the diagnostic groups investigated . Our results suggest that DNA repair genes may play an important role in the recurrence and metastasis of melanomas .", "P00533 - dependent and - independent cell - signaling pathways originating from the urokinase receptor . P00749 ( uPA ) and vitronectin activate cell - signaling pathways by binding to the uPA receptor ( Q03405 ) . Because Q03405 is glycosylphosphatidylinositol - anchored , the signaling receptor is most likely a Q03405 - containing multiprotein complex . This complex may be heterogeneous within a single cell and among different cell types . The goal of this study was to elucidate the role of the P01133 receptor ( P00533 ) as a component of the Q03405 - signaling machinery . uPA activated extracellular signal - regulated kinase ( P29323 ) in COS - 7 cells and in COS - 7 cells that overexpress Q03405 , and this response was blocked by the P00533 inhibitor , tyrphostin AG1478 , implicating the P00533 in the pathway that links Q03405 to P29323 . By contrast , Rac1 activation , which occurred as a result of Q03405 overexpression , was P00533 - independent . COS - 7 cell migration was stimulated , in an additive manner , by Q03405 - dependent pathways leading to P29323 and Rac1 . AG1478 inhibited only the P29323 - dependent component of the response . CHO - P04264 cells do not express P00533 ; however , these cells demonstrated P29323 activation in response to uPA , indicating the presence of an P00533 - independent alternative pathway . As anticipated , this response was insensitive to AG1478 . When CHO - P04264 cells were transfected to express P00533 or a kinase - inactive mutant of P00533 , P29323 activation in response to uPA was unchanged ; however , the P00533 - expressing cells acquired sensitivity to AG1478 . We conclude that the P00533 may function as a transducer of the signal from Q03405 to P29323 , but not Rac1 . In the absence of P00533 , an alternative pathway links Q03405 to P29323 ; however , this pathway is apparently silenced by P00533 expression .", "Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population . To investigate the relationship between amnestic mild cognitive impairment ( aMCI ) and candidate gene polymorphisms in a Chinese population , 116 aMCI patients and 93 normal controls were recruited . Multi - dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects . MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms ( SNPs ) and analyse allelic , genotypic or haplotypic distributions . The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls . The distributions of SNPs relating to the amyloid cascade hypothesis ( O96008 rs157581 G and O96008 rs2075650 G ) , to the cholesterol metabolism hypothesis ( ApoE rs429358 C , P01130 rs11668477 G and O95992 rs7091822 T and P00749 rs2227564 CT ) and to the tau hypothesis ( P10636 / Q8IWL8 rs242562 GG ) in aMCI were significantly different than those in normal controls . Interactions were also found in aMCI amongst SNPs in P01130 rs11668477 , P00749 rs2227564 , and O96008 rs157581 , between SNPs in O96008 rs157580 and Q9Y5Z0 rs9975138 . The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD -- those of the amyloid cascade , tau and cholesterol metabolism pathways . Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways .", "[ GH - secreting pituitary adenomas -- correlation between clinical features , growth potential and histopathological studies ] . We compared clinical features , including endocrinological and radiological findings , histological features and the proliferative parameters ( P12004 , MIB - 1 and AgNORs ) with immunohistochemical features in growth hormone ( GH ) secreting pituitary adenomas . 18 cases were divided into two groups based on immunohistochemical intracytoplasmic stainings for cytokeratin : a prominent dot - like pattern ( group I , 6 cases ) and a diffuse perinuclear pattern ( group II , 12 cases ) . Patients in group I ( 6 females , m = 37 . 6 years old ) were younger , showed female predominance and had a shorter history of acromegaly compared with patients in group II ( 7 males , 5 females , m = 44 . 9 years old ) . Although the size of the adenomas tend to be larger in group I , no difference was recognized in plasma GH levels between the two groups . Increased serum prolactin ( PRL ) levels were accompanied more common in group I . Abnormal GH responses to TRH and P01148 injection and GH suppressions to bromocriptine administration were more frequently noted in group II than group I . Surgical approaches were transcranial in most cases of group I and transphenoidal in group II . There was no difference in surgical results as to the correction rate of GH levels between the two groups . Histopathologically , group I adenomas were mostly chromophobic , weakly positive for GH , and were generally negative for PRL and alpha - subunit . On the other hand , group II adenomas were mostly acidophilic , diffusely stained for GH , and were often positive for PRL and alpha - subunit . However , there was no significant difference in proliferating parameters between the two groups . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Receptor - bound uPA is reversibly protected from inhibition by low molecular weight inhibitors . P00749 ( uPA ) plays a ubiquitous role in cell migration and invasiveness . DB00594 , a competitive inhibitor of uPA , can inhibit endothelial cell ( EC ) outgrowth during angiogenesis . To address the question of whether amiloride blocked angiogenesis by inhibiting uPA , we undertook a study of uPA expression in sprouting EC in vitro and the effects of amiloride on both enzymatic and morphogenetic activity . As expected , amiloride inhibited soluble uPA ( suPA ) with an IC ( 50 ) of 45 - 85 microm , however , receptor - bound uPA ( rbuPA ) from the sprouting EC was insensitive to amiloride . Removal of uPA from its receptors confers sensitivity to inhibition by amiloride suggesting that a reversible conformational change may mediate the insensitivity of rbuPA to amiloride and its analogs . In summary , we found no evidence to support the hypothesis that amiloride blocks capillary outgrowth by inhibition of uPA , but were able to successfully demonstrate a functional difference between two physiological forms of this important matrix - degrading enzyme .", "Growth associated proteins in tumor cells and stroma related to disease progression of colon cancer accounting for tumor tissue DB00917 content . Connections among specific proteins ( Bax , Bcl - 2 , P09038 , P23219 , P35354 , E - cad , p15 , p53 , P12004 , TGFbeta3 , TUNEL , P04275 ) in control of cell proliferation , apoptosis , cell adhesion , tumor vascularity and DB00917 content were evaluated in colon cancer as related to disease progression and survival . Tumor tissue and adjacent normal colon mucosa were obtained at curative resection in 22 patients . DB00917 concentrations were assessed in tumor tissue and tumor derived blood , splanchnic blood , peripheral venous blood and urine . Host inflammation was determined ( CRP , P03372 ) in relationship to tumor differentiation and stage . Patients survived as expected according to Dukes A - D staging . Growth - related proteins correlated between tumor cells and stroma as well as between protein factors within tumor cells and tumor stroma . P35354 predicted tumor tissue content of DB00917 ( p < 0 . 002 ) , without reflection in tumor derived blood . Systemic inflammation was predicted by p15 , TGFbeta3 and Bcl - 2 in tumor tissue ( p < 0 . 001 ) . p15 and P04275 predicted reduced survival in ungrouped patients ( p < 0 . 02 ) , while p15 , P12004 , TGFbeta3 and P04275 predicted reduced survival ( p < 0 . 0001 ) when patient grouping accounted for high tumor content of DB00917 . Our results connect systemic inflammation and survival to P35354 staining and increased DB00917 in colon cancer . Thus , it seems important to understand proximal signals behind upregulation of P35354 and subsequent DB00917 production in certain tumor cells in colon cancer .", "Overexpression of O75807 enhances production of recombinant human antithrombin III in Chinese hamster ovary cells . To improve the production of recombinant human antithrombin III ( DB11598 ) in Chinese hamster ovary ( CHO ) cells , the gene encoding growth arrest and DNA damage inducible protein 34 ( O75807 ) , which is a transcription factor involved in the unfolded protein response ( UPR ) , was cloned from CHO - P04264 cells . Overexpression of O75807 significantly enhanced the production of recombinant DB11598 in CHO 13D - 35D cells . The specific rate of DB11598 production in the O75807 - overexpressing CHO 13D - 35D cells reached approximately 28 pg / cell / d . After 144 h of incubation , the DB11598 concentration in the culture supernatant was approximately 40 % higher than that observed in the case of the parental CHO 13D - 35D cells . The mRNA expression , specific activity , and fucosylation of DB11598 were not affected by O75807 overexpression . Overexpression of O75807 is a promising method of improving the production of secreted protein pharmaceuticals in CHO cells .", "Phosphatase holoenzyme P50391 / O75807 negatively regulates TLR response by inhibiting TAK1 serine 412 phosphorylation . The molecular mechanisms that fine tune TLRs responses need to be fully elucidated . Protein phosphatase - 1 ( P50391 ) has been shown to be important in cell death and differentiation . However , the roles of P50391 in TLR - triggered immune response remain unclear . In this study , we demonstrate that P50391 inhibits the activation of the MAPK and NF - κB pathway and the production of P01375 - α , P05231 in macrophages triggered by O15455 , O00206 , and Q9NR96 in a phosphatase - dependent manner . Conversely , P50391 knockdown increases TLRs - triggered signaling and proinflammatory cytokine production . Tautomycetin , a specific inhibitor of P50391 , aggravates LPS - induced endotoxin shock in mice . We further demonstrate that P50391 negatively regulates TLR - triggered signaling by targeting TGF - β - activated kinase 1 ( TAK1 ) serine 412 ( Ser412 ) phosphorylation , which is required for activation of TAK1 - mediated IL - 1R and TLR signaling . Mutation of TAK1 DB00133 412 to alanine ( S412A ) significantly inhibits TLR / IL - 1R - triggered NF - κB and MAPK activation and induction of proinflammatory cytokines in macrophage and murine embryonic fibroblast cells . DNA damage - inducible protein 34 ( O75807 ) specifies P50391 to dephosphorylate TAK1 at Ser412 . O75807 depletion abolished the interaction between TAK1 and P50391 , and it relieved P50391 overexpression - induced inhibition of TLRs signaling and proinflammatory cytokine production . In addition , knockdown of O75807 significantly promotes TLR - induced TAK1 Ser412 phosphorylation , downstream NF - κB and MAPK activation , and proinflammatory cytokine production . Therefore , P50391 , as a physiologic inhibitor , together with its regulatory subunit O75807 , tightly controls TLR - induced TAK1 Ser412 phosphorylation , preventing excessive activation of TLRs and protecting the host from overwhelmed inflammatory immune responses .", "Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK78___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .", "P00749 : a paracrine factor regulating the bioavailability of IGFs in PA - III cell - induced osteoblastic metastases . The transplantation of PA - III rat prostate cancer cells onto rat skeleton produces osteoblastic metastases . Therefore w e studied the paracrine interactions between the PA - III cells and osteoblast - derived osteosarcoma cells ( UMR 106 cells ) . A serine protease secreted by PA - III cells hydrolyzed IGF - binding protein - 1 and IGF - binding protein - 2 ( P08833 and P18065 ) detected in the cell culture media ( CM ) of OMR 106 cells by western ligand blotting . The serine protease of PA - III cell CM was purified using a benzamidine affinity column . This protease was a protein of 45 - 50 kDa on polyacrylamide gel electrophoresis under non - reducing conditions but generated two protein bands under reducing conditions ; a ) one of 33 - 35 kDa possessing protease activity and b ) another of 20 - 25 kDa which was proteinolytically inactive . Sequence analysis identified the amino acid sequence of the a - chain ( 20 - 25 kDa band ) and of the b - chain ( 33 - 35 kDa band ) of rat urokinase - type plasminogen activator molecule . DB00013 purified from PA - III cell CM hydrolyzed IGFBPs of UMR 106 cells and stimulated the proliferation of UMR 106 cells in serum - free cultures . Its protease activity was abolished by benzamidine and aprotinin . Its mitogenic activity for osteoblasts was inhibited by anti - P05019 monoclonal antibody . Northern blot analysis documented the expression of the urokinase - type plasminogen activator gene in the mRNA extracted from PA - III cells . DB00013 expression was inhibited by dexamethasone . Therefore , we conclude that urokinase - type plasminogen activator stimulates osteoblasts via an P05019 dependent mechanism . Hydrolysis of the IGFBOPs at the sites of PA - III cell - induced bone tumors account for an increased bioavailability of IGFs . This may facilitate the development and the growth of PA - III cell - induced bone tumor and can also mediate the subsequent local osteoblastic reaction .", "N - arachidonoyl - L - serine is neuroprotective after traumatic brain injury by reducing apoptosis . N - arachidonoyl - L - serine ( AraS ) is a brain component structurally related to the endocannabinoid family . We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto - parietal skull and the mechanisms involved . A single injection of AraS following injury led to a significant improvement in functional outcome , and to reduced edema and lesion volume compared with vehicle . Specific antagonists to CB2 receptors , transient receptor potential vanilloid 1 ( Q8NER1 ) or large conductance calcium - activated potassium ( BK ) channels reversed these effects . Specific binding assays did not indicate binding of AraS to the Q9Y2T6 cannabinoid receptor . N - arachidonoyl - L - serine blocked the attenuation in phosphorylated extracellular - signal - regulated kinase 1 / 2 ( P29323 ) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices . Increased levels of the prosurvival factor Bcl - xL were evident 24 hours after injury in AraS - treated mice , followed by a 30 % reduction in caspase - 3 activity , measured 3 days after injury . Treatment with a CB2 antagonist , but not with a P21554 antagonist , reversed this effect . Our results suggest that administration of AraS leads to neuroprotection via P29323 and Akt phosphorylation and induction of their downstream antiapoptotic pathways . These protective effects are related mostly to indirect signaling via the CB2R and Q8NER1 channels but not through P21554 or Q9Y2T6 receptors .", "Dexamethasone reverses adrenalectomy - induced neuronal de - differentiation in midbrain raphe - hippocampus axis . Differentiation leads to specific morphological and biochemical characteristics . We examined whether epigenetic factors ( e . g . , glucocorticoids ) are required to maintain neuronal differentiation in the adult brain . In the midbrain , adrenalectomy ( P10109 ) ( 1 - 2 wk ) reduced the size of tryptophan hydroxylase ( WH ) - immunoreactive ( IR ) neurons . P10109 rats exposed to short - term ( 24 - 72 - h ) dexamethasone ( ST - DEX ) in the drinking saline ( 10 mg / l ) showed an increase in WH protein , somal area and dendritic size of WH - IR neurons . In the hippocampus , P10109 for 2 - 3 mo ( long - term ; LT ) reduced Nissl staining , calbindin ( DB09061 ) - IR and P08908 receptor mRNA in the granular cell layer , and the size of the molecular layer and its DB09061 - IR dendrites . Small vimentin ( Vim ) - IR glial cells emerged in the granular layer . ST - DEX after LT - P10109 rapidly induced a recovery of P08908 mRNA , Nissl labeling and DB09061 - IR in the granule cell layer . In the molecular layer , there was an increase in the area and in the number of DB09061 - IR dendrites . Furthermore , the Vim - IR glial cells were enlarged in size and branching . The rate of cell proliferation was studied in these animals . Immunostaining with antibodies against proliferating cell nuclear antigen ( P12004 ) and use of bromouridine argue against enhanced neurogenesis after ST - DEX in LT - P10109 . We propose that glucocorticoids induce and maintain differentiation of serotonergic and DB09061 - IR neurons in the midbrain - hippocampal axis . A neuronotrophic role for the glial P08908 receptor is suggested .", "5 - Hydroxytryptamine induces cyclooxygenase - 2 in rat vascular smooth muscle cells : Mechanisms involving Src , PKC and MAPK activation [ corrected ] . Considering the importance of 5 - hydroxytryptamine ( 5 - HT ) and cyclooxygenase ( P36551 ) products in vascular pathology , we investigated the effects of 5 - HT on P36551 expression in rat vascular smooth muscle cells ( VSMCs ) , and to provide mechanistic insights into these effects . VSMCs were enzymatically isolated from aortic media of Wistar rats . Incubation of VSMCs with 5 - HT for 24h stimulated prostaglandin I ( 2 ) production , but this stimulation was completely suppressed by NS - 398 , a selective P35354 inhibitor . 5 - HT induced transient P35354 , but not P23219 , protein and mRNA expression in concentration - and time - dependent manners . This effect of 5 - HT was completely inhibited by sarpogrelate , a 5 - HT ( 2A ) receptor antagonist . 5 - HT - induced P35354 expression was markedly blunted by Ca ( 2 +) depletion ; GF 109203X , a protein kinase C ( PKC ) inhibitor ; Q99463 , an inhibitor of Src - family tyrosine kinase ( Src ) ; PD 98059 , an inhibitor of extracellular signal - regulated kinase ( P29323 ) activation ; SB 203580 , an inhibitor of p38 mitogen - activated protein kinase ( MAPK ) ; and SP 600125 , an inhibitor of c - Jun N - terminal kinase ( JNK ) . 5 - HT activated P29323 and p38 MAPK , followed by JNK activation . Q99463 inhibited these activations , while GF 109203X inhibited only JNK activation . Furthermore , PD 98059 inhibited JNK activation . These results suggest that 5 - HT induces P35354 expression in rat VSMCs , and that PKC , Src , and MAPK activation are each essential for the full expression of P35354 pathways .", "Survey of differentially methylated promoters in prostate cancer cell lines . DNA methylation and copy number in the genomes of three immortalized prostate epithelial and five cancer cell lines ( LNCaP , PC3 , PC3M , PC3M - Pro4 , and PC3M - LN4 ) were compared using a microarray - based technique . Genomic DNA is cut with a methylation - sensitive enzyme HpaII , followed by linker ligation , polymerase chain reaction ( PCR ) amplification , labeling , and hybridization to an array of promoter sequences . Only those parts of the genomic DNA that have unmethylated restriction sites within a few hundred base pairs generate PCR products detectable on an array . Of 2732 promoter sequences on a test array , 504 ( 18 . 5 % ) showed differential hybridization between immortalized prostate epithelial and cancer cell lines . Among candidate hypermethylated genes in cancer - derived lines , there were eight ( P16070 , P38936 , P03372 , P00749 , P10826 , SFN , P25445 , and Q01534 ) previously observed in prostate cancer and 13 previously known methylation targets in other cancers ( O95661 , bcl - 2 , P38398 , P42773 , P24522 , Q13126 , P06401 , O43511 , P09486 , P43405 , Q9UDY2 , P09936 , and Q06250 ) . The majority of genes that appear to be both differentially methylated and differentially regulated between prostate epithelial and cancer cell lines are novel methylation targets , including Q9NQU5 , Q92878 , O43711 , Q96B01 , Q13163 , P06213 , P35555 , and GG2 - 1 , representing a rich new source of candidate genes used to study the role of DNA methylation in prostate tumors .", "P00749 and plasminogen activator inhibitor type - 1 mRNA assessment in breast cancer by means of NASBA : correlation with protein expression . DB00013 plasminogen activator ( uPA ) and its main inhibitor , plasminogen activator inhibitor type - 1 ( P05121 ) determined in tumor tissue by means of enzyme - linked immunosorbent assay ( ELISA ) can discriminate patients with primary breast cancer at high risk vs low risk for recurrence . The aim of this study was to analyze uPA and P05121 messenger RNA ( mRNA ) expression by means of quantitative nucleic acid sequence - based amplification ( NASBA ) on 77 primary breast tumor samples and to correlate this expression with the uPA and P05121 protein content . We observed that the 2 markers were significantly overexpressed ( uPA , P < . 0001 ; P05121 , P = . 0042 ) in mRNA in the ELISA + group . The receiver operating characteristic ( ROC ) curves demonstrated high concordance between NASBA and ELISA ( area under the ROC curve of 0 . 84 and 0 . 70 for uPA and P05121 , respectively ) and showed that uPA and P05121 status could be predicted by using the molecular assay with sensitivity and specificity values of 80 . 8 % and 82 . 4 % and sensitivity and specificity values of 66 . 7 % and 74 . 0 % , respectively .", "Gossypin up - regulates P01130 through activation of P29323 pathway : a signaling mechanism for the hypocholesterolemic effect . Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease . This study aims to elucidate the effect of gossypin on cholesterol metabolism in HepG2 cells . Results indicated that gossypin significantly reduced the total cholesterol concentration in a dose - dependent manner . There was a time - and dose - dependent increase in the expression of low - density lipoprotein receptor ( P01130 ) protein . However , 3 - hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase , the rate - limiting enzyme in cholesterol synthesis , was not affected by gossypin . Moreover , gossypin had no effect on nuclear sterol regulatory element binding proteins ( SREBP ) - 2 abundance . The activity of gossypin on P01130 expression was inhibited by the extracellular signal - regulated kinase ( P29323 ) inhibitor PD98059 . Western blotting analysis revealed that gossypin treatment dose - and time - dependently increased P29323 activation and preceded the up - regulation of P01130 expression . Collectively , these new findings identify gossypin as a new hypocholesterolemic agent that up - regulates P01130 expression independent of Q12772 but is dependent on P29323 activation .", "___MASK13___ : kinetic and dynamic profile in the treatment of pain . ___MASK13___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK13___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK13___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK13___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .", "Chemical coding of the human gastrointestinal nervous system : cholinergic , VIPergic , and catecholaminergic phenotypes . The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal ( GI ) tract . For this purpose , antibodies against the vesicular monoamine transporters ( P54219 / 2 ) , the vesicular acetylcholine transporter ( Q16572 ) , tyrosine hydroxylase ( TH ) , dopamine beta - hydroxylase ( P09172 ) , serotonin ( 5 - HT ) , vasoactive intestinal peptide ( P01282 ) , and protein gene product 9 . 5 ( P09936 ) were used . For in situ hybridization ( 35 ) S - labeled P54219 , Q05940 , and Q16572 riboprobes were used . In all regions of the human GI tract , 50 - 70 % of the neurons were cholinergic , as judged by staining for Q16572 . The human gut unlike the rodent gut exhibits a cholinergic innervation , which is characterized by an extensive overlap with VIPergic innervation . Neurons containing Q05940 constituted 14 - 20 % of all intrinsic neurons in the upper GI tract , and there was an equal number of TH - positive neurons . In contrast , P09172 was absent from intrinsic neurons . Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes . In conclusion , the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species , but also significant differences . P01282 is a cholinergic cotransmitter in the intrinsic innervation of the human gut . The substantial overlap between Q05940 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life . The absence of P09172 from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype .", "P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK39___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK39___ is in clinical development as an orally active agent .", "Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK35___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .", "Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .", "Apoptosis induction associated with the ER stress response through up - regulation of JNK in HeLa cells by gambogic acid . BACKGROUND : Gambogic acid ( GA ) was extracted from the dried yellow resin of gamboge ( Garcinia hanburyi ) which is traditionally used as a coloring material for painting and cloth dying . Gamboge has been also used as a folk medicine for an internal purgative and externally infected wound . We focused on the mechanisms of apoptosis induction by GA through the unfold protein response ( ER stress ) in HeLa cells . METHODS : The cytotoxic effect of GA against HeLa cells was determined by trypan blue exclusion assay . Markers of ER stress such as P17861 , P11021 , P35638 , O75807 and Q9UBS3 were analyzed by RT - PCR and Real - time RT - PCR . Cell morphological changes and apoptotic proteins were performed by Hoechst33342 staining and Western blotting technique . RESULTS : Our results indicated a time - and dose - dependent decrease of cell viability by GA . The ER stress induction is determined by the up - regulation of spliced P17861 mRNA and activated P11021 , P35638 , O75807 and Q9UBS3 expression . GA also induced cell morphological changes such as nuclear condensation , membrane blebbing and apoptotic body in Hela cells . Apoptosis cell death detected by increased DR5 , caspase - 8 , - 9 , and - 3 expression as well as increased cleaved - PARP , while decreased Bcl - 2 upon GA treatment . In addition , phosphorylated JNK was up - regulated but phosphorylated P29323 was down - regulated after exposure to GA . CONCLUSIONS : These results suggest that GA induce apoptosis associated with the ER stress response through up - regulation of p - JNK and down - regulation of p - P29323 in HeLa cells .", "Selective cyclooxygenase - 2 inhibitor rofecoxib ( Vioxx ) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer . Recent studies indicate that cyclooxygenase - 2 ( P35354 ) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer . A human pancreatic adenocarcinoma cell line , Mia PaCa - 2 , was incubated for 18 hours with 5 micromol / L of rofecoxib ( Vioxx ) , a selective P35354 inhibitor . Total RNA was isolated and gene expression analyzed by DNA microarray chips . In a separate experiment , athymic mice were orthotopically injected with 7 . 5 x 10 ( 5 ) Mia PaCa - 2 cells through a minilaparotomy . After 1 month , laparotomy was repeated to measure tumor size , and mice were randomized to receive reformulated rodent chow containing either 12 . 5 mg / kg / day of rofecoxib or no drug for 21 days . Tumor growth was assessed by comparing volume before and after treatment . In vitro , rofecoxib decreased gene expression of cyclin D1 / P24385 , a key component of cell cycle progression , while increasing expression of several cell cycle arrest genes , including P38936 / P38936 , p33 / ING , O75807 , and P24522 ( P < 0 . 05 ) . In vivo , tumor growth was significantly reduced in treated vs . control mice ( P < 0 . 05 ) . No systemic toxicity was observed in mice receiving rofecoxib . These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest .", "Purinergic receptors are part of a functional signaling system for proliferation and differentiation of human epidermal keratinocytes . We investigated the expression of Q93086 , Q99572 , P47900 and P41231 receptor subtypes in normal human epidermis and in relation to markers of proliferation ( P12004 and Ki - 67 ) , keratinocyte differentiation ( cytokeratin P13645 and involucrin ) and markers of apoptosis ( TUNEL and anticaspase - 3 ) . Using immunohistochemistry , we showed that each of the four receptors was expressed in a spatially distinct zone of the epidermis , suggesting different functional roles for these receptors . Functional studies were performed on primary cultures of human keratinocytes and on explanted rat skin , where different P2 receptor subtype agonists and antagonists were applied to cultured keratinocytes or injected subcutaneously into the skin , respectively . An increase in cell number was caused by low doses of the nonspecific P2 receptor agonist DB00171 , the P41231 receptor agonist UTP ( p < 0 . 001 ) , and the P47900 receptor agonist 2MeSADP ( p < 0 . 05 ) . There was a significant decrease in cell number as a result of treatment with the Q93086 receptor agonist ATPgammaS ( p < 0 . 001 ) and the Q99572 receptor agonist BzATP ( p < 0 . 001 ) . Suramin caused a significant block in the effect of 100 microm DB00171 ( p < 0 . 01 ) and 1000 microm DB00171 ( p < 0 . 001 ) on cell number . These results imply that different purinergic receptors have different functional roles in the human epidermis with P47900 and P41231 receptors controlling proliferation , while Q93086 and Q99572 receptors control early differentiation , terminal differentiation and death of keratinocytes , respectively .", "[ DB00594 attenuates hypoxia - induced proliferation of rats pulmonary artery smooth muscle cells by suppressing Na +/ H + exchanger - 1 ] . AIM : To study the influence of Na +/ H + exchange inhibitor amiloride on hypoxia - induced proliferation in rats pulmonary artery smooth muscle cells ( PASMCs ) , also observe the change of Na +/ H + exchanger - 1 ( P19634 ) activity and expression . METHODS : Rats PASMGs were cultured in normoxia ( 21 % O2 ) or hypoxia ( 2 % O2 ) for 24 hours , as well as administered amiloride with various concentrations , cultured for 24 hours , then determined MTT OD values and rates of P12004 positive cells to investigate cells proliferation , moreover intracellular pH was determined by interactive Laser Cytometer , and Na +/ H + exchanger - 1 mRNA expression was determined by RT - PCR . RESULTS : Hypoxic exposure heightened intracellular pH and mRNA expression of P19634 in PASMCs , however , 3 . 123 - 50 micromol / L amiloride depressed them gradually . Additionally , hypoxic exposure raised MTT OD value and rates of P12004 positive cells , similarly , the above two indexes descended gradually with presence of 3 . 125 - 50 micromol / L amiloride . CONCLUSION : Na +/ H + exchange inhibitor amiloride can suppress hypoxia - induced proliferation in pulmonary artery smooth muscle cells , which is due to depress activity and expression of P19634 .", "[ ___MASK78___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .", "Acid - sensing ion channels promote the inflammation and migration of cultured rat microglia . Microglia , the major immune cells in central nervous system , act as the surveillance and scavenger of immune defense and inflammatory response . Previous studies suggest that there might be close relationship between acid - sensing ion channels ( ASICs ) and inflammation , however , the exact role of ASICs in microglia during inflammation remains elusive . In the present study , we identified the existence of ASICs in the primary cultured rat microglia and explored their functions . By using reverse transcriptase polymerase chain reaction ( RT - PCR ) , quantitative real - time PCR ( qPCR ) , western blotting , and immunofluorescence experiments , we demonstrated that P78348 , ASIC2a , and Q9UHC3 were existed in cultured and in situ rat microglia . After lipopolysaccharide ( LPS ) stimulation , the expressions of microglial P78348 and ASIC2a were upregulated . Meanwhile , ASIC - like currents and acid - induced elevation of intracellular calcium were increased , which could be inhibited by the nonspecific ASICs antagonist amiloride and specific homomeric ASIC1a blocker PcTx1 . In addition , both inhibitors reduced the expression of inflammatory cytokines , including inducible nitric oxide synthase and cyclooxygenase 2 stimulated by LPS . Furthermore , we also observed significant increase in the expression of P78348 and ASIC2a in scrape - stimulated microglial migration . DB00594 and PcTx1 prevented the migration by inhibiting P29323 phosphorylation . Taken together , these results suggest that ASICs participate in neuroinflammatory response , which will provide a novel therapeutic strategy for controlling the inflammation - relevant neuronal diseases .", "Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair . We present an oligonucleotide microarray ( \" MetaboChip \" ) based on the arrayed primer extension ( P27695 ) technique , allowing genotyping of single nucleotide polymorphisms ( SNPs ) in genes of interest for cancer susceptibility and pharmacogenetics . P27695 consists of a sequencing reaction primed by an oligonucleotide anchored with its 5 ' end to a glass slide and terminating one nucleotide before the polymorphic site . The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism . Ninety - three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project , using a set of 102 reference DNA samples from the Coriell Biorepository . Selected SNPs belong to the following genes : P00325 , P05091 , P27695 , CDKN2A , P21964 , P04798 , P05177 , Q16678 , P11509 , P33261 , P11712 , P05181 , P08684 , P14416 , P21917 , P07099 , P07992 , P18074 , Q92889 , P28715 , P30550 , O15217 , P21266 , P09211 , GSTT2 , LIG3 , Q00987 , P16455 , P05164 , NAT1 , NAT2 , P15559 , O15527 , P12004 , P06746 , Q01959 , P04179 , P04637 , P18887 , O43543 , O43542 , and O15287 . We assessed the performance of P27695 by comparing the results obtained with MetaboChip against those reported by the SNP500 . Among 88 SNPs that yielded signals , 6 showed less than 99 % of concordance , whereas 82 performed accurately , showing that P27695 is a reliable and sensitive genotyping method .", "Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage . BACKGROUND : Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage ( Q53FZ2 ) due to reduced cerebral blood flow ( Q03701 ) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells ( SMC ) via activation of mitogen - activated protein kinase ( MAPK ) of the extracellular signal - regulated kinase ( P29323 ) 1 / 2 signal pathway . We hypothesize that Q53FZ2 initiates cerebrovascular P27361 / 2 activation , resulting in receptor upregulation . The raf inhibitor will inhibit the molecular events upstream P27361 / 2 and may provide a therapeutic window for treatment of cerebral ischemia after Q53FZ2 . RESULTS : Here we demonstrate that Q53FZ2 increases the phosphorylation level of P27361 / 2 in cerebral vessels and reduces the neurology score in rats in additional with the Q03701 measured by an autoradiographic method . The intracisternal administration of SB - 386023 - b , a specific inhibitor of raf , given 6 h after Q53FZ2 , aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h . This is accompanied by reduced phosphorylation of P27361 / 2 in cerebrovascular SMC . Q53FZ2 per se enhances contractile responses to endothelin - 1 ( ET - 1 ) , 5 - carboxamidotryptamine ( 5 - CT ) and angiotensin II ( Ang II ) , upregulates ETB , P28222 and AT1 receptor mRNA and protein levels . Treatment with SB - 386023 - b given as late as at 6 h but not at 12 h after the Q53FZ2 significantly decreased the receptor upregulation , the reduction in Q03701 and the neurology score . CONCLUSION : These results provide evidence for a role of the P27361 / 2 pathway in regulation of expression of cerebrovascular SMC receptors . It is suggested that raf inhibition may reduce late cerebral ischemia after Q53FZ2 and provides a realistic time window for therapy .", "Amelioration of experimental colitis by Na - H exchanger - 1 inhibitor amiloride is associated with reversal of IL - 1ss and P29323 mitogen - activated protein kinase . OBJECTIVE : Na - H exchanger - 1 ( P19634 ) is induced in experimental colitis . It has not yet been established whether its inhibition ameliorates colitis . The effects of amiloride , an inhibitor of P19634 , on colitis were examined in this study . Levels of mitogen - activated protein ( Q96HU1 ) kinases P29323 , p38 and interleukin 1ss which participate in intestinal inflammation were also examined in the colonic smooth muscle of rats with colitis . MATERIAL AND METHODS : Colitis was induced in Sprague - Dawley male rats by intrarectal administration of trinitrobenzenesulphonic acid ( TNBS ) and treated daily with amiloride ( 3 , 5 , and 10 mg / kg b . w . ( body - weight ) , orally ) starting 1 h before induction of colitis . The animals were sacrificed on day 5 post - TNBS . Controls received phosphate buffered saline in a similar manner . RESULTS : The highest dose of amiloride ( 10 mg / kg ) was lethal . The lowest dose ( 3 mg / kg ) was tolerated and was used in this study . DB00594 significantly reversed the colitis - reduced contractility and induction of P05164 activity , P19634 , IL - 1ss and P29323 , but not of p38 in inflamed colonic smooth muscle . Splenomegaly , increased colonic mass and decreased sodium pump activity were significantly reversed by amiloride treatment . There was no recovery of b . w . loss in the treated colitic animals . Urine output was increased , whereas food and water intake remained unchanged following amiloride treatment . CONCLUSIONS : These findings suggest that the beneficial effects of P19634 inhibition in experimental colitis are mediated through IL - 1ss and P29323 Q96HU1 kinase .", "Angiogenic alterations associated with circulating neoplastic DNA in ovarian carcinoma . OBJECTIVES : Forty percent of women with ovarian carcinoma have circulating free neoplastic DNA identified in plasma . Angiogenesis is critical in neoplastic growth and metastasis . We sought to determine whether circulating neoplastic DNA results from alterations in the balance of angiogenesis activators and inhibitors . METHODS : Sixty patients with invasive ovarian carcinomas with somatic P04637 mutations that had been characterized for circulating neoplastic DNA had carcinoma analyzed for microvessel density using immunohistochemistry with CD31 and for the expression of P15692 , Q15389 , O15123 , P35354 , P00749 , P07996 , P09603 , P42336 , Q16665 , P10145 , P08253 , and P14780 message by real - time quantitative polymerase chain reaction . The expression of each gene was calculated relative to P04406 expression for each neoplasm . Patient plasma had been tested for circulating neoplastic DNA using a ligase detection reaction . RESULTS : P08253 expression was significantly correlated with free plasma neoplastic DNA ( P = . 007 ) . Microvessel density was not correlated with plasma neoplastic DNA or P38398 / 2 mutation status . The expression pattern of other angiogenic factors did not correlate with plasma neoplastic DNA but correlated with each other . P38398 / 2 mutated carcinomas had significantly different expression profiles of angiogenesis activators and inhibitors in comparison to sporadic carcinomas . CONCLUSIONS : P08253 expression is associated with the presence of circulating neoplastic DNA in women with ovarian carcinoma . These data are consistent with the proinvasive properties of P08253 and suggest that the presence of circulating neoplastic DNA indicates a more aggressive malignant phenotype . Carcinomas with germ line P38398 / 2 mutations had a lower angiogenic profile than those without mutations .", "___MASK39___ increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : ___MASK39___ is a direct - acting Q9H244 - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non - platelet - directed properties . Animal and in vitro models suggested that the \" pleiotropic \" properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 was measured by liquid chromatography . To assess the mechanism of P25054 variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 - adenosine diphosphate receptor blockade was assessed by the vasodilator - stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 than patients receiving clopidogrel ( 1 . 5 μM [ interquartile range : 0 . 98 to 1 . 7 μM ] vs . 0 . 68 μM [ interquartile range : 0 . 49 to 0 . 78 μM ] ; p < 0 . 01 ) . The P25054 was not correlated with vasodilator - stimulated phosphoprotein ( p = 0 . 16 ) . Serum - containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0 . 01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0 . 1 ) . ___MASK39___ and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : ___MASK39___ increases P25054 in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .", "Distinct signalling pathways of murine histamine H1 - and H4 - receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G - protein - coupled receptors , referred to as histamine H1 - receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro - inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre - clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse ( m ) P35367 or mH4R at similar levels and analyzed HA - induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen - activated protein kinases ( MAPKs ) P29323 1 / 2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA - induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA - induced P18146 gene expression only in Q9H3N8 - expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA - induced gene expression . In summary , using this system which allows a direct comparison of mH1R - and mH4R - induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident .", "DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .", "No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK58___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK58___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK58___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK58___ among adults with ADHD .", "Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .", "The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners . Mutations in the tumor suppressor genes Q92574 and P49815 , encoding hamartin and tuberin , respectively , cause the tumor syndrome tuberous sclerosis with similar phenotypes . Until now , over 50 proteins have been demonstrated to interact with hamartin and / or tuberin . Besides tuberin , the proteins Q96N67 , ezrin / radixin / moesin , Q8TDY2 , IKKbeta , Melted , P35240 , Q00994 ( p75NTR ) , P07196 , Plk1 and Q9P0N9 have been found to interact with hamartin . Whereas Plk1 and Q9P0N9 have been demonstrated not to bind to tuberin , for all the other hamartin - interacting proteins the question , whether they can also bind to tuberin , has not been studied . P49815 interacts with 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , AMPK , P62158 , Q9BUF7 / Q8NI35 , cyclin A , cyclins D1 , D2 , D3 , Dsh , ERalpha , Erk , FoxO1 , Q15751 , HPV16 E6 , HSCP - 70 , P0DMV8 , P49137 , Q96PY6 , p27KIP1 , Pam , PC1 , PP2Ac , Q15276 , Rheb , RxRalpha / P11473 and Q15796 / 3 . 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , Dsh , FoxO1 , Q15751 , p27KIP1 and PP2Ac are known not to bind to hamartin . For the other tuberin - interacting proteins this question remains elusive . The proteins axin , Cdk1 , cyclin B1 , O75807 , GSK3 , P42345 and Q15418 have been found to co - immunoprecipitate with both , hamartin and tuberin . The kinases Cdk1 and IKKbeta phosphorylate hamartin , Erk , Akt , P49137 , AMPK and Q15418 phosphorylate tuberin , and GSK3 phosphorylates both , hamartin and tuberin . This detailed summary of protein interactions allows new insights into their relevance for the wide variety of different functions of hamartin and tuberin .", "P12004 D - 1 , interleukin - 6 , HER - 2 / neu , transforming growth factor receptor - II and prediction of relapse in women with early stage , hormone receptor - positive breast cancer treated with tamoxifen . We hypothesized that amplification or overexpression of HER - 2 ( c - erbB - 2 ) , the Ki - 67 antigen ( Mib1 ) , cyclin D - 1 ( CD1 ) , interleukin - 6 ( P05231 ) , or the transforming growth factor beta II receptor , ( TGFbetaRII ) , would predict relapse in women with early stage , estrogen ( ER ) and / or progesterone receptor ( PR ) positive breast cancer treated with tamoxifen . Conditional logistic regression models and a new novel analytic method - support vector machines ( SVM ) were used to assess the effect of multiple variables on treatment outcome . All patients had stage I - IIIa breast cancer ( AJCC version 5 ) . We paired 63 patients who were disease - free on or after tamoxifen with 63 patients who had relapsed ( total 126 ) ; both disease - free and relapsed patients were matched by duration of tamoxifen therapy and time to recurrence . These 126 patients also served as the training set for SVM analysis and 18 other patients used as a validation set for SVM . In a multivariate analysis , larger tumor size , increasing extent of lymph node involvement , and poorer tumor grade were significant predictors of relapse . When HER - 2 or CD1 were added to the model both were borderline significant predictors of relapse . The SVM model , after including all of the clinical and marker variables in the 126 patients as a training set , correctly predicted relapse in 78 % of the 18 patient validation samples . In this trial , HER - 2 and CD1 proved of borderline significance as predictive factors for recurrence on tamoxifen . An SVM model that included all clinical and biologic variables correctly predicted relapse in > 75 % of patients .", "Anandamide drives cell cycle progression through P21554 receptors in a rat model of synchronized liver regeneration . The endocannabinoid system , through cannabinoid receptor signaling by endocannabinoids , is involved in a wide range of functions and physiopathological conditions . To date , very little is known concerning the role of the endocannabinoids in the control and regulation of cell proliferation . An anti - proliferative action of P21554 signaling blockade in neurogenesis and angiogenesis argues in favor of proliferation - promoting functions of endocannabinoids through P21554 receptors when pro - growth signals are present . Furthermore , liver regeneration , a useful in vivo model of synchronized cell proliferation , is characterized by a peak of anandamide that elicits through P21554 receptor , the expression of critical mitosis genes . The aim of this study was to focus on the timing of endocannabinoid signaling changes during the different phases of the cell cycle , exploiting the rat liver regeneration model following partial hepatectomy , the most useful to study synchronized cell cycle in vivo . Hepatic regeneration led to increased levels of anandamide and endocannabinoid - like molecules oleoylethanolamide ( OEA ) and palmitoylethanolamide ( PEA ) in the P55008 phase of the cell cycle , with a concomitant increase in P21554 mRNA levels , whose protein expression peaked later during the S phase . Blocking of P21554 receptor with a low dose of the selective antagonist / inverse agonist SR141716 ( 0 . 7 mg / kg / dose ) affected cell cycle progression reducing the expression of P12004 , and through the inhibition of pERK and pSTAT3 pathways . These results support the notion that the signaling mediated by anandamide through P21554 receptor may be important for the entry and progression of cells into the cell cycle and hence for their proliferation under mitogenic signals .", "Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .", "The role of heat shock protein 90 in migration and proliferation of vascular smooth muscle cells in the development of atherosclerosis . The molecular chaperone heat shock protein 90 ( HSP90 ) is overexpressed in plaques of atherosclerosis patients , and is associated with plaque instability . However , the role of HSP90 in atherosclerosis remains unclear . The present study investigated the effects of HSP90 inhibition on migration and proliferation of vascular smooth muscle cells ( VSMCs ) and involvement in atherosclerosis . To examine the role of HSP90 in VSMC migration , VSMCs were treated with the specific HSP90 inhibitors , 17 - N - allylamino - 17 - demethoxygeldanamycin ( 17 - P29372 ) and P50402 - 9090 . Results of a chemotaxis assay showed that the HSP90 inhibitors suppress migration of VSMCs . HSP90 inhibition also prevented invasion and sprout formation of VSMCs via inhibition of matrix metalloproteinase - 2 proteolytic activity . Results of a flow cytometric analysis showed that HSP90 inhibition induces cell cycle arrest via regulation of cyclin D3 , P12004 and P06400 . To investigate the role of HSP90 in the development of atherosclerosis , low - density lipoprotein receptor ( P01130 ) deficient mice were fed with a high cholesterol diet for 4weeks and treated with 17 - P29372 for 8weeks . HSP90 inhibition suppressed migration of VSMCs into atherosclerotic plaque lesions in high cholesterol diet - stimulated P01130 (-/-) mice . Inhibition of HSP90 attenuates formation of atherosclerotic plaques via suppression of VSMC migration and proliferation , indicating that HSP90 inhibitors can be used as therapeutic agents for atherosclerosis and in stent restenosis .", "Identification of an amino acid residue important for binding of methiothepin and sumatriptan to the human 5 - HT ( 1B ) receptor . Site - directed mutagenesis of the human P28222 receptor was performed to investigate the role of the amino acid residues cysteine 326 and tryptophan 327 in transmembrane region VI and aspartic acid 352 in transmembrane region VII in ligand binding . Binding studies were performed with the antagonist radioligand [ 3H ] GR125743 on mutant and wild - type receptors stably expressed in Chinese hamster ovary cells ( CHO ) - P04264 cells . Substitution of tryptophan 327 by alanine resulted in decreased affinities of all ligands tested . The most prominent changes in affinity were observed for the antagonist methiothepin and the antimigraine drug sumatriptan , which were reduced approximately 300 - and 60 - fold , respectively . Nevertheless , the affinity of 5 - HT remained the same . Replacement of the aspartic acid 352 by alanine reduced high - affinity binding of 5 - HT . Substitution of cysteine 326 by alanine had minor effects on ligand binding . Some of these results agree with the results from mutagenesis studies of the corresponding amino acids in other receptors . However , some notable differences also emerge showing that functional roles of individual amino acid residues must be tested experimentally in each receptor subtype .", "Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK87___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .", "P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK6___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK6___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .", "DB00594 derivatives induce apoptosis by depleting ER Ca ( 2 +) stores in vascular endothelial cells . BACKGROUND AND PURPOSE : DB00594 derivatives are blockers of the Na (+)/ H (+) exchanger ( NHE ) and at micromolar concentrations have protective effects on cardiac and brain ischaemia / reperfusion injury but at higher concentrations also induce apoptosis . Here , we aimed to elucidate the mechanism related to this cytotoxic action . EXPERIMENTAL APPROACH : We quantified the expression of genes associated with endoplasmic reticulum ( ER ) stress and measured changes in luminal ER Ca ( 2 +) concentration ( [ Ca ( 2 +)]( ER ) ) with a ' cameleon ' indicator , D1ER . KEY RESULTS : DB00594 derivatives induced apoptosis in vascular endothelial cells , an effect that increased at alkaline extracellular pH . The potency order for cytotoxicity was 5 -( N , N - hexamethylene )- amiloride ( HMA ) > 5 -( N - methyl - N - isobutyl ) amiloride > 5 -( N - ethyl - N - isopropyl ) amiloride ( EIPA ) >> amiloride . HMA dose - dependently increased the transcription of the ER stress genes P35638 and O75807 and rapidly depleted [ Ca ( 2 +)]( ER ) , mimicking the effects of the sarco / endoplasmic reticulum ATPase ( SERCA ) inhibitor thapsigargin . The P19634 - specific inhibitor HOE 694 inhibited NHE activity by 87 % but did not alter [ Ca ( 2 +)]( ER ) . The decrease in [ Ca ( 2 +)]( ER ) evoked by amiloride derivatives was also observed in HeLa cells and was mirrored by an increase in cytosolic Ca ( 2 +) concentration . CONCLUSIONS AND IMPLICATIONS : DB00594 derivatives disrupt ER and cytosolic Ca ( 2 +) homeostasis by a mechanism unrelated to NHE inhibition , most likely by interfering with the activity of SERCA . We propose that ER Ca ( 2 +) depletion and subsequent ER stress provide a rationale framework for the apoptotic effects of amiloride derivatives .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .", "Cbl - b is a negative regulator of inflammatory cytokines produced by IgE - activated mast cells . c - Cbl and Cbl - b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules . By comparing bone marrow - derived mast cells from c - Cbl and Cbl - b - deficient mice it has recently been shown that Cbl - b is the dominant family member for negatively regulating signaling responses from high - affinity IgE receptors . In this study , we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl - b - deficient mice is the relatively higher levels of Cbl - b protein over c - Cbl in mast cells compared with other hemopoietic cells . We also directly compare mast cells from c - Cbl and Cbl - b - deficient mice and find that loss of Cbl - b , but not c - Cbl , increases cell growth , retards receptor internalization , and causes the sustained tyrosine phosphorylation of Syk and its substrates . However , loss of Cbl - b does not enhance the activation of P29323 or Akt , nor does it promote a greater calcium response . Furthermore , loss of Cbl - b or c - Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases . Most notable , however , is the extremely large increase in the production of proinflammatory cytokines P01375 , P05231 , and P13500 by Cbl - b (-/-) mast cells compared with levels produced by c - Cbl (-/-) or wild - type cells . This marked induction , which appears to be restricted to these three cytokines , is dependent on IgE receptor activation and correlates with enhanced O15111 phosphorylation . Thus , Cbl - b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions .", "Myosin light chain kinase functions downstream of Ras / P29323 to promote migration of urokinase - type plasminogen activator - stimulated cells in an integrin - selective manner . P00749 ( uPA ) activates the mitogen activated protein ( Q96HU1 ) kinases , extracellular signal - regulated kinase ( P29323 ) 1 and 2 , in diverse cell types . In this study , we demonstrate that uPA stimulates migration of MCF - 7 breast cancer cells , HT 1080 fibrosarcoma cells , and Q03405 - overexpressing MCF - 7 cells by a mechanism that depends on uPA receptor ( Q03405 ) - ligation and P29323 activation . Ras and Q96HU1 kinase kinase ( MEK ) were necessary and sufficient for uPA - induced P29323 activation and stimulation of cellular migration , as demonstrated in experiments with dominant - negative and constitutively active mutants of these signaling proteins . Myosin light chain kinase ( MLCK ) was also required for uPA - stimulated cellular migration , as determined in experiments with three separate MLCK inhibitors . When MCF - 7 cells were treated with uPA , MLCK was phosphorylated by a MEK - dependent pathway and apparently activated , since serine - phosphorylation of myosin II regulatory light chain ( P19105 ) was also increased . Despite the transient nature of P29323 phosphorylation , MLCK remained phosphorylated for at least 6 h . The uPA - induced increase in MCF - 7 cell migration was observed selectively on vitronectin - coated surfaces and was mediated by a beta1 - integrin ( probably alphaVbeta1 ) and alphaVbeta5 . When MCF - 7 cells were transfected to express alphaVbeta3 and treated with uPA , P29323 was still phosphorylated ; however , the cells did not demonstrate increased migration . Neutralizing the function of alphaVbeta3 , with blocking antibody , restored the ability of uPA to promote cellular migration . Thus , we have demonstrated that uPA promotes cellular migration , in an integrin - selective manner , by initiating a Q03405 - dependent signaling cascade in which Ras , MEK , P29323 , and MLCK serve as essential downstream effectors .", "Growth arrest and DNA damage - inducible protein ( O75807 ) enhanced liver inflammation and tumorigenesis in a diethylnitrosamine ( DEN ) - treated murine model . Growth arrest and DNA damage - inducible protein ( O75807 / Ppp1r15a ) is induced by various stimuli including DNA damage and ER stress . DNA damage and oncogene activation , accompanied by tumor - specific DNA repair defects and a failure to stall the cell cycle , are early markers of hepatocellular carcinoma ( HCC ) . However , whether O75807 accounts for regulating HCC tumorigenesis remains elusive . Here , we demonstrated that O75807 expression was upregulated in the liver of mice after exposure to a carcinogen , diethylnitrosamine ( DEN ) . In both acute and chronic DEN treatment models , O75807 deficiency not only decreased oncogene expression , but also reduced hepatic damage . Moreover , loss of O75807 attenuated immune cell infiltration , pro - inflammatory cytokine expression and hepatic compensatory proliferation . Finally , O75807 - deficient mice showed impaired hepatocarcinogenesis . Thus , the process of DEN - induced HCC proceeded as follows . First , DEN treatment induced DNA damage in hepatocytes , resulting in elevated expression of O75807 in the liver . The increased expression of O75807 augmented hepatic necrosis followed by elevated expression of interleukin ( IL ) - 1β and monocyte chemoattractant protein 1 . This process promoted immune cell infiltration and Kupffer cell / macrophage activation followed by production of reactive oxygen species and pro - tumorigenic cytokines such as P05231 and tumor necrosis factor - α . The pro - tumorigenic cytokines stimulated compensatory proliferation of surviving and mutant hepatocytes . Together with oncogene c - Myc expression , these processes led to HCC . Our results suggest therapeutic opportunities for HCC by targeting O75807 - related pathways .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "DB00644 agonists reduce the migratory and the invasive behavior of androgen - independent prostate cancer cells by interfering with the activity of P05019 . Androgen - independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior . We have previously shown that DB00644 agonists exert a direct and specific inhibitory action on the proliferation of androgen - independent prostate cancer cells ( DU 145 ) . These compounds mainly act by interfering with the mitogenic activity of growth factors , such as the insulin - like growth factor - I ( P05019 ) . The present experiments were performed to clarify whether DB00644 agonists might also affect the migratory and the invasive behavior of androgen - independent prostate cancer cells and to define their mechanism of action . First we showed that the DB00644 agonist ___MASK87___ reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane . Experiments were then performed to clarify whether the DB00644 agonist might act by interfering with the pro - metastatic activity of P05019 . We found that , in androgen - independent prostate cancer cells , ___MASK87___ : a ) interferes with the P05019 system ( receptor protein expression and tyrosine - phosphorylation ) ; b ) abrogates the P05019 - induced phosphorylation of Akt ( a kinase previously shown by us to mediate the pro - metastatic activity of P05019 in prostate cancer cells ) ; c ) counteracts the migration and the invasive activity of the cells stimulated by P05019 ; d ) abolishes the effects of P05019 on cell morphology , on actin cytoskeleton organization and on alphavbeta3 integrin expression / cellular localization . These data indicate that DB00644 agonists , in addition to their well known antiproliferative effect , can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen - independent prostate cancer cells , expressing the P30968 . DB00644 agonists act by interfering with the pro - metastatic activity of the growth factor P05019 .", "[ ___MASK10___ sodium ( Photofrin - II ) ] . ___MASK10___ sodium ( ___MASK10___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK10___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .", "AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK83___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .", "Phosphorylation of Grainy head by P29323 is essential for wound - dependent regeneration but not for development of an epidermal barrier . Grainy head ( P01148 ) is a key transcription factor responsible for epidermal barrier formation and repair , whose function is highly conserved across diverse animal species . However , it is not known how P01148 function is reactivated to repair differentiated epidermal barriers after wounding . Here , we show that P01148 is directly regulated by extracellular signal - regulated kinase ( P29323 ) phosphorylation , which is required for wound - dependent expression of P01148 target genes in epidermal cells . DB00133 91 is the principal residue in P01148 that is phosphorylated by P29323 . Although mutations of the P29323 phosphorylation sites in P01148 do not impair its DNA binding function , the P29323 sites in P01148 are required to activate Dopa decarboxylase ( Ddc ) and misshapen ( msn ) epidermal wound enhancers as well as functional regeneration of an epidermal barrier upon wounding . This result indicates that the phosphorylation sites are essential for damaged epidermal barrier repair . However , P01148 with mutant P29323 phosphorylation sites can still promote barrier formation during embryonic epidermal development , suggesting that P29323 sites are dispensable for the P01148 function in establishing epidermal barrier integrity . These results provide mechanistic insight into how tissue repair can be initiated by posttranslational modification of a key transcription factor that normally mediates the developmental generation of that tissue .", "Cholinergic receptor and cyclic stretch - mediated inflammatory gene expression in intact P17405 . We tested the hypothesis that cholinergic stimulation and cyclic stretch regulate inflammatory gene expression in intact airway smooth muscle by measuring mRNA expression in bovine tracheal smooth muscle using limited microarray analysis and RT - PCR . DB00411 ( 1 microM ) induced significant increases in the expression of cyclooxygenase ( P36551 ) - 1 , P35354 , P10145 , and plasminogen activator , urokinase type ( P00749 ) to levels ranging from 1 . 3 - to 3 . 1 - fold of control . Sinusoidal length oscillation at an amplitude of 10 % muscle length and a frequency of 1 Hz induced significant increases in the expression of DB00833 - 2 , P35354 , P01584 , and P05231 to levels ranging from 12 - to 206 - fold of control . Decreasing the oscillatory amplitude by 50 % did not significantly change inflammatory gene expression . In contrast , decreasing the oscillatory frequency by 50 % significantly attenuated inflammatory gene expression by 76 - 93 % . Nifedipine ( 1 microM ) had an insignificant effect on carbachol - induced gene expression , but significantly inhibited sinusoidal length oscillation - induced inflammatory gene expression by 40 - 78 % . Correlation analysis revealed two groups of genes with differential responses to sinusoidal length oscillation . The highly responsive group included P35354 , P05231 , and P10145 , which exhibited 45 - to 364 - fold increases in gene expression in response to sinusoidal length oscillation . The moderately responsive group included P13500 and P00749 , which exhibited 13 - to 19 - fold increases in gene expression in response to sinusoidal oscillation . These findings suggest that cyclic stretch regulates inflammatory gene expression in intact airway smooth muscle in an amplitude - and frequency - dependent manner by modulating the activity of L - type voltage - gated calcium channels ." ]

[ "___MASK10___", "___MASK13___", "___MASK35___", "___MASK39___", "___MASK58___", "___MASK6___", "___MASK78___", "___MASK83___", "___MASK87___" ]

[ "P04626 / P21860 signaling regulates NK cell - mediated cytotoxicity via MHC class I chain - related molecule A and B expression in human breast cancer cell lines . Overexpression of the receptor tyrosine kinases P04626 and P21860 is associated with a poor prognosis in several types of cancer . Presently , P04626 - as well as P21860 - targeted therapies are in clinical practice or evaluated within clinical trials , including treatment with mAbs mediating growth inhibition and / or activation of Ab - induced innate or adaptive cellular immunity . A better understanding of how P04626 / P21860 signaling in tumors influences cellular immune mechanisms is therefore warranted . In this study , we demonstrate that P04626 / P21860 signaling regulates the expression of MHC class I - related chain A and B ( Q29983 and Q29980 ) in breast cancer cell lines . The Q29983 and Q29980 ( Q29983 / B ) molecules act as key ligands for the activating receptor NK group 2 , member D ( P26718 ) and promote NK cell - mediated recognition and cytolysis . Genetic silencing of P21860 but not P04626 downregulated the expression of Q29983 / B , and P21860 overexpression significantly enhanced Q29983 expression . Among the major pathways activated by P04626 / P21860 signaling , the PI3K / AKT pathway was shown to predominantly regulate Q29983 / B expression . Treatment with the P21860 - specific ligand neuregulin 1β promoted the expression in a process that was antagonized by pharmacological and genetic interference with P21860 but not by the ataxia - telangiectasia - mutated ( Q13315 ) and Q13315 and Rad3 - related protein kinases inhibitor caffeine . These observations further emphasize that P04626 / P21860 signaling directly , and not via genotoxic stress , regulates Q29983 / B expression . As anticipated , stimulating P04626 / P21860 enhanced the P26718 - Q29983 / B - dependent NK cell - mediated cytotoxicity . Taken together , we conclude that signaling via the P04626 / P21860 pathway in breast carcinoma cell lines may lead to enhanced P26718 - Q29983 / B recognition by NK cells and T cells .", "Network pharmacology - based prediction and verification of the molecular targets and pathways for schisandrin against cerebrovascular disease . AIM : To illuminate the molecular targets for schisandrin against cerebrovascular disease based on the combined methods of network pharmacology prediction and experimental verification . METHOD : A protein database was established through constructing the drug - protein network from literature mining data . The protein - protein network was built through an in - depth exploration of the relationships between the proteins . The computational platform was implemented to predict and extract the sensitive sub - network with significant P - values from the protein - protein network . Then the key targets and pathways were identified from the sensitive sub - network . The most related targets and pathways were also confirmed in hydrogen peroxide ( H2O2 ) - induced PC12 cells by Western blotting . RESULTS : Twelve differentially expressed proteins ( gene names : P19838 , Q04206 , P50591 , P28482 , O15111 , Q14790 , PIGS2 , Q16539 , P16220 , P01579 , P05067 , and P10415 ) were confirmed as the central nodes of the interaction network ( 45 nodes , 93 edges ) . The NF - κB signaling pathway was suggested as the most related pathway of schisandrin for cerebrovascular disease . Furthermore , schisandrin was found to suppress the expression and phosphorylation of IKKα , as well as p50 and p65 induced by H2O2 in PC12 cells by Western blotting . CONCLUSION : The computational platform that integrates literature mining data , protein - protein interactions , sensitive sub - network , and pathway results in identification of the NF - κB signaling pathway as the key targets and pathways for schisandrin .", "Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK87___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .", "Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK25___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .", "Protective roles of epithelial cells in the survival of adult T - cell leukemia / lymphoma cells . Adult T - cell leukemia / lymphoma ( ATL ) is a highly invasive and intractable T - cell malignancy caused by human T - cell leukemia virus - 1 infection . We demonstrate herein that normal tissue - derived epithelial cells ( NECs ) exert protective effects on the survival of leukemic cells , which may partially account for high resistance to antileukemic therapies in patients with ATL . Viral gene - silenced , ATL - derived cell lines ( ATL cells ) dramatically escaped from histone deacetylase inhibitor - induced apoptosis by direct co - culture with NECs . Adhesions to NECs suppressed P38936 ( Cip1 ) expression and increased a proportion of resting G0 / P55008 phase cells in trichostatin A ( P32119 ) - treated ATL cells . ATL cells adhering to NECs down - regulated CD25 expression and enhanced vimentin expression , suggesting that most ATL cells acquired a quiescent state by cell - cell interactions with NECs . ATL cells adhering to NECs displayed highly elevated expression of the cancer stem cell marker P16070 . Blockade of P16070 signaling diminished the NEC - conferred resistance of ATL cells to P32119 - induced apoptosis . Co - culture with NECs also suppressed the expression of P26718 ligands on P32119 - treated ATL cells , resulting in decreased natural killer cell - mediated cytotoxicity . Combined evidence suggests that interactions with normal epithelial cells augment the resistance of ATL cells to P32119 - induced apoptosis and facilitate immune evasion by ATL cells .", "Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK31___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .", "Regulation of the human P38936 ( waf1 / cip1 ) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor . The main regulator of the human tumor suppresser gene P38936 ( waf1 / cip1 ) is the transcription factor p53 , but more recently it has been suggested to be a primary anti - proliferative target for the nuclear receptor P11473 in the presence of its ligand 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) . To identify P11473 responding regions , we analyzed 20 overlapping regions covering the first 7 . 1 kb of the P38936 ( waf1 / cip1 ) promoter in MCF - 7 human breast cancer cells using chromatin immuno - precipitation assays ( ChIP ) with antibodies against p53 and P11473 . We confirmed two known p53 binding regions at approximate positions - 1400 and - 2300 and identified a novel site at position - 4500 . In addition , we found three P11473 - associated promoter regions at positions - 2300 , - 4500 and - 6900 , i . e . two regions showed binding for both p53 and P11473 . In silico screening and in vitro binding assays using recombinant and in vitro translated proteins identified five p53 binding sites within the three p53 - positive promoter regions and also five DB00136 response elements within the three P11473 - positive regions . Reporter gene assays confirmed the expected responsiveness of the respective promoter regions to the p53 inducer 5 - fluorouracil and DB00136 . Moreover , re - ChIP assays confirmed the functionality of the three DB00136 - reponsive promoter regions by monitoring simultaneous occupancy of P11473 with the co - activator proteins CBP , Q15788 and Q15648 . Taken together , we demonstrated that the human P38936 ( ( waf1 / cip1 ) ) gene is a primary DB00136 - responding gene with at least three P11473 binding promoter regions , in two of which also p53 co - localizes .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK72___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "Candidate genes for the hypoxic tumor phenotype . In this study , we have analyzed changes induced by hypoxia at the transcriptional level of genes that could be responsible for a more aggressive phenotype . Using a series of DNA array membranes , we identified a group of hypoxia - induced genes that included plasminogen activator inhibitor - 1 ( P05121 ) , insulin - like growth factor - binding protein 3 ( P17936 ) , endothelin - 2 , low - density lipoprotein receptor - related protein ( Q14764 ) , P10415 - interacting killer ( Q13323 ) , migration - inhibitory factor ( MIF ) , matrix metalloproteinase - 13 ( P45452 ) , fibroblast growth factor - 3 ( P11487 ) , P24522 , and vascular endothelial growth factor ( P15692 ) . The induction of each gene was confirmed by Northern blot analysis in two different squamous cell carcinoma - derived cell lines . We also analyzed the kinetics of P05121 induction by hypoxia in more detail because it is a secreted protein that may serve as a useful molecular marker of hypoxia . On exposure to hypoxia , there was a gradual increase in P05121 mRNA between 2 and 24 h of hypoxia followed by a rapid decay after 2 h of reoxygenation . P05121 levels were also measured in the serum of a small group of head and neck cancer patients and were found to correlate with the degree of tumor hypoxia found in these patients .", "Drug insight : Use of docetaxel in prostate and urothelial cancers . Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies , with two taxanes now in clinical use . Their mechanism of action against tumor cells is by alteration of microtubule dynamics , which causes cell - cycle arrest during mitosis . DB01248 binds to the microtubules with a higher affinity than paclitaxel , and over a broader range of cell - cycle activities . It has also been shown to promote apoptosis via P10415 phosphorylation . In hormone - refractory prostate cancer , docetaxel has been studied as both a single agent and in combination with estramustine , and in different treatment schedules , with demonstrated efficacy . Two phase III trials have confirmed a survival benefit , making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer . In urothelial cancer , docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens . A phase III trial comparing docetaxel and cisplatin to methotrexate , vinblastine , doxorubicin , and cisplatin was inferior when evaluating response rates and overall survival . More recent phase II trials combining docetaxel with two additional agents have shown promise , but confirmatory trials are needed .", "___MASK16___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .", "Predictive factors for response to docetaxel in human breast cancers . DB01248 has come into wide use recently for the treatment of breast cancer in neoadjuvant , adjuvant and metastatic settings . DB01248 binds to beta - tubulin and causes kinetic abnormalities in the dynamics of microtubules by increasing their polymerization and inhibiting their depolymerization , resulting in elevated levels of microtubule formation . During metaphase , defective spindle formation induced by docetaxel activates the mitotic checkpoint and leads to cell cycle arrest , culminating in apoptosis . However , docetaxel is not effective for all breast cancers . For example , in metastatic settings , the response rate to docetaxel reportedly ranges from 30 to 50 % . It is therefore very important to develop a diagnostic method with high accuracy for the prediction of sensitivity to docetaxel in order to avoid unnecessary treatment . Currently it is impossible to identify , before the initiation of therapy , the patients for whom docetaxel will be effective . Various biological parameters have been studied clinically for their ability to predict response to docetaxel , such as parameters related to : ( 1 ) efflux ( p - glycoprotein ) and metabolism ( P08684 ) ; ( 2 ) beta - tubulin ( somatic mutation of beta - tubulin and changes in beta - tubulin isotypes levels ) ; ( 3 ) cell cycle ( P04626 , P38398 and Aurora - A ) ; and ( 4 ) apoptosis ( p53 , P10415 and thioredoxin ) . More recently , gene expression profiling techniques have been used for the development of a prediction model for response to docetaxel . In the present paper , clinical studies that have been conducted recently to identify predictive factors for response to docetaxel are reviewed together with a presentation of our recent work in this field .", "DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .", "Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK20___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .", "Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .", "Up - regulated cytokine - inducible SH2 - containing protein expression in allergen - stimulated T cells from hen ' s egg - allergic patients . BACKGROUND : Although changes in the fine balance of allergen - specific T cells are crucial in the pathogenesis of allergic diseases , their roles in the allergic reaction to hen ' s eggs ( HE ) have not yet been fully analysed . OBJECTIVE : Using microarray technology , allergen - stimulated T cells from HE - allergic children were analysed to identify genes that are specifically up - regulated in these cells . METHODS : RNA from P01730 (+) P08571 (-) cells , fractionated from allergen - stimulated peripheral mononuclear cells , was analysed using a whole - genome microarray and real - time RT - PCR . The protein expression of selected genes was ascertained by flow cytometry . RESULTS : In microarray analyses of allergen - stimulated T cells , 43 genes were up - regulated in HE - allergic children but not in non - HE - allergic children . Among these , up - regulation of three genes , cytokine - inducible SH2 - containing protein ( Q9NSE2 ) , nuclear factor of kappa light polypeptide gene enhancer in B - cell inhibitor Z ( Q9BYH8 ) and B - cell CLL / lymphoma 2 ( P10415 ) , was confirmed by real - time quantitative RT - PCR . Q9NSE2 , but not Q9BYH8 or P10415 , showed a significantly higher ratio of antigen - stimulated cell transcription over unstimulated cells in HE - allergic than in non - HE - allergic children ( P < 0 . 01 ) . Flow - cytometric analysis revealed that the percentage of CD25 (+) Q9NSE2 (+) cells in P01730 (+) cells from patients with HE allergy was significantly higher than that in controls ( P < 0 . 01 ) . The expression level of Q9NSE2 was significantly higher in P05112 (+) Th2 cells than in P01579 (+) Th1 cells . CONCLUSION : We noted that Q9NSE2 expression in allergen - stimulated P01730 (+) T cells from HE - allergic patients was significantly increased in both mRNA and protein levels compared with that from non - HE - allergic children .", "Substance P induces rapid and transient membrane blebbing in U373MG cells in a P38936 - activated kinase - dependent manner . U373MG astrocytoma cells endogenously express the full - length neurokinin 1 receptor ( P25103 ) . Substance P ( SP ) , the natural ligand for P25103 , triggers rapid and transient membrane blebbing and we report that these morphological changes have different dynamics and intracellular signaling as compared to the changes that we have previously described in HEK293 - P25103 cells . In both cell lines , the SP - induced morphological changes are Gq - independent , and they require the Rho , Rho - associated coiled - coil kinase ( ROCK ) signaling pathway . Using confocal microscopy we have demonstrated that tubulin is phosphorylated subsequent to cell stimulation with SP and that tubulin accumulates inside the blebs . DB01394 , a tubulin polymerization inhibitor , blocked SP - induced blebbing in U373MG but not in HEK293 - P25103 cells . Although P38936 - activated kinase ( PAK ) is expressed in both cell lines , SP induced rapid phosphorylation of PAK in U373MG , but failed to phosphorylate PAK in HEK293 - P25103 cells . The cell - permeable Rho inhibitor P01024 transferase inhibited SP - induced PAK phosphorylation , but the ROCK inhibitor Y27632 had no effect on PAK phosphorylation , suggesting that Rho activates PAK in a ROCK - independent manner . Our study demonstrates that SP triggers rapid changes in cell morphology mediated by distinct intracellular signaling mechanisms in U373MG versus HEK293 - P25103 cells .", "Induction of G2 / M arrest and inhibition of cyclooxygenase - 2 activity by curcumin in human bladder cancer T24 cells . Curcumin , a polyphenol compound derived from Curcuma longa Linn , has been recognized as a promising anti - cancer drug due to its multiple properties including anti - inflammatory , anti - oxidant and anti - carcinogenic activities . To elucidate the mechanisms by which curcumin inhibits human bladder carcinoma T24 cell proliferation , we tested the effects of curcumin on specific cell cycle pathways and on the expression of cyclooxygenases ( COXs ) . Curcumin inhibited the growth of T24 cells and induced G2 / M arrest in a concentration - dependent manner , effects associated with the down - regulation of cyclin A and up - regulation of cyclin - dependent kinase ( Cdk ) inhibitor P38936 ( P38936 / CIP1 ) . However , other G2 / M regulatory molecules , such as cyclin A , Cdc2 , Cdk2 , Wee1 and Cdc25C , were not modulated by curcumin treatment . Furthermore , curcumin decreased the levels of P35354 mRNA and protein expression without significant changes in the levels of P23219 , which correlated with a decrease in prostaglandin E2 ( DB00917 ) synthesis . These observations suggest that curcumin may have therapeutic potential for bladder cancer patients .", "Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .", "Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK40___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .", "Evaluation of cytotoxicity and anticarcinogenic potential of Mentha leaf extracts . We examined the possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic potential of Mentha leaf extracts ( petroleum ether , benzene , chloroform , ethyl acetate , methanol , and water extracts ) on 6 human cancer ( HeLa , MCF - 7 , Jurkat , T24 , HT - 29 , MIAPaCa - 2 ) and normal ( IMR - 90 , P29320 - 293 ) cell lines . Of all the extracts tested , chloroform and ethyl acetate extracts of M piperita showed significant dose - and time - dependent anticarcinogenic activity leading to P55008 cell cycle arrest and mitochondrial - mediated apoptosis , perturbation of oxidative balance , upregulation of Bax gene , elevated expression of p53 and P38936 in the treated cells , acquisition of senescence phenotype , while inducing pro - inflammatory cytokines response . Our results provide the first evidence of direct anticarcinogenic activity of Mentha leaf extracts . Further , bioassay - directed isolation of the active constituents might provide basis for mechanistic and translational studies for designing novel anticancer drugs to be used alone or as adjuvant for prevention of tumor progression and / or treatment of human malignancies .", "Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK69___ and Tissue P00747 Activator in Occluded Arteries .", "P41134 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of P38936 . To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance , we compared the gene expression profiles in high - risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy . Among the molecular signatures associated with chemotherapy , transcripts encoding inhibitor of DNA binding 1 ( P41134 ) were significantly upregulated . The patient biochemical relapse status was monitored in a long - term follow - up . Patients with P41134 upregulation were found to be associated with longer relapse - free survival than patients without P41134 increase . This in vivo clinical association was mechanistically investigated . The chemotherapy - induced P41134 upregulation was recapitulated in the prostate cancer cell line LNCaP . DB01248 dose - dependently induced P41134 transcription , which was mediated by P41134 promoter E - box chromatin modification and c - Myc binding . Stable P41134 overexpression in LNCaP increased cell proliferation , promoted G ( 1 ) cell cycle progression , and enhanced docetaxel - induced cytotoxicity . These changes were accompanied by a decrease in cellular mitochondria content , an increase in P10415 phosphorylation at serine 70 , caspase - 3 activation , and poly ( ADP - ribose ) polymerase cleavage . In contrast , P41134 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel - induced cytotoxicity by inhibiting cell death . P41134 - mediated chemosensitivity enhancement was in part due to P41134 suppression of P38936 . Overexpression of P38936 in LNCaP - P41134 - overexpressing cells restored the P38936 level and reversed P41134 - enhanced chemosensitivity . These molecular data provide a mechanistic rationale for the observed in vivo clinical association between P41134 upregulation and relapse - free survival . Taken together , it shows that P41134 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis .", "Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK10___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 ." ]

[ "___MASK10___", "___MASK16___", "___MASK20___", "___MASK25___", "___MASK31___", "___MASK40___", "___MASK69___", "___MASK72___", "___MASK87___" ]

[ "Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK26___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK26___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .", "PTPsigma binds and dephosphorylates neurotrophin receptors and can suppress P01138 - dependent neurite outgrowth from sensory neurons . Neurotrophin receptors of the Trk family play a vital role in the survival of developing neurons and the process of axonogenesis . The Trk family are receptor protein tyrosine kinases ( RTKs ) and their signalling in response to neurotrophins is critically dependent upon their ability to transphosphorylate and act as signalling centres for multiple adaptor proteins and distinct , downstream pathways . Such phosphotyrosine signalling also depends upon the appropriate counter - regulation by phosphatases . A large family of receptor - like protein tyrosine phosphatases ( RPTPs ) are also expressed in developing neurons and in this study we have examined the ability of the phosphatase PTPsigma to interact with and regulate Trk proteins in transfected P29320 293T cells . PTPsigma can bind differentially to Trk proteins , binding stably in complexes with TrkA and TrkC , but not TrkB . The transmembrane domains of PTPsigma and TrkA appear to be sufficient for the direct or indirect interaction between these two receptors . Furthermore , PTPsigma is shown to dephosphorylate all three Trk receptors and suppress their phosphorylation in the presence of neurotrophins . In addition , overexpression of PTPsigma in primary sensory neurons in culture inhibits neurite outgrowth without affecting the short - term survival of these neurons . PTPsigma can thus show differential complex formation with different Trk family members and in neurons can selectively target the neurite - forming signalling pathway driven by TrkA .", "Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors . Neurotrophins and other neurotrophic factors have been shown to support the survival and differentiation of many neuronal populations of the central and peripheral nervous system . Therefore , administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chronic brain disorders . However , the delivery of neurotrophic factors to the brain is one of the largest obstacles in the development of effective therapy for neurodegenerative disorders , because these proteins are not able to cross the blood - brain barrier . The induction of growth factor synthesis in the brain tissue by systemically administered lipophilic drugs , such as beta - adrenoceptor agonists , shown to increase endogenous nerve growth factor ( P01138 ) synthesis in the brain , would be an elegant way to overcome these problems of application . Stimulation of beta - adrenoceptors with clenbuterol led to increased P01138 synthesis in cultured central nervous system ( CNS ) cells and rat brain tissue . DB01407 - induced P01138 expression was reduced to the control levels by coadministration of beta - adrenoceptor antagonist propranolol . Furthermore , clenbuterol protected rat hippocampal neurons subjected to excitotoxic damage . The neuroprotective effect of clenbuterol in vitro depended on increased P01138 synthesis , since the neuroprotection was abolished by P01138 antisense oligonucleotide as well as by antibodies directed against P01138 itself . In vivo , clenbuterol protected rat hippocampus in a model of transient forebrain ischemia and reduced the infarct volume in a rat model of permanent middle cerebral artery occlusion ( MCAo ) . The neuroprotective effect of clenbuterol in vivo was accompanied by enhanced P01138 synthesis in brain tissue . These findings support our hypothesis that orally active P01138 inducers may have a potential as therapeutic agents for the treatment of neurodegenerative disorders and stroke .", "Human tumor infiltrating lymphocytes . Analysis of lymphokine mRNA expression and relevance to cancer immunotherapy . Tumor infiltrating lymphocytes ( Q15399 ) isolated from 12 patients with metastatic malignant melanoma , renal cell carcinoma , or breast adenocarcinoma were expanded in rIL - 2 for 22 to 45 days ( median 33 days ) and analyzed for lymphokine mRNA expression and patterns of TCR gene rearrangement . All Q15399 cultures were significantly enriched for T cells , with CD3 + CD8 + cells predominant in 8 of 10 cases tested , and demonstrated an oligoclonal ( rather than polyclonal ) pattern of TCR gene rearrangement . Nine of 12 cultures could effectively lyse the autologous targets in short term chromium release assays . P60568 expanded - Q15399 expressed mRNA for P01375 and P01374 ( lymphotoxin ) and , in 5 of 9 ( 41 % ) cases , granulocyte / macrophage - colony stimulating factor mRNA but not P01584 or P60568 transcripts . Cultured Q15399 deprived of rIL - 2 for 4 days did not constitutively express mRNA for any of the lymphokines tested . One long term Q15399 line in culture was followed and periodically tested for lytic activity and P01375 - mRNA expression . Loss of the specific cytolytic but not proliferative activity at day 85 was associated with disappearance of P01375 mRNA . Profiles of lymphokine secretion may provide a useful marker for functionally characterizing different T cell subsets and may provide correlates of the in vivo anti - tumor effects of these cells when Q15399 are adoptively transferred into cancer - bearing patients .", "P09038 stimulates P48061 expression through the Erm transcription factor in Sertoli cells . Ets - related molecule ( Erm ) is a member of the Ets transcription factor family . Erm is known to be an important factor for the self - renewal of Spermatogonial stem cells ( SSCs ) and the maintenance of spermatogenesis . We investigated the molecular mechanism of Erm regulation on P48061 in TM4 Sertoli cells . Erm and Sdf - 1 levels were up - regulated after P09038 treatment in TM4 cells , whereas these levels were significantly decreased by P09038 in ST2 bone marrow stromal cells . Knockdown of Erm by siRNA in the presence of P09038 decreased the Sdf - 1 levels in TM4 cells . The expression levels of Erm were similar and Erm overexpression increased the Sdf - 1 in both TM4 and ST2 cells . FGFR subtype analysis revealed that P22455 was expressed in TM4 cells but not in ST2 cells . A blocking experiment also confirmed that P22455 is partly responsible for the up - regulation of Erm and P48061 induced by P09038 stimulation in TM4 cells . P09038 and P41161 increased the activity of Sdf - 1 gene promoter region in a dose - dependent manner . EMSA revealed that P41161 strongly binds to the - 846 to - 851 nucleotide region of the potential Ets binding site ( Q9BTE0 ) in the Sdf - 1 promoter . In addition , P61073 , the P61073 , was expressed in spermatogonia and Sertoli cells in the seminiferous tubules of the mouse testis . Our results indicate that P41161 directly regulates Sdf - 1 gene expression by interacting with its cis - acting element in response to P09038 stimulation in TM4 cells .", "Sustained viral gene delivery through core - shell fibers . Although viral gene transfer is efficient in achieving transgene expression for tissue engineering , drawbacks of virus dissemination , toxicity and transient gene expression due to immune response have hindered its widespread application . Many tissue engineering studies thus opt to genetically engineer cells in vitro prior to their introduction in vivo . However , it would be attractive to obviate the need for in vitro manipulation by transducing the infiltrating progenitor cells in situ . This study introduces the fabrication of a virus - encapsulated electrospun fibrous scaffold to achieve sustained and localized transduction . Adenovirus encoding the gene for green fluorescent protein was efficiently encapsulated into the core of poly ( epsilon - caprolactone ) fibers through co - axial electrospinning and was subsequently released via a porogen - mediated process . P29320 293 cells seeded on the scaffolds expressed high level of transgene expression over a month , while cells inoculated by scaffold supernatant showed only transient expression for a week . RAW 264 . 7 cells cultured on the virus - encapsulated fibers produced a lower level of P01584 , P01375 and IFN - alpha , suggesting that the activation of macrophage cells by the viral vector was reduced when encapsulated in the core - shell PCL fibers . In demonstrating sustained and localized cell transduction , this study presents an attractive alternative mode of applying viral gene transfer for regenerative medicine .", "DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .", "Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK59___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .", "Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK93___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .", "Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .", "___MASK28___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK28___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .", "Effects of C - phycocyanin and Spirulina on salicylate - induced tinnitus , expression of DB01221 receptor and inflammatory genes . Effects of C - phycocyanin ( C - PC ) , the active component of Spirulina platensis water extract on the expressions of N - methyl D - aspartate receptor subunit 2B ( Q13224 ) , tumor necrosis factor - α ( P01375 - α ) , interleukin - 1β ( IL - 1β ) , and cyclooxygenase type 2 ( P35354 ) genes in the cochlea and inferior colliculus ( IC ) of mice were evaluated after tinnitus was induced by intraperitoneal injection of salicylate . The results showed that 4 - day salicylate treatment ( unlike 4 - day saline treatment ) caused a significant increase in Q13224 , P01375 - α , and IL - 1β mRNAs expression in the cochlea and IC . On the other hand , dietary supplementation with C - PC or Spirulina platensis water extract significantly reduced the salicylate - induced tinnitus and down - regulated the mRNAs expression of Q13224 , P01375 - α , IL - 1β mRNAs , and P35354 genes in the cochlea and IC of mice . The changes of protein expression levels were generally correlated with those of mRNAs expression levels in the IC for above genes .", "Induction of nerve growth factor and basic fibroblast growth factor mRNA following clenbuterol : contrasting anatomical and cellular localization . RNase protection assay and in situ hybridization were used to analyze the temporal and cellular changes in nerve growth factor ( P01138 ) and basic fibroblast growth factor ( P09038 ) mRNA content evoked by the lipophilic beta - adrenergic receptor agonist clenbuterol in adult rat brain . DB01407 elicited a threefold increase in P01138 mRNA expression which was limited to the cerebral cortex . This increase was maximal at 5 h , still evident by 10 h , and declined to control levels by 24 h . By 10 h P01138 protein was also increased . Elevated P01138 mRNA hybridization following clenbuterol was localized in the superficial cortical layers II and III in large Nissl - pale cells , suggesting that P01138 mRNA induction occurs in neurons . In the same animals , clenbuterol induced a twofold increase in the levels of P09038 mRNA in cerebral cortex and hippocampus . This increase was localized primarily in glial cells as demonstrated by P09038 mRNA hybridization over all cortical regions and by labeling of the stratum lacunosum moleculare of the hippocampus . Our results suggest that enhanced noradrenergic tone regulates expression of these two trophic factors by different synaptic mechanisms and suggest that neurotransmitter ( s ) can coordinate trophic influences on different cell populations .", "Combined anti - inflammatory effects of β2 - adrenergic agonists and DB05876 inhibitors on astrocytes by upregulation of intracellular DB02527 . Inflammation is an important hallmark of all neurodegenerative diseases and activation of different glial populations may be involved in the progression of some of these disorders . Especially , the activation of astroglia can lead to long - term detrimental morphological changes , such as scar formation . Therefore , improved strategies to modulate inflammation in these cells are currently being investigated . We investigated the interaction of phosphodiesterase ( PDE ) 4 inhibitors , such as rolipram , with other agents raising cellular DB02527 levels . When used alone , none of the DB05876 inhibitors increased DB02527 levels . The adenylate cyclase activator forskolin , the β ( 2 )- adrenergic agonist clenbuterol and the mixed β ( 1 )/ β ( 2 )- adrenergic agonist isoproterenol increased intracellular DB02527 levels of cortical murine astrocytes . This increase was synergistically elevated by rolipram or the DB05876 inhibitor RO - 201724 , but not by inhibition of PDE3 . Inflammatory stimulation of the cells with the cytokines P01375 - α , IL - 1β and IFN - γ strongly induced Q07343 and augmented overall DB05876 activity , while PDE3 activity was low . DB01407 and forskolin caused downregulation of cytokines and chemokines such as P05231 and P13500 . This effect was further enhanced by rolipram , but not by the PDE3 inhibitor milrinone . The DB02527 - raising drug combinations attenuated the upregulation of P01375 - α and P05231 mRNA and the secretion of P05231 , but did not affect initial NF - κB signalling triggered by the stimulating cytokines . These results indicate that DB05876 may be a valuable anti - inflammatory target in brain diseases , especially under conditions associated with stimulation of DB02527 - augmenting astrocyte receptors as is observed by clenbuterol treatment .", "DB01407 affects the expression of messenger RNA for interleukin 10 in peripheral leukocytes from horses challenged intrabronchially with lipopolysaccharides . On four occasions , four horses with heaves and four horses with small airway inflammatory diseases inhaled 0 . 9 % saline based aerosol mixtures with or without lipopolysaccharides ( LPS ) . Prior to the first saline and LPS inhalation , horses were untreated , while three and a half days prior to the third and forth inhalation horses had received 0 . 8 microg / kg clenbuterol intravenously twice daily . The messenger RNA ( mRNA ) expression of tumour necrosis factor - alpha ( P01375 ) , interleukin ( IL ) - 1beta , P05112 , P05231 , P10145 , P22301 and interferon - gamma ( IFN - gamma ) was investigated by RT - PCR , all of which were expressed in the white blood cells of samples collected . Inhalation of LPS only changed the cytokine expression profile of P22301 , P05112 and P01375 mRNA which were higher after challenge with LPS . However in those horses that were treated with clenbuterol the LPS - induced P22301 mRNA expression was shown to be suppressed . Further changes in P05112 and P01375 were not significant . Thus the results of this study indicated that clenbuterol can modulate the expression of P22301 mRNA in peripheral white blood cells in those horses with small airway diseases that have been exposed to LPS .", "Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK96___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .", "P23219 behaves as a delayed response gene in PC12 cells differentiated by nerve growth factor . Treatment of PC12 cells with nerve growth factor ( P01138 ) results in a differentiation program characterized by expression of immediate early and delayed response genes . In this program , morphological changes such as neurite extension are accompanied by phenotypic changes in enzyme expression , including an increased capacity for prostaglandin synthesis . Cyclooxygenase ( P36551 ) , the enzyme responsible for prostanoid production , exists as two isoforms : constitutive P23219 and inducible P35354 . We report that P23219 behaves as a delayed response gene in PC12 cells exposed to P01138 . Six hours following P01138 treatment , P23219 mRNA levels were elevated in PC12 cells , reaching nearly 5 - fold above basal levels at 12 h . This increase was blocked by cycloheximide and was accompanied by concomitant increases in P23219 protein and enzyme activity . P23219 protein remained elevated for at least 10 days and localized to the cytoplasm and neurites of P01138 - differentiated PC12 cells . Moreover , basic fibroblast growth factor , but not epidermal growth factor , caused similar increases in P23219 , which is consistent with expression characteristics of other delayed response genes in PC12 cells . This is the first example of neurotrophic factor regulation of cyclooxygenase and may have important implications for determination of the differentiated phenotype in PC12 cells .", "Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK54___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .", "P01375 - alpha and X - linked adrenoleukodystrophy . The two most common forms of X - linked adrenoleukodystrophy ( X - P33897 ) , the childhood cerebral form ( CCER ) and the adult form , adrenomyeloneuropathy ( Q9BXJ7 ) , arise from the same mutations in the X - P33897 gene at Xq28 . These two forms are distinguished by the degree of cerebral inflammation . Segregation analysis suggests that an autosomal modifying gene may be a major determinant of phenotype in X - P33897 . Thus , a modifying gene could be involved in initiating or promoting the inflammatory response . In this study we detected a difference in tumor necrosis factor - alpha ( P01375 ) bioactivity , but not P01375 protein levels , in serum from some advanced CCER patients . Early - stage CCER patients and Q9BXJ7 patients were in the normal range . Allelic differences in P01375 or levels of soluble P01375 receptor did not account for bioactivity differences or phenotypic heterogeneity in X - P33897 .", "Neonatal exposure to anti - nerve growth factor antibodies affects exploratory behavior of developing mice in the hole board . The aim of this study was to assess in developing mice whether the neutralization of endogenous P01138 following ICV administration of anti - P01138 antibodies ( 50 micrograms / 2 microliters ) on postnatal days 3 , 6 , 9 , and 12 affected locomotor activity , exploratory behavior , and response to the cholinergic blocker scopolamine . In Experiments 1 and 2 activity and age - typical scopolamine effects were evaluated on P01160 13 or 17 in an automated apparatus . No significant main effect of anti - P01138 treatment was found at either age . On day 13 scopolamine ( 0 . 2 , 1 , or 2 mg / kg ) decreased locomotion in both anti - P01138 and control animals . In Experiment 3 , locomotion and exploratory behavior were analyzed in an open field arena or in a hole board apparatus on P01160 16 . No significant effects of anti - P01138 treatment on general motor activity and investigation of a novel object in the open field was found , though anti - P01138 animals tended to be less active than controls . In the hole board anti - P01138 pups showed a different pattern of head dipping behavior from controls , exploring mainly the holes located in the periphery of the apparatus .", "___MASK21___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK21___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .", "Cordycepin suppresses P01375 - α - induced NF - κB activation by reducing p65 transcriptional activity , inhibiting IκBα phosphorylation , and blocking IKKγ ubiquitination . Cordycepin is reported to participate in multiple pharmacological activities including anti - tumor and anti - inflammation , and is involved in the regulation of NF - κB signaling pathway . However , the detailed molecular mechanism of cordycepin in suppression of NF - κB signaling pathway remains ambiguous . In this study , we first analyzed the effect of cordycepin on NF - κB activity in P29320 - 293T cells , and found that cordycepin resulted in a dose - dependent reduction in P01375 - α - induced NF - κB activation . Although cordycepin did not block P01375 - α - induced nuclear translocation of p65 , high concentration of cordycepin reduced the DNA - binding and transcriptional activities of NF - κB . Moreover , cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα . Further investigation revealed that cordycepin suppressed IKKs - mediated NF - κB activation and inhibited the ubiquitination of IKKγ . In conclusion , cordycepin effectively inhibits NF - κB signaling through suppressing the activities of NF - κB , IκB and IKK . Thus , cordycepin may provide some potential therapeutic application in inflammation - associated disorders and cancer .", "A diarylheptanoid from lesser galangal ( Alpinia officinarum ) inhibits proinflammatory mediators via inhibition of mitogen - activated protein kinase , Q8TCB0 / 42 , and transcription factor nuclear factor - kappa B . The diarylheptanoid 7 -( 4 '- hydroxy - 3 '- methoxyphenyl )- 1 - phenylhept - 4 - en - 3 - one ( Q16891 ) is a naturally occurring phytochemical found in lesser galangal ( Alpinia officinarum ) . In the present study , we have demonstrated the anti - inflammatory properties of this compound on mouse macrophage cell line ( RAW 264 . 7 ) and human peripheral blood mononuclear cells ( PBMCs ) in vitro . Treatment of RAW 264 . 7 cells with Q16891 ( 6 . 25 - 25 microM ) significantly inhibited lipopolysaccharide ( LPS ) - stimulated nitric oxide ( NO ) production . This compound also inhibited the release of LPS - induced proinflammatory cytokines interleukin - 1 beta ( P01584 ) and tumor necrosis factor - alpha ( P01375 ) from human PB - MCs in vitro . In addition , Western blotting and reverse transcription - polymerase chain reaction analysis demonstrated that Q16891 decreased LPS - induced inducible nitric - oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) protein and mRNA expression in RAW 264 . 7 cells . Furthermore , Q16891 treatment also reduced nuclear factor - kappa B ( NF - kappa B ) DNA binding induced by LPS in RAW 264 . 7 cells . To elucidate the molecular mechanism for inhibition of proinflammatory mediators by Q16891 ( 25 microM ) , we have studied the effect of Q16891 on LPS - induced p38 and Q8TCB0 / 42 mitogen - activated protein kinase ( MAPK ) . We observed that the phosphorylation of Q8TCB0 / 42 MAPK in LPS - stimulated RAW 264 . 7 cells was markedly inhibited by Q16891 , whereas activation of p38 MAPK was not affected . These results suggested that Q16891 from lesser galangal suppressed the LPS - induced production of NO , P01584 , and P01375 and expression of P35228 and P35354 gene expression by inhibiting NF - kappa B activation and phosphorylation of Q8TCB0 / 42 MAPK .", "High mobility group box protein - 1 promotes cerebral edema after traumatic brain injury via activation of toll - like receptor 4 . Traumatic brain injury ( TBI ) is a major cause of mortality and morbidity worldwide . Cerebral edema , a life - threatening medical complication , contributes to elevated intracranial pressure ( ICP ) and a poor clinical prognosis after TBI . Unfortunately , treatment options to reduce post - traumatic edema remain suboptimal , due in part , to a dearth of viable therapeutic targets . Herein , we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI . Our results demonstrate that high - mobility group box protein 1 ( P09429 ) was released from necrotic neurons via a Q13224 - mediated mechanism . P09429 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice . The detrimental effects of P09429 were mediated , at least in part , via activation of microglial toll - like receptor 4 ( O00206 ) and the subsequent expression of the astrocytic water channel , aquaporin - 4 ( P55087 ) . Genetic or pharmacological ( VGX - 1027 ) O00206 inhibition attenuated the neuroinflammatory response and limited post - traumatic edema with a delayed , clinically implementable therapeutic window . Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal P09429 initiates the microglial release of interleukin - 6 ( P05231 ) in a O00206 dependent mechanism . In turn , microglial P05231 increased the astrocytic expression of P55087 . Taken together , these data implicate microglia as key mediators of post - traumatic brain edema and suggest P09429 - O00206 signaling promotes neurovascular dysfunction after TBI .", "Platelet rich plasma therapy : inflammatory molecules involved in tissue healing . Inflammation represents a fundamental aspect of the healing process . Besides their primary role in hemostasis , platelets play an active role in the immunological and inflammatory aspect of tissue healing . Indeed , they can be directly involved in the inflammatory response by the production and release of several inflammatory mediators , including a variety of cytokines , such as TGF - beta , P01584 , P29965 , and chemokines , such as P02775 , P02776 , P10720 , CCl5 , P09341 , P10145 , P42830 , P48061 , P13500 , P10147 . Platelet are not only a source of several chemokine involved in the inflammatory response and tissue healing , but they also express chemokine receptors , in particular P32246 P51677 CCR4 and P61073 , thus being able to being able to regulate the inflammatory response associated to the healing process . However , this local inflammation must be taken under control , and platelets can prevent the excess of leukocytes recruitment by anti - inflammatory cytokines , such as TGF - beta . For this biological properties of platelets , platelet rich plasma therapy ( PRP ) is considered an innovative and promising approach that has been extended to many field of medicine , ranging from non - union defects , bone fractures , spinal fusion , bone implant and osteointegration , joint arthroplasty , to the treatment of several traumatic or degenerative pathologies of tendons , cartilage and ligaments .", "Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .", "Chemokine P48061 and its receptor P61073 expression are associated with perineural invasion of prostate cancer . OBJECTIVE : To identify the roles of P48061 and P61073 and the associated mechanism involved in perineural invasion of prostate cancer . METHODS : The distribution and expression of P48061 , P61073 , P08253 and P14780 in human prostate cancer and in tumor cells invading nerve tissue were studied with immunohistochemical staining . The effects of exogenous P48061 and P61073 antagonist DB06809 on PC3 prostate cancer cells invasiveness were assessed in vitro and in vivo . RESULTS : The expression of P48061 , P61073 , P08253 , and P14780 in human prostate cancer were higher than those in hyperplastic prostate tissues ( P < 0 . 05 ) . In vitro P48061 could stimulate the PC3 cells invasiveness ( P < 0 . 05 ) while DB06809 could inhibit invasiveness . In vivo , the number of nerves around the tumor tissue in the group treated with P48061 was significantly higher than that found in the control group ( P < 0 . 05 ) . Both the control group and the P48061 - treated group had more nerves number near the tumor tissue than it found in the DB06809 - treated group . The positive cell number of P48061 , P61073 , P08253 , P14780 , and P01138 expression ranked from highest to lowest , were the P48061 - treated , the control , and the DB06809 - treated group ( P < 0 . 05 ) . CONCLUSION : P48061 and its receptor P61073 along with P08253 and P14780 are related with prostate cancer perineural invasion .", "DB11320 stimulates hydrogen peroxide production by bronchial epithelial cells via histamine H1 receptor and dual oxidase . Oxidative stress has been implicated in the pathogenesis of bronchial asthma . Besides granulocytes , the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma - related oxidative stress . DB11320 is a major inflammatory mediator present in large quantities in asthmatic airways . Whether histamine triggers epithelium - derived oxidative stress is unknown . We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine . We found that air - liquid interface cultures of primary human bronchial epithelial cells ( BECs ) and an immortalized BEC model ( Cdk4 / hTERT HBEC ) produce H2O2 in response to histamine . The main source of airway epithelial H2O2 is an NADPH dual oxidase , Duox1 . Out of the four histamine receptors ( P35367 - Q9H3N8 ) , P35367 has the highest expression in BECs and mediates the H2O2 - producing effects of histamine . P05112 induces Duox1 gene and protein expression levels and enhances histamine - induced H2O2 production by epithelial cells . Using P29320 - 293 cells expressing Duox1 or Duox2 and endogenous P35367 , histamine triggers an immediate intracellular calcium signal and H2O2 release . Overexpression of P35367 further increases the oxidative output of Duox - expressing P29320 - 293 cells . Our observations show that BECs respond to histamine with Duox - mediated H2O2 production . These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways , suggesting novel therapeutic targets for treating asthmatic airway disease .", "___MASK79___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK79___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK79___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .", "___MASK78___ block of cloned human T - type voltage - gated calcium channels . ___MASK78___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .", "Ceramide is responsible for the failure of compensatory nerve sprouting in apolipoprotein E knock - out mice . P02649 ( apoE ) is a key transporter of the cholesterol and phospholipids required for membrane synthesis and nerve growth . We now report a virtual absence in apoE knock - out ( KO ) mice of normal nerve growth factor ( P01138 ) - driven compensatory sprouting of undamaged cutaneous nociceptive nerves . In contrast , P01138 - independent regeneration of crushed axons was unaffected . Essentially similar results came from aged wild - type mice . In apoE KO mice , the endogenous sprouting stimulus was suspect , because P01138 administration induced normal sprouting ; nevertheless , P01138 increased normally in denervated skin , transported normally in the axons , and led to phosphorylation of trkA , erk1 , and erk2 . However , sprouting was restored in apoE KO mice ( although not in aged mice ) by fumonisin B1 , an inhibitor of ceramide synthesis . A shotgun analysis revealed a wide array of changes in individual ceramide species in Q86YR7 neurons of apoE KO mice , and the changes for ceramide species OH_N15 : 0 made it a candidate inhibitor of sprouting ( increased in apoE KO mice and normalized by fumonisin B1 ) . Nevertheless , the unknown effects of individual ceramide species on sprouting , as well as the variability of their changed levels in apoE KO mice and how these were affected by fumonisin B1 , support a different conclusion . We suggest that absence of apoE expression alters the balance among ceramide species to one that collectively inhibits compensatory sprouting , whereas fumonisin B1 establishes a new balance that allows sprouting . Nontoxic ceramide modulators might usefully promote sprouting and circuitry repair in neurodegenerative disorders in which ceramide species are perturbed , adding to the benefits of reducing ceramide - induced neuronal apoptosis .", "Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .", "Lack of functional expression of DB01221 receptors in PC12 cells . PC12 cells are an established model for studying the role of N - methyl - d - aspartate ( DB01221 ) receptors in excitotoxicity and function as multimeric assemblies of Q9UHB4 with at least one NR2 ( A - D ) subunit . We examined Q9UHB4 splice variant and NR2 subunit expression in four PC12 cell - lines ( ATCC , WEHI , Ordway and Flinders ) , correlated mRNA expression with protein expression , and used patch - clamp recordings to test functionality . PCR indicated strong expression of the Q9UHB4 splice variants Q9UHB4 - 2a and Q9UHB4 - 4a in all cell - lines , with the remainder weakly detected or absent . Real - time PCR showed variable levels of Q9UHB4 mRNA expression ( all splice variants ) between cell - lines and a significant increase in response to nerve growth factor in the WEHI and Ordway lines ( P01138 : 50ng / ml , 2 . 1 - and 13 . 4 - fold increases , respectively , P < or = 0 . 05 ) . mRNA for Q12879 or Q13224 was not detected in any PC12 cell - line . Q14957 mRNA expression varied between lines and increased after P01138 treatment ( approximately 4 - fold increase in WEHI and Ordway lines , P < or = 0 . 05 ) . In the Ordway line , O15399 mRNA was seen only after P01138 treatment . Immunohistochemistry confirmed protein expression for Q9UHB4 , Q14957 and O15399 , and while fluorescence intensity changes in response to P01138 paralleled mRNA responses , the degree of increase was of reduced magnitude . Whole - cell patch - clamping of P01138 treated cells failed to detect functional DB01221 receptors in any of the cell - lines . Our study demonstrates that in contrast to neurons from the CNS , PC12 cells do not express a normal complement of DB01221 receptor - subunits , and this may be one factor limiting functional responses to DB01221 / glutamate and consequently the use of PC12 cells as a neuronal model .", "Monoclonal antibodies targeting P01584 reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in P02649 - deficient mice . OBJECTIVE : Atherosclerosis is a condition that is increasingly contributing to worldwide mortality through complications such as stroke and myocardial infarction . IL - 1β plays multiple direct , local roles in the formation and stability of the atheroma by eliciting the production of additional cytokines and proteolytic enzymes from macrophages , endothelial cells ( EC ) and smooth muscle cells ( SMC ) . We therefore tested whether an anti - IL - 1β antibody , DB06062 , might inhibit the secretion of pro - atherogenic cytokines from macrophages in vitro and affect a positive outcome in the P02649 - deficient mouse ( ApoE (-/-) ) model of atherosclerosis in vivo . METHODS AND RESULTS : In an in vitro co - culture model , DB06062 inhibited macrophage - induced secretion of key atherogenic cytokines from EC and SMC , including P05231 , P10145 , P13500 and TNFα . The release of degradative enzymes , such as the matrix metalloproteinases P08254 and P14780 , was also decreased by DB06062 . In addition , DB06062 inhibited the secretion of P13232 from EC and P05112 from SMC , cytokines not previously reported to be driven by IL - 1β in this context . In vivo , XMA052 MG1K , a chimeric murine version of DB06062 , inhibited the formation of atherosclerotic lesions in the ApoE (-/-) model at all three doses tested . This effect was comparable to that reported for complete genetic ablation of IL - 1β or IL - 1R1 on an ApoE (-/-) background and was associated with decreases in plasma non - HDL / HDL cholesterol ratio and plaque lipid content and macrophage infiltration . CONCLUSIONS : These results demonstrate for the first time that an antibody targeting IL - 1β can inhibit the progression of atherosclerosis in vivo , highlighting the importance of this key cytokine in cardiovascular disease .", "[ DB01407 in amyotrophic lateral sclerosis . No indication for a positive effect ] . The anabolic effects of clenbuterol have been recognized for a long time . DB01407 augments the expression of specific muscle proteins with a differential effect on type I and type II fibres . Furthermore , clenbuterol induces the synthesis of endogenous nerve growth factor ( P01138 ) and may itself be a myotrophic factor released by neuron endings . Side effects include tremor and headache and dose dependent abnormalities of laboratory values ( hypokalemia , hypoglycemia ) . After long - term medication increasing fatigue of muscles has been observed . Decreased expression of beta 2 - adrenergic receptors may limit the expected functional improvement . The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved . Controlled treatment trials are warranted to assess this question .", "Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .", "Transcriptional regulation of cyclo - oxygenase expression : three pillars of control . Blocking cyclo - oxygenase ( P36551 ) isoform activities with non - steroidal anti - inflammatory drugs ( NSAIDS ) is widely employed in the treatment of arthritis . These agents also hold great promise in the context of pre and post - neoplastic diseases such as colorectal cancer ( CRC ) . Nevertheless , issues of isoform specificity and delivery necessitate the exploration of other strategies to specifically block expression of the P36551 genes . Approaches that target gene transcription may complement enzyme inhibition . Thus , understanding the regulation of P36551 isoform transcription may improve the specific inhibition of expression . Three tiers of transcriptional regulation are evident : initiation , alternative splicing and messenger RNA stability . Transcription factors that activate P35354 expression are elevated in certain disease states and emergency responses such as infection and are therefore potential targets . These factors include C / EBP - beta , phospho - CREB , NF - P05231 , P05412 , NFkB , and TCF - 4 / Q9UJU2 . In this review we highlight another factor , c - P10242 as a key P35354 regulator in CRC . Alternative exon usage is another tier of regulation that has not received much attention . For instance , P23219 splice variants ( also known as P36551 - 3 and PCOX - 1a ) may broaden the spectrum of P36551 activities in disease . Similarly , whilst mRNA stability is clearly modulated by steroids in the case of P35354 , the wider implications of targeting mRNA stability have not been afforded the same attention . Finally , it seems that some NSAIDS exert part of their action directly on P35354 transcriptional regulation explaining why such agents display greater effects on this isoform than enzyme inhibition data would suggest .", "Th 1 cytokine production by peripheral blood mononuclear cells in X - linked adrenoleukodystrophy . Cerebral adrenoleukodystrophy ( P33897 ) and adrenomyeloneuropathy ( Q9BXJ7 ) are the two most frequent clinical phenotypes of the same genetic defect leading to the accumulation of very long chain fatty acids ( VLCFA ) . Previous studies have suggested that inflammatory cytokines may play a role in the cerebral demyelination and in phenotype expression of the disease . We analyzed cytokine production by stimulated peripheral blood mononuclear cells ( PBMC ) from 17 patients ( four asymptomatic subjects , eight Q9BXJ7 and five P33897 ) . Our results show that lipopolysaccarides ( LPS ) stimulated PBMC from both symptomatic and asymptomatic patients have an increased production of IL - 12 and TNFalpha compared to controls , while after phitoemoagglutinin ( PHA ) stimulation we observed a decreased production of P05231 and P22301 . These data indicate that , following an immunological stimulus , PBMC from patients have an increased production of cytokines typical of a Th1 cell response which is able to promote the inflammatory process . This characteristic profile of cytokine production could be related to the biochemical defect and could have a role in central nervous system ( CNS ) pathogenesis .", "Evaluation of human astrocytoma and glioblastoma cell lines for nerve growth factor release . Nerve growth factor ( P01138 ) prevents degeneration of cholinergic neurons in the central nervous system ( CNS ) , and has potential as a therapeutic treatment for Alzheimer ' s disease . The inability of P01138 to cross the blood - brain barrier has prompted pharmacological approaches investigating peripherally administered compounds that stimulate release of endogenous P01138 . This study describes the P01138 - releasing properties of six human astrocytoma and glioblastoma cell lines ( SW 1088 , SW 1783 and CRL 1718 astrocytomas , and U - 138 , U - 373 , and T98G glioblastomas ) . Using a highly specific two - site ELISA for human P01138 , basal P01138 release could be detected in all cell lines , with the lowest level in the T98G line ( approximately 80 pg P01138 / ml ) . Cell lines tested with a variety of compounds for 24 h in serum - free media demonstrated stimulation of P01138 release by distinct mechanisms . P01138 levels were markedly elevated ( up to 8 - fold above vehicle - treated cells ) when stimulated with the cytokine interleukin - 1 beta ( P01584 ) . Phorbol ester stimulated P01138 release 4 - fold . DB01407 , 4 - methyl catechol , and propentofylline had little activity , while 6 -( 4 - hydroxybutyl )- 2 , 3 , 5 ,- trimethyl - 1 , 4 , benzoquinone ( DB01157 ) , dexamethasone and 1 , 25 - dihydroxyvitamin D3 elevated P01138 levels 3 - fold . These data indicate differences in the ability of human astrocytoma and glioblastoma cells to release P01138 when stimulated with mechanistically distinct compounds .", "Endotoxin - induced liver damage in rats is minimized by beta 2 - adrenoceptor stimulation . OBJECTIVE AND DESIGN : To investigate the effects of beta ( 2 )- adrenoceptor ( beta ( 2 )- AR ) stimulation on endotoxin - induced liver damage and systemic cytokine levels in rats . SUBJECTS : Standard male Wistar rats . TREATMENT : A disease - model of lipopolysaccharide ( LPS ) - induced acute systemic inflammation was used . The beta ( 2 )- selective AR agonist clenbuterol was administered before , during , and after LPS - challenge to investigate its effects on the acute inflammatory response and associated liver - failure . METHODS : The following parameters have been measured in plasma : P01375 alpha , P01584 , P05231 , P22301 , Q9NRA2 , ALT , and Bilirubin . Liver histological examination was performed to look for changes in tissue morphology . RESULTS : Administration of clenbuterol ( p . o . ) one hour before , or intravenous at the same time as LPS - challenge resulted in a marked reduction of plasma levels of P01375 alpha , P01584 , and P05231 . A change both in plasma - level and in time - concentration profile of the anti - inflammatory cytokine P22301 was found . DB01407 minimized LPS - induced liver damage , as represented by significantly lowered concentrations of several parameters for liver - failure ( Q9NRA2 , ALT , Bilirubin ) , and improved hepatic tissue morphology . DB01407 administration after LPS challenge failed to inhibit P01375 alpha - release but reduced liver - damage . Simultaneous use of the beta ( 2 )- AR antagonist propranolol augmented LPS - induced liver failure , suggesting a role of endogenous adrenoceptor - agonists in prevention of organ - failure during systemic inflammation . CONCLUSIONS : The results indicate that a selective beta ( 2 )- AR agonist might be used as an additional therapeutic agent in the clinic for the treatment of ( acute ) systemic inflammatory disorders in order to reduce or prevent subsequent liver failure .", "Effect of isoproterenol and dexamethasone on the lipopolysaccharide induced expression of CD11b on bovine neutrophils . The present experiments investigate the changes in expression of CD11b on bovine neutrophils and its modulation by isopropylnoradrenaline ( IPN , isoproterenol ) , dexamethasone ( DX ) , phenylephrine ( alpha - agonist ) and clenbuterol ( beta - agonist ) . Both IPN and DX caused a dose - dependent inhibition of LPS - induced CD11b expression . A combination of IPN and DX elicited a synergistical decrease of the CD11b expression . DB01407 mimicked the effect of IPN , whereas phenylephrine did not . The effect of IPN and DX could at least partly be mediated through a decreased P01375 production by monocytes since tumor necrosis factor - alpha ( P01375 ) is shown to mediate a dose - dependent CD11b up - regulation . Stimulation of stress hormone receptors partly immuno - suppresses neutrophil functions by inhibition of CD11b expression on the neutrophil surface upon LPS stimulation . This inhibition is probably related to a decrease in P01375 production . A similar mechanism of immuno - suppression could contribute to the higher susceptibility of cattle to Gram - negative bacterial infections of the udder and lung during periods of stress .", "The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK79___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .", "Stimulation of central β2 - adrenoceptors suppresses NFκB activity in rat brain : a role for IκB . In this study we examined the impact of systemic treatment with the long - acting brain penetrant β2 - adrenoceptor agonist clenbuterol on NFκB activity and IκB expression in rat brain . DB01407 decreased NFκB activity ( p65 DNA binding ) in nuclear extracts prepared from rat cortex and hippocampus for up to 8h following a single treatment . This was accompanied by increased expression of IκBα mRNA and protein . The temporal increase in IκB protein expression paralleled the suppression of NFκB activity , suggesting that IκBα mediates the suppression NFκB activity observed . These actions of clenbuterol were prevented by pre - treatment with the non - selective β - adrenoceptor antagonist propranolol , the β2 - adrenoceptor antagonist ICI - 118 , 551 , but not the β1 - adrenoceptor antagonist metoprolol , suggesting that the effects of clenbuterol on IκBα expression and NFκB activity are mediated specifically by the β2 - adrenoceptor . In addition , the actions of clenbuterol were mimicked by systemic administration of another highly selective long - acting β2 - adrenoceptor agonist formoterol . As neurodegenerative diseases are associated with inflammation we determined if clenbuterol could suppress NFκB activation that occurs in response to an inflammatory stimulus . In this regard we demonstrate that clenbuterol inhibited IκB phosphorylation and IκB degradation and inhibited NFκB activity in hippocampus and cortex of rats following a central injection of the inflammagen bacterial lipopolysaccharide ( LPS ) . In tandem , clenbuterol blocked expression of the NFκB - inducible genes P01375 - α and P05362 following LPS administration . Our finding that clenbuterol and formoterol inhibit NFκB activity in the CNS further supports the idea that β2 - adrenoceptors may be an attractive target for treating neuroinflammation and combating inflammation - related neurodegeneration .", "Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity . The HIV - 1 envelope protein gp120 induces apoptosis in hippocampal neurons . Because chemokine receptors act as cellular receptors for HIV - 1 , we examined rat hippocampal neurons for the presence of functional chemokine receptors . Fura - 2 - based Ca imaging showed that numerous chemokines , including SDF - 1alpha , RANTES , and fractalkine , affect neuronal Ca signaling , suggesting that hippocampal neurons possess a wide variety of chemokine receptors . Chemokines also blocked the frequency of spontaneous glutamatergic excitatory postsynaptic currents recorded from these neurons and reduced voltage - dependent Ca currents in the same neurons . Reverse transcription - PCR demonstrated the expression of P32246 , CCR4 , P51681 , P51686 / 10 , P25025 , P61073 , and P49238 , as well as the chemokine fractalkine in these neurons . Both fractalkine and macrophage - derived chemokine ( MDC ) produced a time - dependent activation of extracellular response kinases ( P29323 ) - 1 / 2 , whereas no activation of c - P05412 NH2 - terminal protein kinase ( JNK ) / stress - activated protein kinase , or p38 was evident . Furthermore , these two chemokines , as well as SDF - 1alpha , activated the Ca - and DB02527 - dependent transcription factor CREB . Several chemokines were able also to block gp120 - induced apoptosis of hippocampal neurons , both in the presence and absence of the glial feeder layer . These data suggest that chemokine receptors may directly mediate gp120 neurotoxicity .", "Pharmacological modulation of nerve growth factor synthesis : a mechanistic comparison of vitamin D receptor and beta ( 2 )- adrenoceptor agonists . Increasing nerve growth factor ( P01138 ) in the PNS is a rational strategy for treating certain neurodegenerative disorders . The present studies were undertaken to compare two compounds , a vitamin D ( 3 ) analogue ( CB1093 ) with minimal calcaemic effects , and clenbuterol , a long - acting beta ( 2 )- adrenoceptor agonist , both of which induce P01138 synthesis in vivo . DB01407 caused significant increases in both P01138 mRNA and protein in 3T3 cells ; with maxima at 10 nM and at 8 - 12 h exposure . Effects of clenbuterol on P01138 mRNA were antagonized by propranolol . Mobility shift assays on whole cell extracts showed that clenbuterol increased P05412 binding in 3T3 cells prior to increasing P01138 synthesis . DB01407 was without effect on P01138 mRNA levels in L929 cells , whereas CB1093 caused significant increases in both P01138 mRNA and protein levels in both 3T3 and L929 cells . Stimulation was almost maximal at 24 h exposure and was sustained for at least 72 h . The magnitude of the increase was much greater in L929 ( 700 % increase ) than in 3T3 cells ( 80 % ) . Binding to the vitamin D nuclear receptor ( P11473 ) , which acts as a transcription factor itself , was increased as early as 30 min after exposure to of CB1093 and maintained up to 24 h . Increased P11473 binding preceded increased P01138 mRNA . A 150 % increase in AP - 1 binding was also evident . This study demonstrates that CB1093 and clenbuterol stimulate P01138 levels in vitro and that AP - 1 binding could be a commonality between the mechanism of P01138 induction of these two compounds .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "The β2 - adrenoceptor agonist clenbuterol elicits neuroprotective , anti - inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity . Excitotoxicity is a mechanism of neuronal cell death implicated in a range of neurodegenerative conditions . Systemic administration of the excitotoxin kainic acid ( KA ) induces inflammation and apoptosis in the hippocampus , resulting in neuronal loss . Evidence indicates that stimulation of glial β ( 2 )- adrenoceptors has anti - inflammatory and neurotrophic properties that could result in neuroprotection . Consequently , in this study we examined the effect of the β ( 2 )- adrenoceptor agonist clenbuterol on KA - induced inflammation , neurotrophic factor expression and apoptosis in the hippocampus . DB01407 ( 0 . 5mg / kg ) was administered to rats one hour prior to KA ( 10mg / kg ) . Epileptic behaviour induced by KA was assessed for three hours following administration using the Racine scale . Twenty - four hours later TUNEL staining in the P07451 hippocampal subfield and hippocampal caspase - 3 activity was assessed to measure KA - induced apoptosis . In addition , expression of inflammatory cytokines ( IL - 1β and IFN - γ ) , inducible nitric oxide synthase ( P35228 ) , kynurenine pathway enzymes indolamine 2 , 3 - dioxygenase ( P14902 ) and kynurenine monooxygenase ( O15229 ) , the microglial activation marker CD11b , and the neurotrophins P23560 and P01138 were quantified in the hippocampus using real - time PCR . Whilst clenbuterol treatment did not significantly alter KA - induced epileptic behavior it ameliorated KA - induced apoptosis , and this neuroprotective effect was accompanied by reduced inflammatory cytokine expression , reduced expression of P35228 , P14902 , O15229 and CD11b , coupled with increased P23560 and P01138 expression in KA - treated rats . In conclusion , the β ( 2 )- adrenoceptor agonist clenbuterol has anti - inflammatory and neurotrophic actions and elicits a neuroprotective effect in the KA model of neurodegeneration .", "Exposure to an organophosphate ( ___MASK26___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK26___ ( ___MASK26___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK26___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK26___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK26___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .", "Thiol - sensitive mast cell lines derived from mouse bone marrow respond to a mast cell growth - enhancing activity different from both P08700 and P05112 . A series of permanent P08700 - dependent cell lines have been established from normal BALB / c or C3H bone marrow using alpha - thioglycerol - supplemented culture medium and PWM - stimulated spleen cell - conditioned medium as a source of P08700 . The cell lines and derivatives cloned in agar resembled \" mucosal type \" mast cells with respect to phenotypic and functional properties . In this report we demonstrate that in vitro growth of these mast cell lines was not only dependent on P08700 and synergistically enhanced by P05112 , but in addition regulated by alpha - thioglycerol which could be replaced by 2 - ME or cysteamine . We show that these thiol - sensitive mast cell lines respond to a mast cell growth enhancing activity ( MEA ) present in spleen cell - conditioned medium and acting in concert with P08700 . Partially purified MEA was not able to stimulate the growth of P08700 - dependent 32Dcl . 23 cells , P60568 - dependent CTLL - 2 cells or the mouse T cell line F4 / 4K . 6 ( L3T4 + ) adapted to grow in purified P05112 . Moreover , 11B11 hybridoma - derived anti - P05112 mAb specifically neutralizing mouse Il - 4 were unable to abolish the bioactivity of MEA . PWM , P09603 , GM - P04141 , IL - 1 , P60568 , P05113 , P05231 , P13232 , P01579 , TGF - alpha , P01375 , P01138 , or EPO did not substitute for MEA in our standard proliferation assay .", "DB01407 induces growth factor mRNA , activates astrocytes , and protects rat brain tissue against ischemic damage . The induction of growth factor synthesis in brain tissue by beta2 - adrenoceptor agonists , such as clenbuterol , is a promising approach to protect brain tissue from ischemic damage . DB01407 ( 0 . 01 - 0 . 5 mg / kg ) reduced the cortical infarct volume in Long - Evans rats as measured 7 days after permanent occlusion of the middle cerebral artery . Dosages of clenbuterol higher than 1 mg / kg showed no cerebroprotective effect due to a decrease in blood pressure and an increase in plasma glucose level . The increase in the mRNA level of nerve growth factor ( P01138 ) , basic fibroblast growth factor ( basic FGF ) , and transforming growth factor - beta1 ( TGF - beta1 ) mRNA in cortical and hippocampal tissue occurred earlier after middle cerebral artery occlusion and was more pronounced in animals treated with clenbuterol than in controls . In addition , glial fibrillary acidic protein ( P14136 ) mRNA expression was enhanced in astrocytes 6 h after ischemia in clenbuterol - treated animals . The results suggest that growth factor synthesis is enhanced in activated astrocytes and that this could be the mechanism of clenbuterol - induced cerebroprotection after ischemia .", "Evaluation of cytokine production by equine alveolar macrophages exposed to lipopolysaccharide , Aspergillus fumigatus , and a suspension of hay dust . OBJECTIVE : To evaluate cytokine production by equine alveolar macrophages after exposure to lipopolysaccharide ( LPS ) , Aspergillus fumigatus , and hay dust , and determine the effect of clenbuterol on the cytokine response . ANIMALS : 6 horses . PROCEDURE : Alveolar macrophages were exposed to PBS solution ( negative control ) , LPS , hyphae and conidia of Aspergillus fumigatus ( AF ) , or a suspension of hay dust ( Q86SQ9 ) and incubated for 24 hours at 37 degrees C . Concentrations of tumor necrosis factor ( P01375 ) - alpha and interleukin ( IL ) - 1beta were measured in the supernatant . The procedure was repeated with cells that were concurrently incubated with 0 . 5 microM clenbuterol . RESULTS : Exposure to Q86SQ9 and AF significantly increased production of P01375 by equine alveolar macrophages . The increase in P01375 produced in response to Q86SQ9 and AF was 5 and 7 times as great , respectively , as the increase measured in response to LPS . The concentration of IL - 1beta in the supernatant was significantly increased after exposure of cells to AF . DB01407 was effective at inhibiting P01375 production by cells exposed to LPS , Q86SQ9 , or AF . CONCLUSIONS AND CLINICAL RELEVANCE : Increased production of P01375 and IL - 1 indicated that the pro - inflammatory cytokines produced by alveolar macrophages in response to allergens may play a role in recurrent airway obstruction ( O75106 ) in horses . Equine alveolar macrophages are not only a primary pulmonary defense mechanism but may also influence the pathogenesis of equine O75106 . The beta2 - adrenoceptor agonist clenbuterol , a drug that is commonly used for treatment of equine O75106 , promotes immediate bronchodilation and may also contribute to downward modulation of the inflammatory response .", "P23560 and nerve growth factor correlate with T - cell activation in primary Sjogren ' s syndrome . OBJECTIVES : Identification of factors associated with disease activity and B and T cell activation is a challenge in primary Sjogren ' s syndrome ( pSS ) . Neurotrophins ( NTs ) , recently reported as B cell antiapoptotic , and T - cell activation factors seem to be implicated in autoimmune diseases such as systemic lupus erythematosus ( SLE ) and rheumatoid arthritis ( RA ) . METHODS : Samples from 18 pSS patients and 12 control subjects were studied to determine serum levels of nerve - growth factor ( P01138 ) and brain - derived neurotrophic factor ( P23560 ) , and their relationships with T - and B - cell activation and disease activity . Peripheral blood mononuclear cells ( PBMCs ) from patients with pSS and controls were examined by flow cytometry for HLA - DR expression by activated T cells . B cell activation was evaluated by B cell activating factor ( Q9Y275 ) serum levels measured by enzyme - linked immunosorbent assay ( ELISA ) and immunoglobulin ( Ig ) and free light chain ( FLC ) levels . RESULTS : Mean serum levels of P23560 in pSS patients were significantly higher than in healthy controls and correlated directly with disease activity . P01138 levels were associated with the subgroup of patients with hypergammaglobulinaemia . The pSS group was characterized by peripheral P01730 + and CD8 + T cell activation that correlated positively with P23560 and P01138 levels , respectively . CONCLUSION : NT levels are potential biomarkers for lymphocyte activation in pSS patients ." ]

[ "___MASK21___", "___MASK26___", "___MASK28___", "___MASK54___", "___MASK59___", "___MASK78___", "___MASK79___", "___MASK93___", "___MASK96___" ]

[ "Inhibitory effects of imatinib on vitamin D₃ synthesis in human keratinocytes . Chronic myeloid leukemia ( CML ) is a myeloproliferative disease characterized by the presence of the BCR ‑ P00519 fusion gene , a constitutively active , oncogenic tyrosine kinase that is responsible for the clinical features of CML . Tyrosine kinase inhibitors , such as imatinib , have markedly altered the treatment of CML . However , tyrosine kinase inhibitors are associated with side effects on bone metabolism , in adult and pediatric patients . DB00169 is involved in the complex cycle of bone remodeling , therefore the present study aimed to investigate the influence of imatinib on vitamin D3 metabolism in the HaCaT human keratinocyte cell line , using commercially available enzyme assays . Imatinib was shown to significantly reduce the production of calcidiol and calcitriol . Based on interaction studies of imatinib with the cytochrome P450 ( CYP450 ) inhibitors VID400 and ketoconazole , it is proposed that imatinib may interfere with the vitamin D3 cascade due to its metabolism by O15528 , which is involved in vitamin D3 metabolism .", "Clonal differences in expression of 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase , of 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase , and of the vitamin D receptor in human colon carcinoma cells : effects of epidermal growth factor and 1alpha , 25 - dihydroxyvitamin D ( 3 ) . Human colon carcinoma cells express 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase ( O15528 ) and thus produce the vitamin D receptor ( P11473 ) ligand 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 - D3 ) , which can be metabolized by 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase ( Q07973 ) . Expression of P11473 , O15528 , and Q07973 determines the efficacy of the antimitotic action of 1 , 25 - D3 and is distinctly related to the degree of differentiation of cancerous lesions . In the present study we addressed the question of whether the effects of epidermal growth factor ( P01133 ) and of 1 , 25 - D3 on P11473 , O15528 , and Q07973 gene expression in human colon carcinoma cell lines also depend on the degree of cellular differentiation . We were able to show that slowly dividing , highly differentiated Caco - 2 / 15 cells responded in a dose - dependent manner to both P01133 and 1 , 25 - D3 by up - regulation of P11473 and O15528 expression , whereas in highly proliferative , less differentiated cell lines , such as Caco - 2 / AQ and COGA - 1A and - 1E , negative regulation was observed . Q07973 mRNA was inducible in all clones by 1 , 25 - D3 but not by P01133 . From the observed clonal differences in the regulatory effects of P01133 and 1 , 25 - D3 on P11473 and O15528 gene expression we suggest that P11473 - mediated growth inhibition by 1 , 25 - D3 would be efficient only in highly differentiated carcinomas even when under mitogenic stimulation by P01133 .", "___MASK50___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK50___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK50___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK50___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK50___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK50___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .", "A new cell culture - based assay quantifies vitamin K 2 , 3 - epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol - driven Q9BQB6 assay . BACKGROUND : ___MASK42___ directly inhibits the vitamin K 2 , 3 - epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) - driven vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) assay . ___MASK42___ inhibits wild - type Q9BQB6 function by the DTT - Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance - associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture - based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild - type and variant Q9BQB6 proteins . METHODS : Human coagulation factor ( F ) IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild - type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : ___MASK42___ dose - response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild - type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24 . 7 , 136 . 4 , 152 . 0 and 1226 . 4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild - type Q9BQB6 . Ranked IC50 values from the cell culture - based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation - associated warfarin resistance .", "___MASK28___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .", "Immunologic effects of an orally available BRAFV600E inhibitor in P15056 wild - type murine models . ___MASK59___ is an orally available small molecule that targets constitutively activated BRAFV600E , an integral part of the MAPK pathway involved in melanomagenesis . We examined the effects of vemurafenib on cytokine production and antitumor response in a P15056 wild - type ( WT ) non - tumor - bearing murine model and a P15056 WT murine insulinoma system to determine its effect on immune function during immunotherapy . We demonstrate no significant effect from vemurafenib on P01730 + and CD8 + T - cell cytokine production or on a T - cell - mediated antitumor response . Our data demonstrate that vemurafenib does not significantly affect P15056 WT targets , suggesting that there may be a role for combining vemurafenib treatment with T - cell - directed immunotherapy .", "DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .", "Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK40___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .", "Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .", "Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .", "Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 gene activity is DB00136 itself , which down - regulates the gene . The down - regulation of the O15528 gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 - binding regions in the distal promoter , 2 . 6 and 3 . 2 kb upstream from the TSS , that bind vitamin D receptor - retinoid X receptor complexes . Since the down regulation of the O15528 gene is tissue - and cell - type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non - permissive to the phenomenon of DB00136 - mediated down - regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 gene is repressed in P29320 - 293 but not in MCF - 7 cells .", "Flow cytometry detection of vitamin D receptor changes during vitamin D treatment in Crohn ' s disease . Crohn ' s disease ( CD ) is a chronic inflammatory disease associated with a dysregulated T cell response towards intestinal microflora . Vitamin D has immune modulatory effects on T cells through the nuclear vitamin D receptor ( P11473 ) in vitro . It is unclear how oral vitamin D treatment affects P11473 expression . The aim of this study was to establish a flow cytometry protocol , including nuclear and cytoplasmic P11473 expression , and to investigate the effects of vitamin D treatment on T cell P11473 expression in CD patients . The flow cytometry protocol for P11473 staining was developed using the human acute monocytic leukaemia cell line ( THP - 1 ) . The protocol was evaluated in anti - CD3 / P10747 - stimulated peripheral blood mononuclear cells ( PBMCs ) from vitamin D3 - ( n = 9 ) and placebo - treated ( n = 9 ) CD patients . Anti - P11473 - stained PBMCs were examined by flow cytometry , and their cytokine production was determined by cytokine bead array . P11473 , O15528 and RXRα mRNA expression levels in P01730 (+) T cells were measured by quantitative reverse transcriptase polymerase chain reaction . The flow cytometry protocol enabled detection of cytoplasmic and nuclear P11473 expression . The results were confirmed by confocal microscopy and supported by correlation with P11473 mRNA expression . P11473 expression in P01730 (+) T cells increased following stimulation . This P11473 up - regulation was inhibited with 30 % by vitamin D treatment compared to placebo in CD patients ( P = 0027 ) . P11473 expression was correlated with in - vitro interferon - γ production in stimulated PBMCs ( P = 0 . 01 ) . Flow cytometry is a useful method with which to measure intracellular P11473 expression . Vitamin D treatment in CD patients reduces T cell receptor - mediated P11473 up - regulation .", "Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis - affected brain tissue . Vitamin D deficiency has been implicated as a risk factor for multiple sclerosis ( MS ) , but how vitamin D metabolism affects MS pathophysiology is not understood . We studied the expression of vitamin D receptor ( P11473 ) and related enzymes , including 1 , 25 ( OH )( 2 ) D - 24 - hydroxylase ( Q07973 ; Q07973 ) and 25 ( OH ) D - 1α - hydroxylase ( O15528 ) , in CNS tissues of 39 MS patients and 20 controls and in primary human glial cells in vitro . In control and MS normal - appearing white matter ( NAWM ) , nuclear P11473 immunostaining was observed in oligodendrocyte - like cells , human leukocyte antigen ( HLA ) - positive microglia , and glial fibrillary acidic protein - positive astrocytes . There was a 2 - fold increase in P11473 transcripts in MS NAWM versus control white matter ( p = 0 . 03 ) . In chronic active MS lesions , HLA - positive microglia / macrophages showed nuclear P11473 staining ; astrocytes showed nuclear and cytoplasmic P11473 staining . Staining for Q07973 was restricted to astrocytes . P11473 and O15528 mRNA expressions were increased in active MS lesions versus NAWM ( p < 0 . 01 , p = 0 . 04 , respectively ) . In primary human astrocytes in vitro , the active form of vitamin D , 1 , 25 ( OH )( 2 ) D ( 3 ) , induced upregulation of P11473 and Q07973 . P01375 and interferon - γ upregulated O15528 mRNA in primary human microglia and astrocytes . Increased P11473 expression in MS NAWM and inflammatory cytokine - induced amplified expression of P11473 and O15528 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions .", "Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK18___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .", "___MASK56___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK56___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .", "Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK44___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .", "Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK41___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .", "Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development ." ]

[ "___MASK18___", "___MASK28___", "___MASK40___", "___MASK41___", "___MASK42___", "___MASK44___", "___MASK50___", "___MASK56___", "___MASK59___" ]

[ "An important role for P24941 in P55008 to S checkpoint activation and DNA damage response in human embryonic stem cells . A precise understanding of mechanisms used by human embryonic stem cells ( hESCs ) to maintain genomic integrity is very important for their potential clinical applications . The P55008 checkpoint serves to protect genomic integrity and prevents cells with damaged DNA from entering S - phase . Previously , we have shown that downregulation of cyclin - dependent kinase 2 ( P24941 ) in hESC causes P55008 arrest , loss of pluripotency , upregulation of cell cycle inhibitors P38936 and p27 and differentiation toward extraembryonic lineages . In this study , we investigate in detail the role of P24941 in cellular processes , which are crucial to the maintenance of genomic stability in hESC such as P55008 checkpoint activation , DNA repair , and apoptosis . Our results suggest that downregulation of P24941 triggers the P55008 checkpoint through the activation of the Q13315 - O96017 - p53 - P38936 pathway . Downregulation of P24941 is able to induce sustained DNA damage and to elicit the DNA damage response ( DDR ) as evidenced by the formation of distinct γ - H2 . AX and P43351 - P38398 foci in hESC nuclei . P24941 downregulation causes high apoptosis at the early time points ; however , this is gradually decreased overtime as the DDR is initiated . Our mass spectrometry analysis suggest that P24941 does interact with a large number of proteins that are involved in key cellular processes such as DNA replication , cell cycle progression , DNA repair , chromatin modeling , thus , suggesting a crucial role for P24941 in orchestrating a fine balance between cellular proliferation , cell death , and DNA repair in hESC .", "Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK95___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK95___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK95___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK95___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK95___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .", "Retinal gene expression and Müller cell responses after branch retinal vein occlusion in the rat . PURPOSE : In a rat model of branch retinal vein occlusion ( BRVO ) , changes in gene expression of factors implicated in the development of retinal edema and alterations in the properties of Müller cells were determined . METHODS : In adult Long - Evans rats , BRVO was induced by laser photocoagulation of retinal veins ; untreated eyes served as controls . The mRNA levels of after factors were determined with real - time RT - PCR in the neural retina and retinal pigment epithelium after 1 and 3 days of BRVO : P15692 , pigment epithelium - derived factor ( P36955 ) , tissue factor , prothrombin , the potassium channel Kir4 . 1 , and aquaporins 1 and 4 . DB01345 currents were recorded in isolated Müller cells , and cellular swelling was assessed in retinal slices . RESULTS : In the neural retina , the expression of P15692 was upregulated within 1 day of BRVO and returned to the control level after 3 days . P36955 was upregulated in the neuroretina and retinal pigment epithelium after 3 days of BRVO . P00734 , Kir4 . 1 , and both aquaporins were downregulated in the neuroretina . After BRVO , Müller cells displayed a decrease in their potassium currents and an altered distribution of Kir4 . 1 protein , an increase in the size of their somata , and cellular swelling under hypoosmotic stress that was not observed in control tissues . CONCLUSIONS : BRVO results in a rapid transient increase in the expression of P15692 and a delayed increase in the expression of P36955 . The downregulation of Kir4 . 1 and aquaporins , the mislocation of Kir4 . 1 protein , and the osmotic swelling of Müller cells may contribute to the development of edema and neuronal degeneration .", "___MASK4___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK4___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK4___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .", "___MASK4___ for joints and bones . ___MASK4___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK4___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK4___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .", "[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK41___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .", "Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK19___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .", "Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells . Stromal cells such as myofibroblasts influence tumor progression . The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow - derived mesenchymal stromal cells ( MSCs ) which then colonize tumors . Using iTRAQ and LC - MS / MS we identified the adipokine , chemerin , as overexpressed in esophageal squamous cancer associated myofibroblasts ( CAMs ) compared with adjacent tissue myofibroblasts ( ATMs ) . The chemerin receptor , ChemR23 , is expressed by MSCs . Conditioned media ( CM ) from CAMs significantly increased O60682 cell migration compared to Q13315 - CM ; the action of P62158 - CM was significantly reduced by chemerin - neutralising antibody , pretreatment of CAMs with chemerin siRNA , pretreatment of MSCs with ChemR23 siRNA , and by a ChemR23 receptor antagonist , CCX832 . Stimulation of MSCs by chemerin increased phosphorylation of Q8NFH3 / 44 , p38 and JNK - II kinases and inhibitors of these kinases and PKC reversed chemerin - stimulated O60682 migration . Q99969 stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor ( MIF ) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations . In a xenograft model consisting of OE21 esophageal cancer cells and CAMs , homing of MSCs administered i . v . was inhibited by CCX832 . Thus , chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression .", "Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "Follow - up evaluation of radiation - induced DNA damage in P04141 disseminated high - grade glioma using phospho - histone P16104 antibody . Cytological examination of cerebrospinal fluid ( P04141 ) is used not only for the diagnosis of spinal disease , but also to assess the postoperative effect of treatment . We experienced a case of high - grade glioma in disseminated P04141 , and retrospectively examined the clinical , pathological and cytological features . We further investigated radiation - induced DNA damage in glioma cells using phospho - P16104 antibody . A five - year - old boy received a clinical diagnosis of optic nerve glioma , and was followed - up for three months after chemotherapy . Magnetic resonance imaging was repeated , revealing abnormalities in other brain areas . The pathological diagnosis was anaplastic astrocytoma . P04141 dissemination was detected , and increases in the number and mitosis of tumor cells were observed in P04141 cytology . After radiotherapy the tumor cells in P04141 decreased markedly . On cytomorphologic and immunocytochemical evaluation post - irradiation , tumor cells showed vacuolation of both the nucleus and cytoplasm , degeneration of nuclear chromatin , and alteration of the phospho - P16104 expression , compared with tumor cells before the irradiation . P04141 cytology is an effective means of evaluating DNA damage in tumor cells after irradiation , and may be useful in assessing the therapeutic response .", "An ataxia telangiectasia model : inefficient cell differentiation and possible reversal by serine protease inhibitors , tumor necrosis factor inhibitors , dexamethasone , and glutathione enhancers . Ataxia telangiectasia ( AT ) is a rare genetic disorder . Symptoms of the disease include cerebellar ataxia , depressed immunoresponsiveness , increased sensitivity to radiation , and leukemias . Various kinds of AT cells show reduced efficiency of differentiation . The ataxia telangiectasia gene ( Q13315 ) may reduce differentiation by suppressing cell responsivity to insulin . P01308 sensitivity seems lower in AT . P01375 may overactivate NF - kappa B in AT , and this increases the radiosensitivity of AT cells . Intracellular reduced glutathione may also become depleted . The reduced levels of glutathione may further alter differentiation of AT cells . DB00133 protease inhibitors may counteract the effects of tumor necrosis factor . Glutathione enhancers may also prove valuable as therapy .", "Methylphenidate and atomoxetine enhance prefrontal function through α2 - adrenergic and dopamine D1 receptors . OBJECTIVE : This study examined the effects of the attention - deficit / hyperactivity disorder treatments , methylphenidate ( DB00422 ) and atomoxetine ( Q13315 ) , on prefrontal cortex ( P27918 ) function in monkeys and explored the receptor mechanisms underlying enhancement of P27918 function at the behavioral and cellular levels . METHOD : Monkeys performed a working memory task after administration of a wide range of DB00422 or Q13315 doses . The optimal doses were challenged with the α ( 2 )- adrenoceptor antagonist , idazoxan , or the D ( 1 ) dopamine receptor antagonist , SCH23390 ( P35240 ) . In a parallel physiology study , neurons were recorded from the dorsolateral P27918 of a monkey performing a working memory task . Q13315 , P35240 , or the α ( 2 ) antagonist , yohimbine , were applied to the neurons by iontophoresis . RESULTS : DB00422 and Q13315 generally produced inverted - U dose - response curves , with improvement occurring at moderate doses , but not at higher doses . The beneficial effects of these drugs were blocked by idazoxan or P35240 . At the cellular level , Q13315 produced an inverted - U dose - response effect on memory - related firing , enhancing firing for preferred directions ( increasing \" signals \" ) and decreasing firing for the nonpreferred directions ( decreasing \" noise \" ) . The increase in persistent firing for the preferred direction was blocked by yohimbine , whereas the suppression of firing for the nonpreferred directions was blocked by P35240 . CONCLUSIONS : Optimal doses of DB00422 or Q13315 improved P27918 cognitive function in monkeys . These enhancing effects appeared to involve indirect stimulation of α ( 2 ) adrenoceptors and D ( 1 ) dopamine receptors in the P27918 . These receptor actions likely contribute to their therapeutic effects in the treatment of attention - deficit / hyperactivity disorder .", "Acidic pH induces topoisomerase II - mediated DNA damage . Acidic pH plays an important role in various pathophysiological states and has been demonstrated to be carcinogenic in animal models . Recent studies have also implicated acidic pH in the development of preneoplastic Barrett ' s esophagus in human . However , little is known about the molecular mechanism underlying acidic pH - induced carcinogenesis . In the current study , we show that acidic pH , like the topoisomerase II ( P11388 ) poison DB00773 ( demethylepipodophyllotoxin ethylidene - beta - D - glucoside ) , induces tumors in 9 , 10 - dimethyl - 1 , 2 - benzanthracene ( DMBA )- initiated mice . The following studies in tissue culture models have suggested that acidic pH acts like a P11388 poison to induce P11388 - mediated DNA damage : ( i ) acidic pH induces P11388 - dependent DNA damage signals as evidenced by up - regulation of p53 and DB00133 - 139 phosphorylation of P16104 [ a substrate for ataxia telangiectasia mutated ( Q13315 ) Q13315 and Rad3 - related ( ATR ) kinases ] ; ( ii ) acidic pH - induced cytotoxicity in tumor cells is reduced in P11388 - deficient cells ; ( iii ) acidic pH increases the mutation frequency of the hypoxanthine phosphoribosyl transferase ( P00492 ) gene in a P11388 - dependent manner ; and ( iv ) acidic pH induces reversible P11388 - mediated DNA strand breaks in vitro . We discuss the possibility that P11388 - mediated DNA damage may contribute to acidic pH - induced carcinogenesis .", "NSA9 , a human prothrombin kringle - 2 - derived peptide , acts as an inhibitor of kringle - 2 - induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer ' s and Parkinson ' s , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle - 2 increase levels of NO and the mRNA expression of P35228 , IL - 1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle - 2 derived peptide NSA9 inhibits NO release and the production of pro - inflammatory cytokines such as IL - 1beta , P01375 , and P05231 in LPS - activated EOC2 microglia . In this study , we investigated the anti - inflammatory effects of NSA9 in human prothrombin - and kringle - 2 - stimulated EOC2 microglia . Treatment with 20 - 100 muM of NSA9 attenuated both prothrombin - and kringle - 2 - induced microglial activation . NO production induced by MAPKs and NF - kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF - kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle - 2 .", "P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .", "Revelation of p53 - independent function of Q13330 in DNA damage response via modulation of the P38936 P38936 - proliferating cell nuclear antigen pathway . Although metastasis - associated protein 1 ( Q13330 ) , a component of the nucleosome remodeling and deacetylase ( NuRD ) complex , is a DNA - damage response protein and regulates p53 - dependent DNA repair , it remains unknown whether Q13330 also participates in p53 - independent DNA damage response . Here , we provide evidence that Q13330 is a p53 - independent transcriptional corepressor of P38936 ( P38936 ) , and the underlying mechanism involves recruitment of Q13330 - histone deacetylase 2 ( Q92769 ) complexes onto two selective regions of the P38936 ( P38936 ) promoter . Accordingly , Q13330 depletion , despite its effect on p53 down - regulation , superinduces P38936 ( P38936 ) , increases P38936 ( P38936 ) binding to proliferating cell nuclear antigen ( P12004 ) , and decreases the nuclear accumulation of P12004 in response to ionizing radiation . In support of a p53 - independent role of Q13330 in DNA damage response , we further demonstrate that induced expression of Q13330 in p53 - null cells inhibits P38936 ( P38936 ) promoter activity and P38936 ( P38936 ) binding to P12004 . Consequently , Q13330 expression in p53 - null cells results in increased induction of gamma P16104 foci and DNA double strand break repair , and decreased DNA damage sensitivity following ionizing radiation treatment . These findings uncover a new target of Q13330 and the existence of an additional p53 - independent role of Q13330 in DNA damage response , at least in part , by modulating the P38936 ( P38936 )- P12004 pathway , and thus , linking two previously unconnected NuRD complex and DNA - damage response pathways .", "Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her - 2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab - based chemotherapy . ___MASK19___ will likely be effective against trastuzumab - resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 - VEGFR - associated tumor growth .", "___MASK3___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK3___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "Mitoxantrone inhibits HIF - 1α expression in a topoisomerase II - independent pathway . PURPOSE : Solid tumors encounter a growth - limiting hypoxic microenvironment as they develop . Hypoxia - inducible factors ( HIF ) play important roles in hypoxia - associated tumor development and therapeutic resistance . Targeting the HIF pathway ( especially HIF - 1α ) represents a promising cancer treatment strategy . Here , we report a novel class of HIF - 1α inhibitors and the possible molecular basis of inhibition . EXPERIMENTAL DESIGN : We analyzed the inhibitory effects of clinically used topoisomerase II ( P11388 ) - targeting drugs on HIF - 1α expression with a primary focus on mitoxantrone . The potential role of P11388 in mitoxantrone - inhibited HIF - 1α expression was studied using pharmacologic inhibition , a knockdown approach , and P11388 mutant cells . Moreover , involvement of mitoxantrone in proteasome - mediated degradation , transcription , and translation of HIF - 1α was examined . RESULTS : The P11388 - targeting mitoxantrone , but neither doxorubicin nor etoposide ( DB00773 ) , strongly inhibited HIF - 1α expression under hypoxic conditions in a dose - and time - dependent manner . Surprisingly , the mitoxantrone - mediated inhibition of HIF - 1α expression was largely independent of two P11388 isozymes , proteasomal degradation , and transcription . Furthermore , mitoxantrone inhibited HIF - 1α expression and function in a similar fashion as cycloheximide , suggesting that mitoxantrone might inhibit HIF - 1α via a blockage at its translation step . In vitro translation experiments using HIF - 1α mRNA further confirmed inhibition of HIF - 1α translation by mitoxantrone . Interestingly , levels of the polysome - bound HIF - 1α and P15692 mRNA were elevated and decreased after mitoxantrone treatment , respectively . CONCLUSIONS : We have identified the P11388 - targeting compound , mitoxantrone , as an HIF - 1α inhibitor possibly through a translation inhibition mechanism , suggesting the possibility of an additional anticancer activity for mitoxantrone .", "P35354 regulates the proliferation of glioma stem like cells . Cancer stem - like cells ( CSCs ) possessing features of neural precursor cells ( NPC ) influence initiation , recurrence and chemoresistance of glioblastoma multiforme ( GBM ) . As inflammation is crucial for glioblastoma progression we investigated the effect of chronic IL - 1β treatment on CSCs derived from glioblastoma cell line U87MG . Exposure to IL - 1β for 10 days increased ( i ) accumulation of 8 - OHdG - a key biomarker of oxidative DNA damage ; ( ii ) DNA damage response ( DDR ) indicators γ P16104 , Q13315 and DNA - PK ; ( iii ) nuclear and cytoplasmic p53 and P35354 levels and ( iv ) interaction between P35354 and p53 . Despite upregulating p53 expression IL - 1β had no effect on cell cycle progression , apoptosis or self renewal capacity of CSCs . P35354 inhibitor Celecoxib reduced self renewal capacity and increased apoptosis of both control and IL - 1β treated CSCs . Therefore the ability of P35354 to regulate proliferation of CSCs irrespective of exposure to IL - 1β , warrants further investigation of P35354 as a potential anti - glioma target .", "mRNA expression , functional profiling and multivariate classification of colon biopsy specimen by cDNA overall glass microarray . AIM : To understand the local pathophysiological alterations and gene ontology - based functional classification of colonic biopsies into inflammatory and neoplastic diseases . METHODS : Total RNA was extracted from frozen biopsies and amplified by T7 - method . Expression profile was evaluated by Atlas Glass 1K microarrays . After microarray quality control , applicable data were available from 10 adenomas , 6 colorectal adenocarcinomas ( CRCs ) , and 6 inflammatory bowel diseases ( IBDs ) . Multivariate statistical and cell functional analyses were performed . Real - time RT - PCR and immunohistochemistry were used for validation . RESULTS : Discriminant analysis of selected genes , could correctly reclassify all 22 samples using 4 parameters ( heat shock transcription factor - 1 , bystin - like , calgranulin - A , O14798 ) . Q9UKU7 samples were characterized by overregulated chemokine ( C - X - C motif ) ligand 13 , replication protein A1 , Q15723 and downregulated Q9Y4K3 , P10415 - interacting killer genes . In adenomas upregulation of Q9Y4K3 , replication protein A1 , Q15723 and underexpression of P10415 - associated X protein , calgranulin - A genes were found . CRC cases had significantly increased epidermal growth factor receptor , topoisomerase - 1 , v - jun , Q9Y4K3 and O14798 , and decreased Q06609 and P43351 DNA repair gene , protein phosphatase - 2A and P10415 - interacting killer mRNA levels . P00533 RT - PCR and immunohistochemistry , topoisomerase - 1 RT - PCR confirmed the chip results . CONCLUSION : Different histological alterations can be reclassified by functional , multivariate analysis using cDNA microarrays . Further studies with expanded sample number are needed for subclassification of pathological alterations .", "Evidence of an Epigenetic Modification in Cell - cycle Arrest Caused by the Use of Ultra - highly - diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra - highly - diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically - diluted anti - cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 (- 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis - a - vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 ( WAF ) , p53 , Akt , P40763 ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell - cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de - acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 activity quite strikingly , it apparently did not alter the Q13547 enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 ( WAF ) , p53 , Akt , and P40763 activities and a cell - cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell - cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .", "P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK67___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .", "Anti - angiogenic effects of the water extract of HangAmDan ( WEHAD ) , a Korean traditional medicine . We investigated the anti - angiogenic effects of the water extract of HangAmDan ( WEHAD ) , which is a crude extract of nine Korean medicinal substances of animal and plant origin . In human umbilical vein endothelial cells , WEHAD significantly inhibited P09038 - induced proliferation , adhesion , migration , and capillary tube formation . We used an antibody array to perform an analysis of signaling proteins , which showed up - regulated expression of various proteins including Q06609 , P43351 , and p73 , and down - regulated expression of pFAK . Blood vessel formation in a chick chorioallantoic membrane ( P62158 ) treated with WEHAD was markedly reduced in length compared with a PBS - treated control group . These results suggest that inhibition of angiogenesis by WEHAD may be the mechanism of action for the anti - cancer effects of HAD .", "P01308 - like growth factor - 1 attenuates cisplatin - induced gammaH2AX formation and DNA double - strand breaks repair pathway in non - small cell lung cancer . Because insulin - like growth factor - 1 ( DB01277 ) counteracts the anti - neoplastic effect of cisplatin that induces DNA damage and cell death through the formation of platinum - DNA adducts , we investigated the effects of DB01277 on the DNA double - strand breaks ( DSBs ) repair system induced by cisplatin . NCI - H1299 and H460 non - small cell lung cancer ( NSCLC ) cells treated with DB01277 recovered from cisplatin - derived inhibited proliferation and apoptosis . Decreased tail length in comet assay and suppressed phosphorylation of histone P16104 at Ser139 with DB01277 cotreatment indicates that DB01277 attenuates cisplatin - induced DNA damage . Cotreatment with DB01277 attenuates phosphorylation of ataxia - telangiectasia mutated ( Q13315 ) at Ser1981 , and Q13315 - Rad3 - related ( ATR ) at Ser428 and subsequent phosphorylation of Chk2 , Chk1 , and p53 also dwindled by DB01277 . On the other hand , suppression of the IGF system with AG1024 or siRNA of insulin receptor substrate - 1 ( P35568 ) , a major adaptor molecule of the IGF system , augmented cisplatin - induced gammaH2AX , Ser1981 - pATM , and Ser428 - pATR generation . Q13315 , which plays an important role in the phosphorylation of histone P16104 and Chk2 at Thr68 , strongly binds with P35568 under the influence of cisplatin , and the interaction was partially inhibited by DB01277 . Immunocytochemistry revealed that cisplatin induces nuclear translocation of P35568 with Ser1981 - pATM , which is suppressed by cotreatment with DB01277 . In conclusion , cisplatin - induced gammaH2AX formation , DNA DSBs repair , and damage checkpoint pathway is inhibited by DB01277 . DB00515 derives interaction between Q13315 and P35568 , which is suppressed by DB01277 . Modulation of biologic activity of the DB01277 system could be a promising modality that raises the response rate of conventional chemotherapy .", "Effects of lurasidone on executive function in common marmosets . Cognitive impairment is one of the major symptoms of schizophrenia , and is considered largely due to dysfunctions in the prefrontal cortex ( P27918 ) . ___MASK69___ , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 , 5 - Q13049 and P08908 receptors has been reported to have superior efficacy in rodents ' models of cognitive impairment . However , the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non - human primates . In this study , we investigated the effect of lurasidone on executive function , which is one of the cognitive domains , in common marmosets and compared the results to those of other antipsychotics . The effects of lurasidone , haloperidol , olanzapine , risperidone , quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours ( ORD ) task . Before drug treatment , marmosets ' success rates in the easy trial of the test were almost 90 % . However , maximum success in the difficult trial of the task reached only 50 % after 8 days of training . DB00502 , olanzapine and risperidone decreased correct performance even in the easy trial of the task . All drugs , except lurasidone , impaired success rate in the difficult trial . On the other hand , lurasidone dose - dependently increased marmosets ' success rates in the difficult trial with significant effect at 10mg / kg . In conclusion , we have shown in this study that lurasidone , unlike conventional antipsychotics , improves cognition associated with executive function in common marmosets . These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics .", "aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK91___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .", "Loss of P38398 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo . BACKGROUND : Previous reports suggested a central role of P38398 in DNA - damage repair mechanisms elicited by cell exposure to anti - tumor agents . Here we studied if P38398 - defective HCC1937 or P38398 - reconstituted HCC1937 /( WT ) P38398 human breast cancer xenografts ( HBCXs ) generated in SCID mice were differentially sensitive to cisplatin ( DB00515 ) in vivo and we investigated potential molecular correlates of this effect . RESULTS : DB00515 induced almost complete growth inhibition of P38398 - defective HBCXs , while P38398 - reconstituted HBCXs were only partially inhibited . Cell cycle analysis showed a significant S - and G ( 2 )/ M blockade in P38398 - defective as compared with parental P38398 - reconstituted cells . Comparative gene expression profiling of HCC1937 and HCC1937 /( WT ) P38398 showed upregulation of P43351 and Q13426 , whereas P07992 and P23921 were downregulated . Pathway finder analysis of gene arrays data indicated perturbations of major proliferation and survival pathways suggesting that P38398 is mostly involved in G ( 2 )/ M but also in G ( 1 )/ S - phase checkpoints as well as in several important signaling pathways , including IGF , P15692 , estrogen receptor , PI3K / AKT and P01133 . METHODS : HCC1937 or HCC1937 /( WT ) P38398 HBCXs were generated in SCID mice . Animals were then weekly treated with 5 mg / kg DB00515 i . p . or with vehicle for 4 w . Tumor volume and mice survival were evaluated . Tumors were retrieved from animals 12 hours after the last treatment with DB00515 or vehicle treatment and the cell suspension underwent cell cycle analysis . Differential gene expression and pathway modulation between HCC1937 and HCC1937 /( WT ) P38398 cells were also studied . CONCLUSION : Our data suggest that P38398 - defective in vivo HBCXs express a molecular scenario predictive of high sensitivity to platinum - derived compounds strongly supporting the rationale for prospective tailored clinical trials in hereditary breast cancer .", "Induction of apoptosis of Beta cells of the pancreas by advanced glycation end - products , important mediators of chronic complications of diabetes mellitus . We herein report cytotoxicity of advanced glycation end - products ( AGEs ) on pancreatic beta cells . AGEs stimulated reactive oxygen species ( ROS ) generation but did not arrest proliferation of the P01308 - 1 cell line . Pancreatic beta cell lines or primary cultured islets possess a receptor for P51606 ( RAGE ) , and its expression increased after P51606 treatment . TUNEL staining and FACS analysis using annexin V / PI antibodies showed that apoptosis increased in P01308 - 1 cells or primary cultured islets when incubated with BSA conjugated with glyceraldehyde ( AGE2 ) or glucoaldehyde ( AGE3 ) , compared with those conjugated with glucose ( AGE1 ) . Reaction of P01308 - 1 cells to Ki67 , which is a cellular marker for proliferation , was also increased after P51606 treatment . The ability of primary cultured islets to secrete insulin was retained even after P51606 treatment under either low or high glucose conditions . The antiserum against RAGE partially prevented P51606 - induced cellular events . Treatment of beta cells with the antioxidant metallothionein results in a significant reduction in pathologic changes . AGEs might be able to induce apoptosis as well as proliferation of pancreatic beta cell lines or primary cultured islets . Moreover , antibody array showed that Q06609 and P43351 were significantly decreased in AGE2 - treated P01308 - 1 cells . AGEs might inhibit homologous DNA recombination for repairing DNA of P01308 - 1 cells damaged by ROS generation . It might be suggested that treatment of AGEs resulted in ROS production and apoptosis through their receptor on pancreatic beta cells . AGEs might deteriorate function of pancreatic beta cells in patients with long - term hyperglycemia .", "Current researches on breast cancer epidemiology in Korea . As a cause of death in women , breast cancer ranks second to stomach cancer in Korea . Age - standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s . There are big differences in the incidence rates for breast cancer compared with Western countries . Epidemiological features , trends in morbidity and mortality , various age - specific incidence curves , migrant study results , and analysis of the risk factors , however , suggest that the incidence of breast cancer might be further increasing in Korea . The key epidemiological hormonal risk factors for breast cancer are all explicable in terms of the estrogen augmented by progesterone hypothesis . These include older age , family history of breast cancer , early menarche , late menopause , late full - term pregnancy , and never a breast feeding . Both the establishment of high - risk groups and the estimation of lifetime risk are essential to develop a control strategy against breast cancer . Invasive ductal carcinoma is the most common histologic type of breast cancer in Korea , and the five - year survival rate has been estimated as 80 - 83 % . Recent studies on the identification of susceptibility factors such as genetic polymorphisms of P09488 / T1 / P1 , P21964 , P05181 , P11511 , P05093 , P03372 , P18887 , O43542 , P43351 , TGF - alpha , P01375 , IL - 1B , IL - 1RN , P50613 etc . that predispose individuals to breast cancer by gene - environment or gene - gene interactions may possibly give further insight into both the etiology and the prevention of this malignancy .", "Role of nitrative and oxidative DNA damage in inflammation - related carcinogenesis . Chronic inflammation induced by biological , chemical , and physical factors has been found to be associated with the increased risk of cancer in various organs . We revealed that infectious agents including liver fluke , Helicobacter pylori , and human papilloma virus and noninfectious agents such as asbestos fiber induced P35228 - dependent formation of 8 - nitroguanine and 8 - oxo - 7 , 8 - dihydro - 2 '- deoxyguanosine ( 8 - oxodG ) in cancer tissues and precancerous regions . Our results with the colocalization of phosphorylated Q13315 and γ - P16104 with 8 - oxodG and 8 - nitroguanine in inflammation - related cancer tissues suggest that DNA base damage leads to double - stranded breaks . It is interesting from the aspect of genetic instability . We also demonstrated P05231 - modulated P35228 expression via P40763 and P00533 in Epstein - Barr - virus - associated nasopharyngeal carcinoma and found promoter hypermethylation in several tumor suppressor genes . Such epigenetic alteration may occur by controlling the DNA methylation through P05231 - mediated JAK / P40763 pathways . Collectively , 8 - nitroguanine would be a useful biomarker for predicting the risk of inflammation - related cancers .", "Effect of Q13315 , O96017 and P04626 TAGSNPs and haplotypes on endometrial cancer risk . Family history of endometrial cancer increases the risk of developing the disease , but it is still largely unknown which germ - line genetic factors are involved in the aetiology of endometrial cancer . In a Swedish population - based case - control study including 705 cases and 1565 controls , we examined common variation in the Q13315 , O96017 and P04626 genes in relation to endometrial cancer risk overall , restricted to tumours of certain characteristics or stratified by various endometrial cancer risk factors . We genotyped a large number of single - nucleotide polymorphisms ( SNPs ) in the genes and selected seven haplotype - tagging SNPs ( tagSNPs ) in Q13315 , six tagSNPs in O96017 and seven tagSNPs in P04626 that could predict common variants and haplotypes ( frequency > or = 0 . 03 ) in each gene with R ( 2 ) > or = 0 . 8 . We included the tagSNPs or their haplotypes as explanatory variables in unconditional logistic regression models adjusted for age . Our results indicated an increased risk of developing endometroid endometrial cancer for homozygous carriers of the rare allele ( AA ) of a tagSNP ( rs4987886 ) in O96017 ( P = 0 . 005 ) when contrasted with GG carriers . We also found a decreased endometrial cancer risk among non - smoking carriers of a haplotype in Q13315 ( P = 0 . 0007 ) and among carriers of a haplotype in O96017 , who had experienced menopause below 49 years of age ( P = 0 . 0009 ) compared with non - carriers of these haplotypes . We found no effect of genetic variation in P04626 on endometrial cancer risk . In conclusion , it is possible that common variants in the Q13315 and O96017 genes , in interaction with oestrogen - related exposures , are involved in endometrial cancer aetiology .", "Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER - 2 and P00533 . ___MASK19___ is a potent dual inhibitor of HER - 2 and P00533 . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side - effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER - 2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER - 2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab - refractory metastatic breast cancer . ___MASK19___ may have a specific role in treating HER - 2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated .", "Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II . Increasing the cellular concentration of DNA topoisomerase II in yeast by expressing constitutively a plasmid - borne P11388 gene encoding the enzyme greatly increases the sensitivity of the cells to amsacrine and etoposide ( DB00773 ) . This increased drug sensitivity at a higher intracellular DNA topoisomerase II level is observed in both P43351 + repair - proficient strains and rad52 mutants that are defective in the repair of double - stranded breaks . These results provide strong support of the hypothesis that the cellular target of these drugs is DNA topoisomerase II , and that these drugs kill cells by converting DNA topoisomerase II into a DNA damaging agent .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "TGF - β1 - ROS - Q13315 - CREB signaling axis in macrophage mediated migration of human breast cancer MCF7 cells . Macrophages in the tumor microenvironment play an important role in tumor cell survival . They influence the tumor cell to proliferate , invade into surrounding normal tissues and metastasize to local and distant sites . In this study , we evaluated the effect of conditioned medium from monocytes and macrophages on growth and migration of breast cancer cells . Macrophage conditioned medium ( MϕCM ) containing elevated levels of cytokines P01375 - α , IL - 1β and P05231 had a differential effect on non - invasive ( MCF7 ) and highly invasive ( MDA - MB - 231 ) breast cancer cell lines . MϕCM induced the secretion of TGF - β1 in MCF7 cells . This was associated with apoptosis in a fraction of cells and generation of reactive oxygen and nitrogen species ( ROS and RNS ) and DNA damage in the remaining cells . This , in turn , increased expression of DB02527 response element binding protein ( CREB ) and vimentin resulting in migration of cells . These effects were inhibited by neutralization of P01375 - α , IL - 1β and P05231 , inhibition of ROS and RNS , DNA damage and siRNA mediated knockdown of Q13315 . In contrast , MDA - MB - 231 cells which had higher basal levels of pCREB were not affected by MϕCM . In summary , we have found that pro - inflammatory cytokines secreted by macrophages induce TGF - β1 in tumor cells , which activate pCREB signaling , epithelial - mesenchymal - transition ( EMT ) responses and enhanced migration .", "___MASK26___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK26___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .", "The dynamic alterations of P16104 complex during DNA repair detected by a proteomic approach reveal the critical roles of Ca ( 2 +)/ calmodulin in the ionizing radiation - induced cell cycle arrest . By using DNA nuclease digestion and a quantitative \" dual tagging \" proteomic approach that integrated mass spectrometry , stable isotope labeling , and affinity purification , we studied the histone P16104 - associating protein complex in chromatin in mammalian cells in response to ionizing radiation ( IR ) . In the non - irradiated control cells , calmodulin ( P62158 ) and the transcription elongation factor facilitates chromatin transcription ( FACT ) were associated with P16104 . Thirty minutes after exposing cells to IR the P62158 and FACT complexes dissociated , whereas two DNA repair proteins , poly ( ADP - ribose ) polymerase - 1 and DEAH box polypeptide 30 isoform 1 , interacted with P16104 . Two hours and 30 min after exposure , none of the above proteins were in the complex . H2B , nucleophosmin / B23 , and calreticulin were associated with P16104 in both non - irradiated and irradiated cells . The results suggest that the P16104 complex undergoes dynamic changes upon induction of DNA damage and during DNA repair . The genuine interactions between P16104 and H2B , nucleophosmin / B23 , calreticulin , poly ( ADP - ribose ) polymerase - 1 , and P62158 under each condition were validated by immunoprecipitation / Western blotting and mammalian two - hybrid assays . Because multiple Ca ( 2 +)- binding proteins were found in the P16104 complex , the roles of Ca ( 2 +) were examined . The results indicate that Ca ( 2 +)/ P62158 plays important roles in regulating IR - induced cell cycle arrest , possibly through mediating chromatin structure . The dataset presented here demonstrates that sensitive profiling of the dynamics of functional cellular protein - protein interactions can successfully lead to the dissection of important metabolic or signaling pathways .", "Rad10 exhibits lesion - dependent genetic requirements for recruitment to DNA double - strand breaks in Saccharomyces cerevisiae . In the yeast Saccharomyces cerevisiae , the Rad1 - Rad10 protein complex participates in nucleotide excision repair ( P55055 ) and homologous recombination ( HR ) . During HR , the Rad1 - Rad10 endonuclease cleaves 3 ' branches of DNA and aberrant 3 ' DNA ends that are refractory to other 3 ' processing enzymes . Here we show that yeast strains expressing fluorescently labeled Rad10 protein ( Rad10 - YFP ) form foci in response to double - strand breaks ( DSBs ) induced by a site - specific restriction enzyme , I - SceI or by ionizing radiation ( IR ) . Additionally , for endonuclease - induced DSBs , Rad10 - YFP localization to DSB sites depends on both Q06609 and P43351 , but not P49959 while IR - induced breaks do not require Q06609 . Finally , Rad10 - YFP colocalizes with Rad51 - P27918 and with Rad52 - P27918 at DSB sites , indicating a temporal overlap of Rad52 , Rad51 and Rad10 functions at DSBs . These observations are consistent with a putative role of Rad10 protein in excising overhanging DNA ends after homology searching and refine the potential role ( s ) of the Rad1 - Rad10 complex in DSB repair in yeast .", "Vascular endothelial growth factor receptors in osteoclast differentiation and function . Osteoclasts are derived from haematopoietic stem cell precursors of the monocyte / macrophage cell lineage , through interaction with factors that are believed to include P09603 and O14788 . P15692 is a proangiogenic cytokine that has been shown to promote osteoclast differentiation and survival . In this study , we assessed the role of P15692 and its receptors in osteoclastogenesis , in vitro , by culturing osteoclast precursors in the presence of P15692 , P15692 receptor - specific ligands , and blocking antibodies to P15692 receptors . Activation of P17948 in the presence of O14788 induces osteoclast differentiation . Stimulating the receptors individually induced increased resorption by osteoclasts compared to controls but not to the level observed when stimulating both receptors simultaneously . We have shown that P15692 induces osteoclast differentiation through its action on P17948 . The way in which P15692 mediates its effect on mature osteoclast activity , however , may be through its interaction with both receptor subtypes .", "DB00072 has opposing effects on SN - 38 - induced double - strand breaks and cytotoxicity in P04626 - positive gastric cancer cells depending on administration sequence . AIM : We investigated the effects of trastuzumab , an anti - P04626 humanized monoclonal antibody , on DNA breaks induced by SN - 38 , a topoisomerase - 1 inhibitor , in gastric cancer cell lines positive or negative for P04626 expression . MATERIALS AND METHODS : NCI - N87 ( P04626 + ) and MKN74 ( P04626 - ) cells were exposed to SN - 38 in the presence or absence of trastuzumab . DB00072 was added either prior to or after SN - 38 . Effects of trastuzumab on the induction of gamma - P16104 , a marker of DNA double - strand breaks , the cytotoxicity of SN - 38 and cell cycle progression were determined . RESULTS : When trastuzumab was administered following SN - 38 , it increased γ P16104 levels and cytotoxicity of SN - 38 in NCI - N87 cells , but not in MKN74 cells . In contrast , pretreatment with trastuzumab reduced SN - 38 - induced γ P16104 expression and cytotoxicity of SN - 38 in NCI - N87 cells , but not in MKN74 cells . DB00072 delayed cell cycle progression in NCI - N87 cells only . CONCLUSION : DB00072 has opposing effects on SN - 38 - induced double - strand breaks and cytotoxicity depending on the order of administration of the two agents .", "DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .", "Topoisomerase II - mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation - associated tumorigenesis . AIMS : Both cancer - suppressing and cancer - promoting properties of reactive nitrogen and oxygen species ( RNOS ) have been suggested to play a role in tumor pathology , particularly those activities associated with chronic inflammation . Here , we address the impact of nitric oxide ( NO ) on the induction of DNA damage and genome instability with a specific focus on the involvement of topoisomerase II ( P11388 ) . We also investigate the contribution of NO to the formation of skin melanoma in mice . RESULTS : Similar to the P11388 - targeting drug , etoposide ( DB00773 ) , the NO - donor , S - nitrosoglutathione ( GSNO ) , induces skin melanomas formation in 7 , 12 - dimethyl - benz [ a ] anthracene ( DMBA ) - initiated mice . To explore the mechanism ( s ) underlying this NO - induced tumorigenesis , we use a co - culture model system to demonstrate that inflamed macrophages with inducible NO synthase ( P35228 ) expression cause γ - P16104 activation , p53 phosphorylation , and chromosome DNA breaks in the target cells . Inhibitor experiments revealed that NO and P11388 isozymes are responsible for the above described cellular phenotypes . Notably , NO , unlike DB00773 , preferentially induces the formation of TOP2β cleavable complexes ( TOP2βcc ) in cells . Moreover , GSNO induced P11388 - dependent DNA sequence rearrangements and cytotoxicity . Furthermore , the incidences of GSNO - and DB00773 - induced skin melanomas were also observed to be lower in the skin - specific top2β - knockout mice . Our results suggest that P11388 isozymes contribute to NO - induced mutagenesis and subsequent cancer development during chronic inflammation . INNOVATION AND CONCLUSIONS : We provide the first experimental evidence for the functional role of P11388 in NO - caused DNA damage , mutagenesis , and carcinogenesis . Notably , these studies contribute to our molecular understanding of the cancer - promoting actions of RNOS during chronic inflammation .", "Loss of epigenetic Kruppel - like factor 4 histone deacetylase ( KLF - 4 - HDAC ) - mediated transcriptional suppression is crucial in increasing vascular endothelial growth factor ( P15692 ) expression in breast cancer . Vascular endothelial growth factor ( P15692 ) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions , including cancer , inflammation , and ischemic disorders . We have recently shown that the inflammatory transcription factor P56270 is , at least in part , responsible for the marked increase of P15692 levels in breast cancer . Here , we show that P56270 - mediated induction of P15692 is repressed by KLF - 4 transcription factor . KLF - 4 is abundantly present in normal breast epithelial cells , but its level is considerably reduced in breast cancer cells and clinical cancer tissues . In the human P15692 promoter , P56270 - and KLF - 4 - binding elements are overlapping , whereas P56270 induces and KLF - 4 suppresses P15692 expression . Ectopic overexpression of KLF - 4 and RNAi - mediated inhibition of endogenous KLF - 4 supported the role of KLF - 4 as a transcriptional repressor of P15692 and an inhibitor of angiogenesis in breast cancer cells . We show that KLF - 4 recruits histone deacetylases ( HDACs ) - 2 and - 3 at the P15692 promoter . Chronological ChIP assays demonstrated the occupancy of KLF - 4 , Q92769 , and O15379 in the P15692 promoter in normal MCF - 10A cells but not in MDA - MB - 231 cancer cells . Co - transfection of KLF - 4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of P15692 expression and inhibition of angiogenic potential of these carcinoma cells . Together these results identify a new mechanism of P15692 up - regulation in cancer that involves concomitant loss of KLF - 4 - HDAC - mediated transcriptional repression and active recruitment of P56270 - mediated transcriptional activation .", "Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .", "The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK69___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK69___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .", "15 - deoxy - Δ¹² , ¹⁴ - PGJ₂ promotes inflammation and apoptosis in cardiomyocytes via the Q14188 / MAPK / P01375 α axis . BACKGROUND : Prostaglandins ( PGs ) , lipid autacoids derived from arachidonic acid , play a pivotal role during inflammation . P52209 ₂ synthase is abundantly expressed in heart tissue and P52209 ₂ has recently been found to induce cardiomyocyte apoptosis . P52209 ₂ is an unstable prostanoid metabolite ; therefore the objective of the present study was to elucidate whether its final dehydration product , 15 - deoxy - Δ¹² , ¹⁴ - PGJ₂ ( 15d - PGJ₂ , present at high levels in ischemic myocardium ) might cause cardiomyocyte damage . METHODS AND RESULTS : Using specific ( ant ) agonists we show that 15d - PGJ₂ induced formation of intracellular reactive oxygen species ( ROS ) and phosphorylation of p38 and Q8NFH3 / 44 MAPKs via the Q13258 Q14188 ( but not DP1 or Q07869 γ ) in the murine atrial cardiomyocyte P07306 cell line . Activation of the Q14188 - ROS - MAPK axis by 15d - PGJ₂ enhanced transcription and translation of P01375 α and induced apoptosis in P07306 cardiomyocytes . Silencing of P01375 α significantly attenuated the extrinsic ( caspase - 8 ) and intrinsic apoptotic pathways ( bax and caspase - 9 ) , caspase - 3 activation and downstream PARP cleavage and γ P16104 activation . The apoptotic machinery was unaffected by intracellular calcium , transcription factor NF - κB and its downstream target p53 . Of note , 9 , 10 - dihydro - 15d - PGJ₂ ( lacking the electrophilic carbon atom in the cyclopentenone ring ) did not activate cellular responses . Selected experiments performed in primary murine cardiomyocytes confirmed data obtained in P07306 cells namely that the intrinsic and extrinsic apoptotic cascades are activated via Q14188 / MAPK / P01375 α signaling . CONCLUSIONS : We conclude that the reactive α , β - unsaturated carbonyl group of 15d - PGJ₂ is responsible for the pronounced upregulation of P01375 α promoting cardiomyocyte apoptosis . We propose that inhibition of Q14188 receptors could provide a possibility to modulate 15d - PGJ₂ - induced myocardial injury .", "Recombinant P17936 inhibits allergic lung inflammation , P15692 production , and vascular leak in a mouse model of asthma . BACKGROUND : Vascular endothelial growth factor ( P15692 ) plays a pro - inflammatory mediator as well as a vascular permeability factor in bronchial asthma . P01308 - like growth factor ( IGF ) - I is also involved in the inflammatory process associated with bronchial asthma and stimulates P15692 expression . The IGF - binding proteins ( IGFBPs ) , especially P17936 , display distinctive properties and can interfere with various biological processes . METHODS : In this study , an ovalbumin ( OVA ) - induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of P17936 administered exogenously on allergen - induced bronchial inflammation and airway hyper - responsiveness , in particular focusing on the regulation of P15692 expression . RESULTS : Administration of recombinant human P17936 to OVA - inhaled mice substantially attenuated the increases in hypoxia - inducible factor ( HIF ) - α activity , P05019 production , and P15692 protein levels in the lung . In addition , the blockade of P05019 action decreased the OVA - induced P15692 expression , airway inflammation , and bronchial hyper - responsiveness . The administration of recombinant human P17936 or CBO - P11 also reduced significantly increases in inflammatory cells , airway hyper - responsiveness , levels of P05112 , P05113 , P35225 , and vascular permeability in the lung of OVA - inhaled mice . Moreover , when recombinant human P17936 was administered after the completion of OVA inhalation , these therapeutic effects of P17936 were also observed . CONCLUSIONS : These results indicate that P17936 administered exogenously may attenuate antigen - induced airway inflammation and hyper - responsiveness through the modulation of vascular leakage and P15692 expression mediated by HIF - 1α / HIF - 2α signaling as well as P05019 action in allergic airway disease of mice ." ]

[ "___MASK19___", "___MASK26___", "___MASK3___", "___MASK41___", "___MASK4___", "___MASK67___", "___MASK69___", "___MASK91___", "___MASK95___" ]

[ "Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK7___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK7___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .", "Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .", "Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK60___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .", "DB06288 is a potent P34969 antagonist : relevance for antidepressant actions in vivo . RATIONALE : DB06288 is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia , a mild form of depression , in Italy . DB06288 has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials . In part because of the selective D ( 2 )/ D ( 3 ) receptor antagonist properties of amisulpride , it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties . OBJECTIVES : The purpose of these studies was to determine if amisulpride ' s antidepressant actions are mediated by off - target interactions with other receptors . MATERIALS AND METHODS : We performed experiments that : ( 1 ) examined the pharmacological profile of amisulpride at a large number of central nervous system ( CNS ) molecular targets and , ( 2 ) after finding high potency antagonist affinity for human 5 - HT ( 7a ) serotonin receptors , characterized the actions of amisulpride as an antidepressant in wild - type and 5 - HT ( 7 ) receptor knockout mice . RESULTS : We discovered that amisulpride was a potent competitive antagonist at 5 - HT ( 7a ) receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo . Significantly , and in contrast to their wild - type littermates , 5 - HT ( 7 ) receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression , the tail suspension test and the forced swim test . CONCLUSIONS : These results indicate that 5 - HT ( 7a ) receptor antagonism , and not D ( 2 )/ D ( 3 ) receptor antagonism , likely underlies the antidepressant actions of amisulpride .", "\" In vitro \" postnatal expression of P34969 receptors in the rat hypothalamus : an immunohistochemical analysis . The neurotransmitter serotonin ( 5 - HT ) is involved in various physiological functions via multiple receptor subtypes . These have been classified in seven receptor families ( 5 - HT1 - 7 ) on the basis of their structures and functional characteristics . In this study , we examined the expression of P34969 receptors in the rat hypothalamic neurons cultured \" in vitro \" during postnatal development . Neuronal cultures were prepared from postnatal pups P2 , P09131 and Q15084 , were treated with P09038 and processed by means of immunofluorescence technique using a polyclonal P34969 receptor antibody . In P2 , we found a low density of P34969 labeled hypothalamic P09038 - treated neurons and no P34969 immunolabeling in control cultures ; in P09131 , a moderate number of P09038 - treated neurons were observed but they were not bright . No P34969 immunolabeling was found in controls . In Q15084 , a heavy labeling of small sized bipolar neurons was seen in P09038 - treated neurons , while in control cultures , few labeled neurons with a low stained density were observed . These results suggest that P34969 receptors in hypothalamic neurons begin to appear at Q15084 and then could be involved in many physiological implications that are not exerted at P2 and P09131 . This indicates that P34969 receptors have a potential significance in the rat hypothalamus during early postnatal development .", "The antimalarial drug mefloquine inhibits cardiac inward rectifier K + channels : evidence for interference in PIP2 - channel interaction . The antimalarial drug mefloquine was found to inhibit the KATP channel by an unknown mechanism . Because mefloquine is a Cationic amphiphilic drug and is known to insert into lipid bilayers , we postulate that mefloquine interferes with the interaction between PIP2 and Kir channels resulting in channel inhibition . We studied the inhibitory effects of mefloquine on Kir2 . 1 , Kir2 . 3 , Kir2 . 3 ( I213L ) , and Kir6 . 2 / SUR2A channels expressed in P29320 - 293 cells , and on IK1 and Q14654 from feline cardiac myocytes . The order of mefloquine inhibition was Kir6 . 2 / SUR2A ≈ Kir2 . 3 ( IC50 ≈ 2 μM ) > Kir2 . 1 ( IC50 > 30 μM ) . Similar results were obtained in cardiac myocytes . The Kir2 . 3 ( I213L ) mutant , which enhances the strength of interaction with PIP2 ( compared to WT ) , was significantly less sensitive ( IC50 = 9 μM ) . In inside - out patches , continuous application of PIP2 strikingly prevented the mefloquine inhibition . Our results support the idea that mefloquine interferes with PIP2 - Kir channels interactions .", "Activation of P34969 receptor stimulates neurite elongation through P42345 , Cdc42 and actin filaments dynamics . Recent studies have indicated that the serotonin receptor subtype 7 ( 5 - HT7R ) plays a crucial role in shaping neuronal morphology during embryonic and early postnatal life . Here we show that pharmacological stimulation of 5 - HT7R using a highly selective agonist , LP - 211 , enhances neurite outgrowth in neuronal primary cultures from the cortex , hippocampus and striatal complex of embryonic mouse brain , through multiple signal transduction pathways . All these signaling systems , involving P42345 , the Rho GTPase Cdc42 , Cdk5 , and P29323 , are known to converge on the reorganization of cytoskeletal proteins that subserve neurite outgrowth . Indeed , our data indicate that neurite elongation stimulated by 5 - HT7R is modulated by drugs affecting actin polymerization . In addition , we show , by 2D Western blot analyses , that treatment of neuronal cultures with LP - 211 alters the expression profile of cofilin , an actin binding protein involved in microfilaments dynamics . Furthermore , by using microfluidic chambers that physically separate axons from the soma and dendrites , we demonstrate that agonist - dependent activation of 5 - HT7R stimulates axonal elongation . Our results identify for the first time several signal transduction pathways , activated by stimulation of 5 - HT7R , that converge to promote cytoskeleton reorganization and consequent modulation of axonal elongation . Therefore , the activation of 5 - HT7R might represent one of the key elements regulating CNS connectivity and plasticity during development .", "DB06288 promotes cognitive flexibility in rats : the role of P34969 receptors . The antagonism of P34969 receptors may contribute to the antidepressant and procognitive actions of the atypical antipsychotic drug , amisulpride . It has been previously demonstrated that the selective P34969 receptor antagonist reversed restraint stress - induced cognitive impairments in a rat model of frontal - dependent attentional set - shifting task ( ASST ) . Therefore , the first aim of the present study was to assess the effectiveness of amisulpride against stress - evoked cognitive inflexibility . The second goal was to elucidate whether the pro - cognitive effect of amisulpride could be due to the compound ' s action at P34969 receptors . Rats repeatedly exposed ( 1 h daily for 7 days ) to restraint stress demonstrated impaired performance on the extra - dimensional ( ED ) set - shifting stage of the ASST . DB06288 ( 3 mg / kg ) given to stressed rats 30 min before testing reversed this restraint - induced cognitive inflexibility and improved ED performance of the unstressed control group . The P34969 receptor agonist , AS19 ( 10 mg / kg ) , abolished the pro - cognitive efficacy of amisulpride ( 3 mg / kg ) . The present study suggests that the antagonism of P34969 receptors may contribute to the mechanisms underlining the pro - cognitive action of amisulpride . These results may have therapeutic implications in frontal - like deficits associated with stress - related disorders .", "Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \" dominant negative \" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .", "P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK29___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .", "Novel P34969 receptor inverse agonists . Synthesis and molecular modeling of arylpiperazine - and 1 , 2 , 3 , 4 - tetrahydroisoquinoline - based arylsulfonamides . A series of arylpiperazine - and 1 , 2 , 3 , 4 - tetrahydroisoquinoline - based arylsulfonamides was synthesized and evaluated for their interactions with the constitutively active P34969 receptor . Effects on basal adenylate cyclase activity were measured using P29320 - 293 cells expressing the rat P34969 . All ligands produced a decrease of adenylate cyclase activity , indicative of their inverse agonism . Additionally , computational studies with a set of 22 inverse agonists , including these novel inverse agonists and inverse agonists known from literature , resulted in a pharmacophore model and a CoMFA model ( R2 = 0 . 97 , SE = 0 . 18 ) . Docking of inverse agonists at the binding site of a model of the helical parts of the P34969 receptor , based on the alpha carbon template for 7 - TM GPCRs , revealed interesting molecular interactions and a possible explanation for observed structure - activity relationships .", "Direct analysis of candidate genes in impulsive behaviours . Antisocial behaviour is both heterogeneous and the product of interacting genetic and environmental factors acting at different levels of causation . Heritability studies show that individual differences in predisposition to antisocial behaviour are transmitted vertically in families by genetic mechanisms . Owing to aetiological heterogeneity and complexity , study of a variety of other behavioural phenotypes may shed more light on the antecedents of antisocial behaviour than direct studies on antisocial behaviour . Identification of genetic vulnerability factors would clarify mechanisms of vulnerability and the role of the environment . Direct gene analysis and genetic linkage analysis have identified structural variants in genes involved in neurotransmitter function , and some progress has been made towards relating these genetic variants to antisocial personality and other behaviours . Thyroid hormone receptor variants can cause attention deficit / hyperactivity disorder , and a monoamine oxidase A variant leads to aggressive behaviour in one family . Direct gene analyses have revealed non - conservative amino acid substitutions and structural variants ( generally rare ) at P14416 , P35462 and P21917 dopamine receptors and P08908 , 5 - Q13049 , P28335 and P34969 serotonin receptors . The stage is set to identify the phenotypic significance of these as well as genetic variants at other loci which may be relevant as candidate genes for antisocial behaviour and related behavioural differences .", "Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK23___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .", "Transforming growth factor - beta1 induces tumor stroma and reduces tumor infiltrate in cervical cancer . Cervical carcinomas consist of tumor cell nests surrounded by varying amounts of intratumoral stroma containing different quantities and types of immune cells . Besides controlling ( epithelial ) cell growth , the multifunctional cytokine transforming growth factor - beta ( 1 ) ( TGF - beta ( 1 ) ) is involved in the formation of stroma and extracellular matrix ( Q13201 ) and in immunosuppression . Several malignancies are known to be associated with enhanced production of TGF - beta ( 1 ) , repression or mutation of TGF - beta transmembrane receptors , or mutations at the postreceptor intracellular signaling pathway . The aim of our study was to investigate the role of tumor cell - derived TGF - beta ( 1 ) on the amount of intratumoral stroma ; the deposition of collagen IV , fibronectin , and laminin ; and the tumor infiltrate in cervical carcinoma . The expression of TGF - beta ( 1 ) mRNA in 108 paraffin - embedded cervical carcinomas was detected by mRNA in situ hybridization . Immunohistochemistry was used to investigate the amount of tumor stroma and Q13201 proteins and the extent of the tumor infiltrate . P00747 activator inhibitor - 1 ( P05121 ) protein expression in tumor cells was determined to verify the biological activity of TGF - beta ( 1 .) Cytoplasmatic TGF - beta ( 1 ) mRNA expression in tumor cells was significantly correlated with the amount of intratumoral stroma and the deposition of collagen IV . TGF - beta ( 1 ) mRNA expression in every tumor was accompanied by P05121 expression , indicating biological activity of TGF - beta ( 1 ) . An inverse relationship between TGF - beta ( 1 ) mRNA expression in tumor cells and the extent of the tumor infiltrate was demonstrated . Our results indicate that cervical cancer cells affect the amount and the composition of the intratumoral stroma and the tumor infiltrate by the production and secretion of TGF - beta ( 1 ) .", "Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK78___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .", "___MASK63___ prevents growth factor - induced proliferation of bovine retinal endothelial cells under hypoxia . Ocular diseases such as proliferative diabetic retinopathy are the major cause of blindness in industrialized countries . The main pathologic features of these diseases are hypoxia and overproduction of growth factors resulting in pathologic proliferation of endothelial cells and new vessel formation . Particularly , hypoxia and growth factors , such as P15692 , DB01277 , P09038 and TGF beta ( 2 ) , show a complex interaction in the onset and progression of the diseases . Therefore , to date , most therapeutic strategies for proliferative retinopathies have targeted proliferation of endothelial cells evoked by growth factors . Recently , a synthetic analog of somatostatin , octreotide , has been shown to inhibit the proliferation of various cells in vitro , including endothelial cells . In this study , we have investigated the proliferative response of bovine retinal endothelial cells ( BREC ) to growth factors under hypoxic conditions and the modulation by octreotide . We found a dose - dependent increase of cell proliferation with P15692 , DB01277 and P09038 , and inhibition of hypoxia - induced cell proliferation with TGF beta ( 2 ) . Moreover , growth factor - induced , but not hypoxia - induced , cell proliferation was attenuated in the presence of octreotide . In contrast , TGF beta ( 2 ) abolished hypoxia - induced BREC proliferation . Similar to octreotide BIM23027 , a somatastatin receptor subtype 2 ( P30874 ) receptor agonist was able to attenuate the growth factor - induced proliferation of BREC expressing mRNA and protein for P30874 . Therefore , we postulate that octreotide exerts its effects mainly through binding to the P30874 . Taken together , our findings point to octreotide as a promising candidate for the treatment of eye disorders involving growth factor - dependent proliferation of endothelial cells .", "Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .", "Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK100___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .", "Serotonin P34969 receptors coupled to induction of interleukin - 6 in human microglial MC - 3 cells . Brain serotonin 5 - HT ( 7 ) receptors are known to be expressed in neurons and astrocytes . We now report the presence of these receptors in a third type of cell , microglial cells . 5 - Hydroxytryptamine ( 5 - HT ) , 5 - carboxamidotryptamine ( 5 - CT ) , 5 - methoxytryptamine ( 5 - MeOT ) and 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) induced concentration - dependent stimulations of DB02527 accumulation in the human microglial MC - 3 cell line . The maximal effect of 5 - HT was 3 . 4 +/- 0 . 3 - fold stimulation ( mean +/- S . E . M . , n = 5 ) above basal levels . The rank order of agonist potency ( pEC50 values ) was 5 - CT ( 7 . 09 ) > 5 - HT ( 6 . 13 ) > or = 5 - MeOT ( 5 . 78 ) >> 8 - OH - DPAT ( ca . 5 ) . The effect of 5 - CT was inhibited in a concentration - dependent manner by the selective P34969 receptor antagonist SB - 269970 ( pA2 value 9 . 03 ) . Western blot analysis revealed the presence of immunoreactive bands corresponding to the human P34969 receptor in extracts of MC - 3 cells . The presence of two splice variants of the P34969 receptor ( P34969 ( a / b ) ) was visualized by reverse transcriptase - polymerase chain reaction ( RT - PCR ) analysis with specific primers . In real - time PCR studies , the mRNA for interleukin - 6 ( P05231 ) was found to be increased by 2 . 5 - fold in MC - 3 cells after 1 h incubation with 5 - CT ( 1 microM ) and this effect was fully blocked by the P34969 receptor antagonist SB - 269970 ( 1 microM ) . These data show that functional P34969 receptors are present in human microglial MC - 3 cells , suggesting that they are involved in neuroinflammatory processes .", "Synergism between bosutinib ( ___MASK69___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .", "___MASK71___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK71___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK71___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK71___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .", "Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples ." ]

[ "___MASK100___", "___MASK23___", "___MASK29___", "___MASK60___", "___MASK63___", "___MASK69___", "___MASK71___", "___MASK78___", "___MASK7___" ]

[ "DB06655 : clinical pharmacology and considerations for therapy . DB06655 is a United States Food and Drug Administration ( FDA ) - approved glucagon - like peptide - 1 ( P0C6A0 ) analog that is 97 % homologous to native human P0C6A0 . The additional 16 - carbon fatty acid chain causes noncovalent binding to albumin , which slows absorption from the injection site and protects the molecule from degradation by the enzyme dipeptidyl peptidase - 4 , allowing for protraction of action . Albumin binding and an elimination half - life of 13 hours combine to allow for once - daily dosing . DB06655 1 . 2 and 1 . 8 mg / day given as monotherapy for up to 52 weeks produced mean reductions in hemoglobin A1c ( A1C ) of 0 . 6 - 1 . 6 % ; combination therapy of liraglutide with oral antidiabetic agents demonstrated mean A1C reductions up to 1 . 5 % . The satiety effect of P43220 agonists and documented weight loss as great as 3 . 38 kg in clinical trials may make liraglutide ideal for obese patients with type 2 diabetes mellitus . Like other incretin - based agents , preliminary studies suggest liraglutide may also increase β - cell mass and function . Hypoglycemia is rare with liraglutide and tends to occur when used in combination with sulfonylureas ; liraglutide in combination with insulin is not yet FDA approved . The pharmacokinetic parameters of liraglutide are unaffected by age , sex , race , or ethnicity , and no special recommendations for altered dosing of liraglutide need apply to populations with hepatic or renal impairment . Results from clinical trials have not shown an increased risk of medullary thyroid cancer , pancreatitis , or poor cardiovascular outcomes with liraglutide treatment . Ongoing , long - term monitoring studies continue to evaluate the safety of liraglutide treatment in these outcomes .", "The endocrine pancreas in non - diabetic rats after short - term and long - term treatment with the long - acting P0C6A0 derivative DB06655 . Glucagon - like peptide 1 ( P0C6A0 ) and P43220 agonists increase the beta - cell mass in rodent models of type 2 diabetes and enhance the proliferation rate of beta cells in vitro , while the long - term effect in vivo in non - diabetic animals is unknown . We studied the endocrine pancreas in non - diabetic Sprague - Dawley rats after short - and long - term treatment with DB06655 , an acetylated long - acting derivative of P0C6A0 . Four groups of rats ( n = 6 for each group ) received two daily injections with either DB06655 or vehicle for 1 or 6 weeks . DB06655 - treated rats displayed a 10 % lower body weight after both 1 week ( p < 0 . 001 ) and 6 weeks ( p < 0 . 005 ) of treatment . The mean beta - cell mass in DB06655 - treated rats was increased by 19 % after 1 week of treatment ( p < 0 . 05 ) , but normalized after 6 weeks of treatment . No difference in alpha - cell mass , volume - weighted mean islet volume , or pancreas mass was found after 1 or 6 weeks of treatment . We conclude that DB06655 treatment of non - diabetic rats induces a sustained lower body weight , and an only temporary increase in the beta - cell mass , while the alpha - cell mass and the volume - weighted mean islet volume are unaffected by the treatment .", "___MASK60___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .", "Glucagon - like peptide - 1 stimulates luteinizing hormone - releasing hormone secretion in a rodent hypothalamic neuronal cell line . To examine the influence of the putative satiety factor ( P0C6A0 ) on the hypothalamo - pituitary - gonadal axis , we used GT1 - 7 cells as a model of neuronal luteinizing hormone - releasing hormone ( P01148 ) release . P0C6A0 caused a concentration - dependent increase in P01148 release from GT1 - 7 cells . Specific , saturable P0C6A0 binding sites were demonstrated on these cells . The binding of [ 125I ] P0C6A0 was time - dependent and consistent with a single binding site ( Kd = 0 . 07 +/- 0 . 016 nM ; binding capacity = 160 +/- 11 fmol / mg protein ) . The specific P43220 agonists , exendin - 3 and exendin - 4 , also showed high affinity ( Ki = 0 . 3 +/- 0 . 05 and 0 . 32 +/- 0 . 06 nM , respectively ) as did the antagonist exendin -( 9 - 39 ) ( Ki = 0 . 98 +/- 0 . 24 nM ) . At concentrations that increased P01148 release , P0C6A0 ( 0 . 5 - 10 nM ) also caused an increase in intracellular DB02527 in GT1 - 7 cells ( 10 nM P0C6A0 : 7 . 66 +/- 0 . 4 vs . control : 0 . 23 +/- 0 . 02 nmol / mg protein ; P < 0 . 001 ) . Intracerebroventricular injection of P0C6A0 at a single concentration ( 10 microg ) produced a prompt increase in the plasma luteinizing hormone concentration in male rats ( P0C6A0 : 1 . 09 +/- 0 . 11 vs . saline : 0 . 69 +/- 0 . 06 ng / ml ; P < 0 . 005 ) . P0C6A0 levels in the hypothalami of 48 - h - fasted male rats showed a decrease , indicating a possible association of the satiety factor with the low luteinizing hormone levels in animals with a negative energy balance .", "A P43220 agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE -/- mouse model . The glucagon like peptide - 1 receptor ( P43220 ) agonist liraglutide attenuates induction of plasminogen activator inhibitor type - 1 ( P05121 ) and vascular adhesion molecule ( VAM ) expression in human vascular endothelial cells ( hVECs ) in vitro and may afford protection against endothelial cell dysfunction ( O95905 ) , an early abnormality in diabetic vascular disease . Our study aimed to establish the dependence of the in vitro effects of liraglutide on the P43220 and characterise its in vivo effects in a mouse model of O95905 . In vitro studies utilised the human vascular endothelial cell line P10144 - Q8IWL8 and enzyme - linked immunosorbent assays ( ELISA ) for determination of P05121 and VAM expression . In vivo studies of vascular reactivity and immunohistochemical analysis were performed in the ApoE (-/-) mouse model . In vitro studies demonstrated P43220 - dependent liraglutide - mediated inhibition of stimulated P05121 and VAM expression . In vivo studies demonstrated significant improvement in endothelial function in liraglutide treated mice , a P43220 dependent effect . DB06655 treatment also increased endothelial nitric oxide synthase ( P29474 ) and reduced intercellular adhesion molecule - 1 ( P05362 ) expression in aortic endothelium , an effect again dependent on the P43220 . Together these studies identify in vivo protection , by the P43220 agonist liraglutide , against O95905 and provide a potential molecular mechanism responsible for these effects .", "P43220 agonist - induced polyarthritis : a case report . Occasional cases of bilateral , symmetrical , seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase - 4 inhibitors ( Crickx et al . in Rheumatol Int , 2013 ) . We report here a similar case observed during treatment with a P43220 agonist . A 42 - year - old man with type 2 diabetes treated with metformin 1 , 500 mg / day and liraglutide 1 . 8 mg / day . After 6 months from the beginning of treatment , the patient complained of bilateral arthralgia ( hands , feet , ankles , knees , and hips ) . Erythrocyte sedimentation rate ( P03372 ) , P02741 ( CRP ) , and leukocytes were increased . Rheumatoid factor , anticyclic citrullinated protein antibody , antinuclear antibodies , anti - Borrelia , and burgdorferi antibodies were all negative , and myoglobin and calcitonin were normal . DB06655 was withdrawn , and the symptoms completely disappeared within 1 week , with normalization of P03372 , CRP , fibrinogen , and leukocytes . Previously described cases of polyarthritis associated with P27487 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme . The present case , occurred during treatment with a P43220 agonists , suggests a possibly different mechanism , mediated by P43220 stimulation , which deserved further investigation .", "P43220 activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure . Glucagon - like peptide - 1 receptor ( P43220 ) agonists exert antihypertensive actions through incompletely understood mechanisms . Here we demonstrate that cardiac Glp1r expression is localized to cardiac atria and that P43220 activation promotes the secretion of atrial natriuretic peptide ( P01160 ) and a reduction of blood pressure . Consistent with an indirect P01160 - dependent mechanism for the antihypertensive effects of P43220 activation , the P43220 agonist liraglutide did not directly increase the amount of cyclic GMP ( cGMP ) or relax preconstricted aortic rings ; however , conditioned medium from liraglutide - treated hearts relaxed aortic rings in an endothelium - independent , P43220 - dependent manner . DB06655 did not induce P01160 secretion , vasorelaxation or lower blood pressure in Glp1r (-/-) or Nppa (-/-) mice . Cardiomyocyte P43220 activation promoted the translocation of the Rap guanine nucleotide exchange factor Epac2 ( also known as Rapgef4 ) to the membrane , whereas Epac2 deficiency eliminated P43220 - dependent stimulation of P01160 secretion . Plasma P01160 concentrations were increased after refeeding in wild - type but not Glp1r (-/-) mice , and liraglutide increased urine sodium excretion in wild - type but not Nppa (-/-) mice . These findings define a gut - heart P43220 - dependent and P01160 - dependent axis that regulates blood pressure .", "Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high - fat - diet - fed mice . Twenty - four hours before perfusion , animals were injected with 5 '- bromo - 2 '- deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin - positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100 - 150 % ( P < 0 . 001 ) . We also found an increase in young neurons in the DG of high - fat - diet - fed mice after drug treatment ( P < 0 . 001 ) . The P43220 antagonist exendin ( 9 - 36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood - brain barrier and increase neuroneogenesis .", "P43220 agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice . OBJECTIVE : Glucagon - like peptide - 1 receptor ( P43220 ) agonists are used to treat type 2 diabetes , and transient P0C6A0 administration improved cardiac function in humans after acute myocardial infarction ( MI ) and percutaneous revascularization . However , the consequences of P43220 activation before ischemic myocardial injury remain unclear . RESEARCH DESIGN AND METHODS : We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pretreated with the P43220 agonist liraglutide . RESULTS : Male C57BL / 6 mice were treated twice daily for 7 days with liraglutide or saline followed by induction of MI . Survival was significantly higher in liraglutide - treated mice . DB06655 reduced cardiac rupture ( 12 of 60 versus 46 of 60 ; P = 0 . 0001 ) and infarct size ( 21 +/- 2 % versus 29 +/- 3 % , P = 0 . 02 ) and improved cardiac output ( 12 . 4 +/- 0 . 6 versus 9 . 7 +/- 0 . 6 ml / min ; P = 0 . 002 ) . DB06655 also modulated the expression and activity of cardioprotective genes in the mouse heart , including Akt , GSK3beta , PPARbeta - delta , Nrf - 2 , and P09601 . The effects of liraglutide on survival were independent of weight loss . Moreover , liraglutide conferred cardioprotection and survival advantages over metformin , despite equivalent glycemic control , in diabetic mice with experimental MI . The cardioprotective effects of liraglutide remained detectable 4 days after cessation of therapy and may be partly direct , because liraglutide increased cyclic AMP formation and reduced the extent of caspase - 3 activation in cardiomyocytes in a P43220 - dependent manner in vitro . CONCLUSIONS : These findings demonstrate that P43220 activation engages prosurvival pathways in the normal and diabetic mouse heart , leading to improved outcomes and enhanced survival after MI in vivo .", "DB06655 : can it make a difference in the treatment of type 2 diabetes ? Despite advances in the management of type 2 diabetes , glycaemic control remains suboptimal for many patients because of the complexities of disease progression and the need to balance improved glycaemic control against adverse treatment effects , particularly weight gain and hypoglycaemia . Thus , the development of new antidiabetes therapies continues in earnest . Incretin hormones have been the recent focus of research , as they account for up to 70 % of the insulin response following a meal . There is also a high concordance between the physiological actions of one hormone , glucagon - like peptide - 1 ( P0C6A0 ) , and the therapeutic needs of patients . As native human P0C6A0 has a half life of only approximately 2 min , researchers have developed molecules that act as P43220 agonists or inhibit the enzyme responsible for P0C6A0 degradation ( dipeptidyl peptidase - 4 ) . DB06655 , a human P0C6A0 analogue sharing 97 % of its amino acid sequence identity with native P0C6A0 , has been approved for use as monotherapy ( not in Europe ) and in combination with selected oral agents . In this supplement , we summarise key liraglutide data , offer practical insight into what we might expect of liraglutide in clinical use and examine selected case studies . For reasons of the safety and efficacy of P43220 agonists , many thought leaders believe that these will become background therapy for majority of patients in the coming years . This supplement will serve as a resource from which readers can extract information concerning the potential benefits for patients who are overweight , losing pancreatic beta - cell function and drifting towards the ravaging effects of chronic hyperglycaemia .", "PEGylated exendin - 4 , a modified P0C6A0 analog exhibits more potent cardioprotection than its unmodified parent molecule on a dose to dose basis in a murine model of myocardial infarction . A Site - specifically PEGylated exendin - 4 ( denoted as PEG - Ex4 ) is an exendin - 4 ( denoted as Ex4 ) analog we developed by site - specific PEGylation of exendin - 4 with a high molecular weight trimeric poly ( ethylene glycol ) ( tPEG ) . It has been shown to possess prolonged half - life in vivo with similar receptor binding affinity compared to unmodified exendin - 4 by our previous work . This study is sought to test whether PEG - Ex4 is suitable for treating myocardial infarction ( MI ) . In the MI model , PEG - Ex4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily . Animal survival rate , heart function , remodeling and neoangiogenesis were evaluated and compared . Tube formation was examined in endothelial cells . In addition , Western blotting and histology were performed to determine the markers of cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved . PEG - Ex4 and Ex4 showed comparable binding affinity to P43220 . In MI mice , PEG - Ex4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily , while Ex4 given at 3 days interval failed to produce protection . PEG - Ex4 elevated endothelial tube formation in vitro and capillary density in the border area of MI . PEG - Ex4 increased Akt activity and P15692 production in a P43220 dependent manner in endothelial cells and antagonism of P43220 , Akt or P15692 abolished the protection of PEG - Ex4 in the MI model . PEG - Ex4 is a potent long - acting P43220 agonist for the treatment of chronic heart disease . Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and P15692 .", "Adverse drug reactions associated with the use of liraglutide in patients with type 2 diabetes -- focus on pancreatitis and pancreas cancer . INTRODUCTION : The glucagon - like peptide - 1 ( P0C6A0 ) receptor agonist , liraglutide , is a widely used drug for the treatment of type 2 diabetes . DB06655 is one of several incretin - based agents that have been suggested to be associated with pancreatitis and pancreas cancer . The suspicion accelerated after publication of an autopsy study claiming increased incidences of several pathological changes in pancreata from patients with diabetes treated with incretin - based drugs . AREAS COVERED : The aim of the present review is to give an overview of the pharmacology of liraglutide and provide a review of adverse reactions associated with liraglutide with a focus on the risk of pancreatitis and pancreas cancer . EXPERT OPINION : When comprehensively reviewing the available literature , no clear and significant associations between liraglutide and pancreatitis and / or pancreas cancer seem evident . However , a recently published analysis suggests a trend toward a slightly elevated risk of pancreatitis with P43220 agonists ( including liraglutide ) , which may become statistical significant as more data become available . Well - established side effects are of gastrointestinal origin , typical mild - to - moderate and of transient character . The risk of hypoglycemia associated with liraglutide treatment is low .", "DB06655 and DPP - 4 inhibitors - side effects comparative clinical study . The objective of this study was to monitor the side effects of the P43220 agonist liraglutide in comparison to those of DPP - 4 inhibitors ( sitagliptin and vildagliptin ) , in order to determine their safety , tolerability and therapeutic efficiency . The study was carried out in the \" Heart and Diabetes Center NRW \" and included overweight patients with type 2 diabetes whose therapeutic regimen was switched to liraglutide or DPP - 4 inhibitors . A validated questionnaire method was used to monitor the side effects during the hospitalization period , then again at 3 , and 6 months after the beginning of the therapy . The therapy with liraglutide was associated with more side effects than the one with DPP - 4 inhibitors . In general , side effects were declining with time , thus only few patients stopped therapy . The incretin therapy turned out to be a safe and effective therapeutic option for patients with type 2 diabetes mellitus .", "P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK63___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .", "Exendin - 4 , a P43220 agonist , stimulates pituitary - adrenocortical axis in the rat : Investigations into the mechanism ( s ) underlying Ex4 effect . Exendin - 4 ( Ex4 ) is a potent and long - lasting agonist of glucagon - like peptide - 1 ( P0C6A0 ) , which has been previously found to stimulate pituitary - adrenal axis in the rat . Aim of the present study was to gain insight into the mechanism ( s ) involved in the Ex4 - induced rise in the rat plasma concentrations of ___MASK59___ , aldosterone and corticosterone . Preliminary time - and dose - response studies showed that the maximum stimulating effect of Ex4 occurred within 1 or 2 h and at dose ranging from 0 . 5 to 2 . 0 nmol / 100 g body weight . The P43220 ( P43220 ) antagonist Ex ( 9 - 39 ) did not significantly affect ___MASK59___ , aldosterone and cortico - sterone responses to Ex4 . Neither the administration of P06850 and arginine vasopressin ( AVP ) - receptor antagonists nor adrenal demedullation prevented pituitary - adrenal axis responses to Ex4 . The prolonged ( 4 or 6 days ) suppression of the pituitary ___MASK59___ release by dexamethasone impaired corticosterone , but not aldosterone response to Ex4 . The following conclusions are drawn : i ) Ex4 stimulates rat pituitary - adrenal axis through receptors other than the classic P43220 ; ii ) neither P06850 and AVP nor medullary catecholamines are involved in the Ex4 - induced stimulation of ___MASK59___ release ; iii ) ___MASK59___ stimulation accounts for the rise in corticosterone plasma concentration ; and iv ) the aldosterone secretagogue effect of Ex4 occurs via a mechanism independent of the stimulation of either ___MASK59___ or medullary catecholamines .", "Molecular mechanisms of gastrin - dependent gene regulation . The peptide hormone gastrin is the key regulator of gastric acid secretion . P01350 exerts its effects as acid secretagogue through functional activation of gastric enterochromaffin - like ( ECL ) cells , which control acid secretion through biosynthesis and release of histamine . In ECL cells , concerted activation of histidine decarboxylase ( HDC ) , vesicular monoamine transporter 2 ( Q05940 ) , and chromogranin A ( P10645 ) genes by gastrin is a prerequisite for proper acid control . To elucidate the molecular pathways underlying gastrin - dependent control of ECL cell genes , we recently analyzed the signaling cascades , regulatory promoter elements , and transcription factors mediating the transcriptional effects of gastrin . Our studies identified the Raf > Q02750 > P29323 1 /- 2 kinase module as the common signaling pathway mediating gastrin - dependent ECL cell gene transcription . In contrast to this uniform signaling cascade , pronounced heterogeneity was detected between cis - and trans - activating regulatory factors conferring gastrin responsiveness . The molecular diversity of transcription factors and regulatory enhancer elements transmitting gastrin - triggered gene transcription offers the molecular basis for synergistic , but differential , regulation of HDC , Q05940 , and P10645 genes during a secretory challenge of ECL cells by gastrin and possibly other acid secretagogues .", "Dopamine modulating drugs influence striatal (+)-[ 11C ] DTBZ binding in rats : Q05940 binding is sensitive to changes in vesicular dopamine concentration . Binding of (+)-[ 11C ] DTBZ ( dihydrotetrabenazine ) to the striatal vesicular monoamine transporter ( Q05940 ) is widely considered to be a stable marker of dopamine neurone integrity . However , we now find that specific binding of a tracer dose of (+)-[ 11C ] DTBZ is modestly increased in rat striatum following dopamine depletion with alpha - methyl - p - tyrosine ( alpha - MPT , + 14 % ) or ___MASK22___ ( d - P49418 , 20 mg / kg , + 12 % ) and decreased following dopamine elevation with gamma - hydroxybutyrate ( DB01440 , - 16 % ) or levodopa ( - 20 % ) . We suggest that in vivo (+)-[ 11C ] DTBZ binding in imaging studies is subject to competition by vesicular dopamine and , in this respect , is not a \" stable \" dopamine biomarker as is generally assumed .", "DB06655 : effects beyond glycaemic control in diabetes treatment . AIMS : To review the non - glycaemic effects of liraglutide , including potential improvements in body weight , systolic blood pressure ( SBP ) and pancreatic beta - cell function . KEY FINDINGS : DB06655 induced weight loss of around 2 - 3 kg compared with weight increases of 1 - 2 kg with active comparators such as insulin glargine , rosiglitazone and glimepiride . Exenatide demonstrated similar weight benefits to liraglutide , but the dipeptidyl peptidase - 4 ( DPP - 4 ) inhibitors , sitagliptin , saxagliptin and vildagliptin , were weight neutral . DB06655 was associated with decreases in SBP of 2 - 7 mmHg , whereas exenatide , vildagliptin and sitagliptin demonstrated SBP reductions of around 2 - 3 mmHg . Measures of pancreatic beta - cell function were improved with liraglutide vs . placebo , rosiglitazone and exenatide . However , DPP - 4 inhibitors appear to have less effect on beta - cell function than glucagon - like peptide - 1 ( P0C6A0 ) receptor agonists . CONCLUSIONS : In addition to glycaemic control , liraglutide and the other incretin - based therapies offer additional non - glycaemic benefits to varying degrees . The ability of P43220 agonists to provide modest , but clinically relevant improvements in body weight and SBP , and to potentially benefit beta - cell function make them an exciting therapeutic option for individuals with diabetes . In contrast , DPP - 4 inhibitors are weight neutral and may have lesser benefits on beta - cell function .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "P43220 agonists and the thyroid : C - cell effects in mice are mediated via the P43220 and not associated with P07949 activation . DB06655 and exenatide are glucagon - like peptide receptor ( P43220 ) agonists used in the treatment of type 2 diabetes . Both molecules have been associated with the development of thyroid C - cell tumors after lifetime exposure in rodents . Previously , it has been reported that these tumors are preceded by increased plasma calcitonin and C - cell hyperplasia . We can now document that the murine C - cell effects are mediated via P43220 . Thus , 13 wk of continuous exposure to P43220 agonists was associated with marked increases in plasma calcitonin and in the incidence of C - cell hyperplasia in wild - type mice . In contrast , similar effects were not seen in P43220 knockout mice . Human C - cell cancer is often caused by activating mutations in the rearranged - during - transfection ( P07949 ) protooncogene . We developed an immunohistochemical method to assess P07949 activation in tissues . DB06655 dosing to mice was not found to activate P07949 . Further evaluation of the signaling pathways demonstrated that liraglutide increased ribosomal S6 , but not MAPK kinase , phosphorylation . These observations are consistent with effects of P43220 agonists on rodent C cells being mediated via mammalian target of rapamycin activation in a P07949 - and MAPK - independent manner .", "The effects of glucagon - like peptide - 1 on the beta cell . Type 2 diabetes is a progressive disease characterized by insulin resistance and impaired beta - cell function . Treatments that prevent further beta - cell decline are therefore essential for the management of type 2 diabetes . Glucagon - like peptide - 1 ( P0C6A0 ) is an incretin hormone that is known to stimulate glucose - dependent insulin secretion . Furthermore , P0C6A0 appears to have multiple positive effects on beta cells . However , P0C6A0 is rapidly degraded by dipeptidyl peptidase - 4 ( DPP - 4 ) , which limits the clinical relevance of P0C6A0 for the treatment of type 2 diabetes . Two main classes of P0C6A0 - based therapies have now been developed : DPP - 4 inhibitors and P43220 agonists . DB06655 and exenatide are examples of P43220 agonists that have been developed to mimic the insulinotropic characteristics of endogenous P0C6A0 . Both have demonstrated improved beta - cell function in patients with type 2 diabetes , as assessed by homoeostasis model assessment - B analysis and proinsulin : insulin ratio . Additionally , liraglutide and exenatide are able to enhance first - and second - phase insulin secretion and are able to restore beta - cell sensitivity to glucose . Preclinical studies have shown that both liraglutide and exenatide treatment can increase beta - cell mass , stimulate beta - cell proliferation , increase beta - cell neogenesis and inhibit beta - cell apoptosis . Clinical studies are needed to confirm these findings in humans . Replication of these data in humans could have important clinical implications for the treatment of type 2 diabetes .", "___MASK31___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK31___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .", "A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK3___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .", "First fixed - ratio combination of insulin degludec and liraglutide for the treatment of type 2 diabetes . When oral hypoglycemic agents do not successfully suppress hyperglycemia , the traditional approach has been to add insulin injections . With the coming of glucagon - like peptide 1 ( P0C6A0 ) receptor agonists carrying the benefits of weight loss and reduced risk of hypoglycemia , it has been suggested that P0C6A0 agents should be used instead . There is equivalent lowering of HbA1c with either treatment . P01308 therapy is associated with hypoglycemia and weight gain while P43220 agonists promote weight loss . Gastrointestinal ( GI ) intolerance is the chief obstacle to P0C6A0 treatment . The combined use of basal insulin and P43220 agonists results in improved glycemic control and mitigates weight gain . The recent approval of insulin degludec / liraglutide administered in a fixed ratio combination is unique not simply for the additive benefits of the two agents , but because it now permits adjustable dosing of liraglutide together with insulin , providing better glucose control than with either agent alone at lower dose levels . Lower dosage of insulin degludec reduces the risk of hypoglycemia . DB06655 combats the weight gain that accompanies the introduction of insulin therapy , and a reduced dose of liraglutide induces less GI intolerance . This first combined basal insulin - P43220 agonist combination represents a conceptual advance in the treatment of insulin - requiring type 2 diabetes .", "Population pharmacokinetic study of memantine : effects of clinical and genetic factors . BACKGROUND AND OBJECTIVE : Memantine , a frequently prescribed anti - dementia drug , is mainly eliminated unchanged by the kidneys , partly via tubular secretion . Considerable inter - individual variability in plasma concentrations has been reported . We aimed to investigate clinical and genetic factors influencing memantine disposition . METHODS : A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting . Patients were genotyped for common polymorphisms in renal cation transporters ( O15245 / 2 / 5 , Q96FL8 , P08183 ) and nuclear receptors ( O75469 , Q14994 , RXR , Q07869 ) involved in transporter expression . RESULTS : The average clearance was 5 . 2 L / h with a 27 % inter - individual variability ( percentage coefficient of variation ) . Glomerular filtration rate ( p = 0 . 007 ) and sex ( p = 0 . 001 ) markedly influenced memantine clearance . O75469 rs1523130 was identified as the unique significant genetic covariate for memantine clearance ( p = 0 . 006 ) , with carriers of the O75469 rs1523130 CT / TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype . CONCLUSION : The better understanding of inter - individual variability of memantine disposition might be beneficial in the context of individual dose optimization .", "Molecular physiology of glucagon - like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon - like peptide - 1 ( P0C6A0 ) , a blood glucose - lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase - IV ( DPP - IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post - prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage - dependent K ⁺ channels , O94759 cation channels , intracellular Ca ⁺ release channels , and Ca ⁺- dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .", "Serum concentrations of growth factors in women with and without endometriosis : the action of anti - endometriosis medicines . Endometriosis is a common gynecologic syndrome of unknown etiology and pathogenesis . Growth factors and inflammatory mediators produced by peritoneal leukocytes have recently been postulated to participate in the pathogenesis of endometriosis . Angiogenic factors released from peritoneal macrophages may also play a role in the development of this disease . In the present study , we investigate the soluble levels of vascular endothelial growth factor ( P15692 ) , epidermal growth factor - receptor ( P01133 - R ) , granulocyte / macrophage - colony stimulating factor ( GM - P04141 ) , P01308 - like growth factor - 1 ( DB01277 ) and interferon - gamma ( P01579 ) in the serum of 28 women with and 20 without endometriosis . We also compared these levels before , during and after treatment with danazol and leuprorelin acetate depot , the two therapeutic regiments of choice concerning this disease . We found that only sVEGF levels were higher in women with endometriosis in comparison to controls ( P < 0 . 001 ) while sEGF - R is not present . GM - P04141 , DB01277 and P01579 soluble levels are not affected in either healthy or endometriotic subjects . The 6 - month treatment with danazol decreased sVEGF levels ( P < 0 . 02 ) and increased sEGF - R levels ( P < 0 . 001 ) . These observations support the view that P15692 may be associated with the disease process and that danazol may bring sVEGF levels to a normal threshold . However , future studies will be focused on the anti - angiogenic control of the action of P15692 in patients with endometriosis .", "The arcuate nucleus mediates P43220 agonist liraglutide - dependent weight loss . DB06655 is a glucagon - like peptide - 1 ( P0C6A0 ) analog marketed for the treatment of type 2 diabetes . Besides lowering blood glucose , liraglutide also reduces body weight . It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain . Here , we determined that liraglutide does not activate P0C6A0 - producing neurons in the hindbrain , and liraglutide - dependent body weight reduction in rats was independent of P0C6A0 receptors ( GLP - 1Rs ) in the vagus nerve , area postrema , and paraventricular nucleus . Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs . Moreover , labeled liraglutide bound neurons within the arcuate nucleus ( ARC ) and other discrete sites in the hypothalamus . P43220 was necessary for liraglutide uptake in the brain , as liraglutide binding was not seen in Glp1r (-/-) mice . In the ARC , liraglutide was internalized in neurons expressing proopiomelanocortin ( P01189 ) and cocaine - and amphetamine - regulated transcript ( Q16568 ) . Electrophysiological measurements of murine brain slices revealed that P0C6A0 directly stimulates P01189 / Q16568 neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y ( P01303 ) and agouti - related peptide ( AgRP ) via GABA - dependent signaling . Collectively , our findings indicate that the P43220 on P01189 / Q16568 - expressing ARC neurons likely mediates liraglutide - induced weight loss .", "Effect of the combination of metformin and fenofibrate on glucose homeostasis in diabetic Goto - Kakizaki rats . Metformin has been reported to increase the expression of the glucagon - like peptide - 1 ( P0C6A0 ) receptor in pancreatic beta cells in a peroxisome proliferator - activated receptor ( Q07869 ) - α - dependent manner . We investigated whether a PPARα agonist , fenofibrate , exhibits an additive or synergistic effect on glucose metabolism , independent of its lipid - lowering effect , when added to metformin . Non - obese diabetic Goto - Kakizaki ( GK ) rats were divided into four groups and treated for 28 days with metformin , fenofibrate , metformin plus fenofibrate or vehicle . The random blood glucose levels , body weights , food intake and serum lipid profiles were not significantly different among the groups . After 4 weeks , metformin , but not fenofibrate , markedly reduced the blood glucose levels during oral glucose tolerance tests , and this effect was attenuated by adding fenofibrate . Metformin increased the expression of the P43220 in pancreatic islets , whereas fenofibrate did not . During the intraperitoneal glucose tolerance tests with the injection of a P0C6A0 analog , metformin and / or fenofibrate did not alter the insulin secretory responses . In conclusion , fenofibrate did not confer any beneficial effect on glucose homeostasis but reduced metformin ' s glucose - lowering activity in GK rats , thus discouraging the addition of fenofibrate to metformin to improve glycemic control .", "Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .", "Protective effects of dipeptidyl peptidase - 4 ( DPP - 4 ) inhibitor against increased β cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes . Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis , leading to the exacerbation of type 2 diabetes . Oleic acid and linoleic acid are two major dietary fatty acids , but their effects in diabetes are unclear . We challenged β cell - specific glucokinase haploinsufficient ( Gck (+/-) ) mice with a diet containing sucrose and oleic acid ( SO ) or sucrose and linoleic acid ( SL ) and analyzed β cell apoptosis . In Gck (+/-) but not wild - type mice , SL significantly decreased the β cell mass and β cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO . The mRNA expression of SREBP - 1c was significantly higher , and that of P12830 was significantly lower in the islets of Gck (+/-) mice fed SL compared with mice fed SO . We next evaluated monotherapy with desfluorositagliptin , a dipeptidyl peptidase - 4 ( DPP - 4 ) inhibitor , in these mouse groups . DPP - 4 inhibitor protected against β cell apoptosis , restored the β cell mass , and normalized islet morphology in Gck (+/-) mice fed SL . DPP - 4 inhibition normalized the changes in the islet expression of SREBP - 1c and P12830 mRNA induced by the SL diet . Furthermore , linoleic acid induced β cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells , whereas a P43220 agonist prevented apoptosis . In conclusion , SL exacerbated β cell apoptosis in diabetic Gck (+/-) mice but not in euglycemic wild - type mice , and DPP - 4 inhibition protected against these effects .", "On - target effects of P43220 agonists on thyroid C - cells in rats and mice . Glucagon - like peptide - 1 is an incretin hormone from the gastrointestinal tract , which enhances insulin secretion , slows gastric emptying , and reduces food intake . P43220 agonists are being developed for Type 2 diabetes mellitus . P0C6A0 is rapidly degraded by serum dipeptidyl peptidase IV , so analogues with a prolonged serum half - life are used clinically . Exenatide was the first P0C6A0 agonist approved and is a synthetic version of exendin - 4 derived from the Gila monster . DB06655 was approved for clinical use in 2010 . P43220 agonists have been shown to increase calcitonin secretion and stimulate C - cell hyperplasia and neoplasia in rats and mice of both sexes . Rat C - cells are more sensitive to the effects of P0C6A0 agonists than mice . The effects of P0C6A0 agonists on C - cell proliferation or neoplasia have not been documented in nonhuman primates or humans . The proliferative C - cell effects may be rodent - specific . P0C6A0 receptors have been demonstrated on normal rodent C - cells , but are either not present or occur in low numbers on C - cells of nonhuman primates and humans . Hyperplasia and neoplasia of C - cells in rodents treated with P0C6A0 agonists represent a unique example of an on - target species - specific effect that may not have relevance to humans .", "Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK94___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .", "Glucagon - like peptide - 1 analogue therapy for psoriasis patients with obesity and type 2 diabetes : a prospective cohort study . BACKGROUND : Diabetes and obesity are more prevalent amongst psoriasis patients as is disturbance of the innate immune system . P0C6A0 analogue therapy considerably improves weight and glycaemic control in people with type 2 diabetes and its receptor is present on innate immune cells . OBJECTIVE : We aimed to determine the effect of liraglutide , a P0C6A0 analogue , on psoriasis severity . METHODS : Before and after 10 weeks of liraglutide therapy ( 1 . 2 mg subcutaneously daily ) we determined the psoriasis area and severity index ( PASI ) and the dermatology life quality index ( DLQI ) in seven people with both psoriasis and diabetes ( median age 48 years , median body mass index 48 . 2 kg / m ( 2 ) ) . We also evaluated the immunomodulatory properties of liraglutide by measuring circulating lymphocyte subset numbers and monocyte cytokine production . RESULTS : DB06655 therapy decreased the median PASI from 4 . 8 to 3 . 0 ( P = 0 . 03 ) and the median DLQI from 6 . 0 to 2 . 0 ( P = 0 . 03 ) . Weight and glycaemic control improved significantly . Circulating invariant natural killer T ( iNKT ) cells increased from 0 . 13 % of T lymphocytes to 0 . 40 % ( P = 0 . 03 ) . DB06655 therapy also effected a non - significant 54 % decrease in the proportion of circulating monocytes that produced tumour necrosis factor alpha ( P = 0 . 07 ) . CONCLUSION : P0C6A0 analogue therapy improves psoriasis severity , increases circulating iNKT cell number and modulates monocyte cytokine secretion . These effects may result from improvements in weight and glycaemic control as well as from direct immune effects of P43220 activation . Prospective controlled trials of P0C6A0 therapies are warranted , across all weight groups , in psoriasis patients with and without type 2 diabetes .", "P01308 - like growth factor binding proteins in the bovine anterior pituitary . P01308 - like growth factor binding proteins ( IGFBPs ) were characterized in bovine anterior pituitary tissue , pituitary conditioned media , and serum collected during the preovulatory and early luteal phases of the estrous cycle . Effects of in vitro treatments of pituitaries with luteinizing hormone - releasing hormone ( P01148 ) , estradiol , and progesterone on IGFBP secretion were also evaluated . Predominant IGFBPs detected in anterior pituitary tissue by immunoprecipitation , ligand blotting , and Northern blotting were P24593 ( 29 kDa ) , P18065 ( 32 kDa ) , and P17936 ( 36 and 39 kDa doublet ) . Conditioned culture media contained P24593 , a slightly larger form of P18065 ( 33 kDa ) , the 36 - and 39 - kDa forms of P17936 , and a more extensively glycosylated form of P17936 ( 44 kDa ) . In serum , P24593 was not readily detected , and P17936 ( 40 - and 44 - kDa doublet ) and P18065 ( 34 kDa ) were larger than in pituitary tissue . Levels of P18065 , - 3 , and - 5 in pituitary tissue decreased during the preovulatory period and were lowest in the early luteal phase . Treatment with P01148 increased P18065 levels in media twofold . Estradiol or progesterone did not alter IGFBP secretion in vitro . Predominant IGFBPs produced and released by anterior pituitary tissue were P18065 , - 3 and - 5 . The activity of IGFBPs fluctuates in the pituitary in association with changes in stage of estrous cycle , implicating IGFBPs as potential regulators of gonadotrope function .", "Exendin - 4 decreases amphetamine - induced locomotor activity . Glucagon - like peptide - 1 ( P0C6A0 ) is released in response to nutrient ingestion and is a regulator of energy metabolism and consummatory behaviors through both peripheral and central mechanisms . The P43220 ( P43220 ) is widely distributed in the central nervous system , however little is known about how GLP - 1Rs regulate ambulatory behavior . The abused psychostimulant amphetamine ( P49418 ) promotes behavioral locomotor activity primarily by inducing the release of the neurotransmitter dopamine . Here , we identify the P43220 agonist exendin - 4 ( Ex - 4 ) as a modulator of behavioral activation by P49418 . We report that in rats a single acute administration of Ex - 4 decreases both basal locomotor activity as well as P49418 - induced locomotor activity . Ex - 4 did not induce behavioral responses reflecting anxiety or aversion . Our findings implicate P43220 signaling as a novel modulator of psychostimulant - induced behavior and therefore a potential therapeutic target for psychostimulant abuse .", "Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK82___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK82___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .", "Effect of liraglutide on proliferation and differentiation of human adipose stem cells . Glucagon - Like Peptide - 1 ( P0C6A0 ) receptor agonists , used as glucose - lowering drugs , also induce weight loss by inhibiting food intake . The present study was aimed at the assessment of the in vitro effects of the P43220 agonist liraglutide on proliferation and differentiation of human adipose stem cells ( ASC ) obtained from subcutaneous adipose tissue of morbidly obese subjects undergoing bariatric surgery . DB06655 ( 10 - 100 nM ) significantly inhibited ASC proliferation and viability , with a maximum effect at 6 days of culture ( 45 % and 50 % , for liraglutide 10 and 100 nM , respectively ) ; the effect was reverted by exendin 9 - 39 . DB09341 uptake was significantly reduced by liraglutide in a dose dependent manner . Treatment with liraglutide reduced intracellular lipid accumulation in differentiating ASC , together with FABP - 4 mRNA expression ( - 18 % , - 23 % , - 46 % , for 1 nM , 10 nM and 100 nM , respectively ) , whereas it stimulated adiponectin ( P15144 ) expression ( 1 . 86 - , 2 . 64 - , 2 . 28 - fold increase , for 1 nM , 10 nM and 100 nM , respectively ) . DB06655 exerts effects on human adipose cell precursors , inhibiting proliferation and differentiation , while stimulating the expression of the insulin - sensitizing adipokine P15144 . These effects could contribute to the actions of P43220 agonists on body weight and insulin sensitivity .", "Vesiculopustular dermatosis : an uncommon side - effect of liraglutide ? DB06655 is a P43220 agonist , a novel medication for type 2 diabetes . We describe a case of pustules in a patient recently started on liraglutide . Common side effects of liraglutide are gastrointestinal disorders . Skin and tissue reactions are less well - known side effects . DB06655 could be the cause of skin eruptions in this patient , possibly by immunogenicity .", "Neuronal P43220 mediates liraglutide ' s anorectic but not glucose - lowering effect . DB09341 control and weight loss are cornerstones of type 2 diabetes treatment . Currently , only glucagon - like peptide - 1 ( GLP1 ) analogs are able to achieve both weight loss and glucose tolerance . Both glucose and body weight are regulated by the brain , which contains GLP1 receptors ( P43220 ) . Even though the brain is poised to mediate the effects of GLP1 analogs , it remains unclear whether the glucose - and body weight - lowering effects of long - acting P43220 agonists are via direct action on CNS P43220 or the result of downstream activation of afferent neuronal P43220 . We generated mice with either neuronal or visceral nerve - specific deletion of Glp1r and then administered liraglutide , a long - acting P43220 agonist . We found that neither reduction of P43220 in the CNS nor in the visceral nerves resulted in alterations in body weight or food intake in animals fed normal chow or a high - fat diet . DB06655 treatment provided beneficial glucose - lowering effects in both chow - and high - fat - fed mice lacking P43220 in the CNS or visceral nerves ; however , liraglutide was ineffective at altering food intake , body weight , or causing a conditioned taste aversion in mice lacking neuronal P43220 . These data indicate that neuronal GLP1Rs mediate body weight and anorectic effects of liraglutide , but are not required for glucose - lowering effects .", "Glucagon - like peptide - 1 analogues enhance synaptic plasticity in the brain : a link between diabetes and Alzheimer ' s disease . Type 2 diabetes has been identified as a risk factor for patients with Alzheimer ' s disease . P01308 signalling is often impaired in Alzheimer ' s disease , contributing to the neurodegenerative process . One potential strategy to help prevent this is the normalisation of insulin signalling in the brain . Therefore , the present study was designed to test the effects of novel enzyme - resistant analogues of the insulin - releasing incretin hormone , glucagon - like peptide 1 ( P0C6A0 ) . The effects of DB06655 ( DB06655 ) and other novel P0C6A0 analogues were tested on synaptic plasticity ( LTP ) in area P00915 of the hippocampus . At a dose of 15nmol in 5microl i . c . v . , DB06655 ( P < 0 . 005 ) , DB00128 ( 7 ) P0C6A0 ( P < 0 . 001 ) , N - glyc - P0C6A0 ( P < 0 . 01 ) , and Pro ( 9 ) P0C6A0 ( P < 0 . 001 ) . In contrast , the P43220 antagonist exendin ( 9 - 39 ) amide impaired LTP ( P < 0 . 001 ) . Co - injection of exendin ( 9 - 39 ) and DB06655 showed no effect on LTP . These results clearly demonstrate that DB06655 and other P0C6A0 analogues elicit effects on neurotransmission in the brain . Furthermore , P0C6A0 peptides are not only effective in modulating insulin - release and achieving glycaemic control in type 2 diabetes , but are also effective in modulating synaptic plasticity . These findings are consistent with our previous observations that the novel analogue ( DB00161 ( 8 )) P0C6A0 enhances LTP and reverses the impairments of LTP induced by beta - amyoid fragments . Therefore , the drug effects seen here could potentially ameliorate the impairments in neuronal communication and cognitive processes observed in Alzheimer ' s disease .", "Differential effects of placental restriction on P01344 , Q01718 and steroidogenic enzyme mRNA levels in the foetal sheep adrenal . We have investigated the effects of restriction of placental growth on foetal adrenal growth and adrenal expression of mRNAs for P01308 - like Growth Factor II ( P01344 ) , the IGF binding protein P18065 , Steroidogenic Factor 1 ( Q13285 ) and adrenocorticotrophic hormone ( ___MASK59___ ) receptor ( Q01718 ) and the steroidogenic cytochrome P - 450 enzymes : cholesterol side chain cleavage ( P05108 ) , 17alpha - hydroxylase ( P05093 ) and 21 - hydroxylase ( CYP21A1 ) ; and 3beta - hydroxysteroid dehydrogenase / Delta5Delta4 isomerase ( 3betaHSD ) . Endometrial caruncles were removed from non - pregnant ewes before mating ( placental restriction group ; PR ) . The total adrenal : foetal weight ratio was higher in PR ( n = 6 foetuses ) than in control foetuses ( n = 6 foetuses ) . There was no difference in plasma ___MASK59___ concentrations between the PR and control foetuses between 130 and 140 days gestation . Adrenal P01344 mRNA levels were lower ( P < 0 . 05 ) in the PR group , however , adrenal P18065 mRNA levels were not different between the PR and control groups . Adrenal Q01718 mRNA levels were also lower whilst P05108 mRNA levels were increased ( P < 0 . 005 ) in the PR group . We conclude that foetal adrenal growth and steroidogenesis are stimulated as a consequence of foetal growth restriction and that factors other than ___MASK59___ are important in foetal adrenal activation during chronic , sustained hypoxaemia .", "A comparison of currently available P43220 agonists for the treatment of type 2 diabetes . INTRODUCTION : Glucagon - like peptide - 1 ( P0C6A0 ) receptor agonists are a valuable addition to the type 2 diabetes armamentarium . They increase insulin secretion and reduce glucagon secretion in a glucose - dependent manner , posing a relatively low hypoglycemia risk . P43220 agonists also offer weight - loss benefits . Because P43220 agonists are relatively new agents , there is limited direction on their use . AREAS COVERED : This article aims to provide guidance to physicians when considering P43220 agonist use in individual patients . It examines the clinical profiles of the currently available P43220 agonists : exenatide twice - daily ( P55957 ) , liraglutide once daily and exenatide extended release ( ER ) once weekly . Phase III clinical trial data on efficacy , safety and patient satisfaction are compared , with a primary focus on head - to - head trials . EXPERT OPINION : DB06655 seems to be the most effective P43220 agonist in terms of HbA ( 1c ) reduction and weight loss . Exenatide P55957 may offer an advantage where postprandial glucose control is a primary concern . Exenatide ER generally outperforms exenatide P55957 and is a good option for patients who struggle to adhere to more frequent regimens . The future may hold interesting developments in terms of reduced dosing frequency , oral formulations and alternative therapeutic uses .", "___MASK74___ - induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . ___MASK74___ - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin - induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 function - blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin - induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin - enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 .", "The P04035 inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides . The 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids . Because pravastatin is a water - soluble organic anion , it can not easily penetrate the lipid bilayer of the cell membrane . As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified , we examined the roles of the organic anion transporter family on pravastatin - treated islet and adipocyte functions . Rat oatp1 / slco1a1 , oatp2 / slco1a4 and oatp3 / slco1a5 were expressed in the pancreas , and rat oatp3 / slco1a5 was also detected in rat insulinoma cell line P01308 - 1e . ___MASK74___ was transported not only by oatp1 / slco1a1 and oatp2 / slco1a4 , but also by rat oatp3 / slco1a5 . ___MASK74___ uptake into P01308 - 1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin , both of which are known to inhibit oatp family - mediated uptake . In addition , pravastatin enhanced the glucose - stimulated insulin secretion from P01308 - 1e cells . When fat - loaded db / db mice were treated with pravastatin , glucose intolerance and insulin resistance were prevented . In addition , insulin secretion from isolated islets was enhanced by pravastatin . These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat / glucose conditions .", "Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague - Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0 . 02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real - time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .", "Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .", "Efficacy of liraglutide as a follow - up therapy after resolution of glucotoxicity with intensive insulin therapy . OBJECTIVE : To assess the utility of liraglutide , a P43220 agonist , as additional therapy following resolution of glucotoxicity with insulin therapy . METHODS : The subjects were 13 Japanese patients with short - duration type 2 diabetes mellitus ( 2 . 0 ± 2 . 1 years ) . At first , treatment with insulin therapy consisted of bolus insulin before each meal and basal insulin at bed time commenced to improve every preprandial glucose levels below 130 mg / dL . Then , insulin therapy was replaced with liraglutide monotherapy in case in which 50 % or more self - monitoring of blood glucose ( SMBG ) tests revealed preprandial glucose levels of less than 130 mg / dL at least for one month . DB06655 dosing was initiated at 0 . 3 mg / day and increased in weekly or biweekly increments of 0 . 3 mg / day , to the maximum permissible dose ( in Japan ) of 0 . 9 mg / day . The participants were treated with liraglutide for 24 weeks . RESULTS : The average insulin therapy period was 13 . 2 ± 5 . 4 weeks , and insulin therapy significantly improved HbA1c values from 12 . 4 % ± 1 . 6 % to 6 . 8 % ± 0 . 9 % ( P < 0 . 05 ) . After improvement of hyperglycemia with insulin therapy and switching to liraglutide monotherapy for 24 weeks , HbA1c values remained constant ( 6 . 2 % ± 1 . 0 % at week 24 ) and the rates of hypoglycemic episodes significantly decreased ( P < 0 . 05 ) . CONCLUSIONS : These data suggest that liraglutide is proposed as an alternative follow - up therapy subsequent to eliminate glucotoxicity with insulin therapy .", "Endorphin patterns within the headache spectrum disorders . The role of opioid peptides in modulating the nervous system adaptability has been demonstrated recently ; proopiomelanocortin ( P01189 ) - related peptides , in particular , serve in pain perception , in adaptation to stress , and in modulating higher brain functions . Primary headaches , besides pain , involve neuroendocrine / autonomic / adaptive processes as well as mood and personality factors . The view that primary headaches can be taken as a possible model of P01189 - related peptides dysfunction led us to evaluate the resting plasma and P04141 peptide levels and their plasma changes in response to various stimuli affecting their release . The data obtained from basal and dynamic studies agree with the concept that primary headaches are sustained by opioid system disturbance . In particular the reduced release of endogenous opioids by anterior pituitary in response to physical , endocrine or pharmacological stimuli agrees with a weak adaptive ability of headache sufferers . This impairment of endorphin responsiveness could play a key role in headache susceptibility to environmental stimuli . Primary headaches constitute a wide , intriguing field , including several subgroups bordering on \" ischemic \" and behavioral / affective disorders . The development of neuroendocrine techniques could be a useful means for supporting the clinical criteria identifying subpopulations of headache sufferers .", "P43220 antagonist exendin -( 9 - 39 ) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the DB00171 - sensitive K + channel . Infants with congenital hyperinsulinism owing to inactivating mutations in the K ( DB00171 ) channel ( K ( DB00171 ) HI ) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia . In preclinical studies , we showed that the P43220 antagonist exendin -( 9 - 39 ) suppresses insulin secretion and corrects fasting hypoglycemia in Q09428 - 1 (-/-) mice . The aim of this study was to examine the effects of exendin -( 9 - 39 ) on fasting blood glucose in subjects with K ( DB00171 ) HI . This was a randomized , open - label , two - period crossover pilot clinical study . Nine subjects with K ( DB00171 ) HI received either exendin -( 9 - 39 ) or vehicle on two different days . The primary outcome was blood glucose ; secondary outcomes were insulin , glucagon , and P0C6A0 . In all subjects , mean nadir blood glucose and glucose area under the curve were significantly increased by exendin -( 9 - 39 ) . P01308 - to - glucose ratios were significantly lower during exendin -( 9 - 39 ) infusion compared with vehicle . Fasting glucagon and intact P0C6A0 were not affected by treatment . In addition , exendin -( 9 - 39 ) significantly inhibited amino acid - stimulated insulin secretion in pancreatic islets isolated from neonates with K ( DB00171 ) HI . Our findings have two important implications : 1 ) P0C6A0 and its receptor play a role in the regulation of fasting glycemia in K ( DB00171 ) HI ; and 2 ) the P43220 may be a therapeutic target for the treatment of children with K ( DB00171 ) HI .", "HRAS1 and P01308 genes are relocated but not structurally altered as a result of the t ( 7 ; 11 )( p15 ; p15 ) in a clone from a patient with acute myeloid leukaemia ( M4 ) . A patient whose leukaemic cells carried the rare t ( 7 ; 11 )( p15 ; p15 ) was diagnosed as having acute myelomonocytic leukaemia ( AML - M4 ) , and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation . Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the P00519 and P11274 genes . Chromosome in situ hybridization studies showed that both the HRAS1 and P01308 genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p . Neither HRAS1 nor P01308 were structurally rearranged . Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA . Because the P01308 gene , which was also translocated , is probably located proximal to HRAS1 on chromosome 11p , it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia .", "Synaptic vesicular monoamine transporter expression : distribution and pharmacologic profile . The human vesicular monoamine transporter ( hSVMT ) cDNA predicts a protein of 515 amino acids that shares 92 % amino acid identity with the rat cDNA . Northern analyses reveal expression of 4 . 3 kb Q05940 mRNAs in rat hypothalamus , midbrain and brainstem , a 3 kb hSVMT mRNA in human brainstem and a 4 . 8 kb hSVMT mRNA in human hypothalamus . In situ hybridization documents significant Q05940 expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers . COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine , micromolar affinities for haloperidol , GBR12909 , serotonin , mazindol , nomifensin and ___MASK22___ , while dopamine , epinephrine , norepinephrine and histamine each displayed millimolar affinities . These observations extend the pharmacological characterization of hSVMT and studies of its distribution , and indicate likely physiological roles for Q05940 in packaging monoamine transmitters including histamine .", "The human glucagon - like peptide - 1 analogue liraglutide regulates pancreatic beta - cell proliferation and apoptosis via an AMPK / P42345 / P70S6K signaling pathway . Glucagon - like peptide - 1 ( P0C6A0 ) , an effective therapeutic agent for the treatment of diabetes , has been proven to protect pancreatic beta cells through many pathways . Recent evidence demonstrates that AMP - activated protein kinase ( AMPK ) , as a metabolic regulator , coordinates beta - cell protein synthesis through regulation of the mammalian target of rapamycin ( P42345 ) signaling pathway . The purpose of the present study was to explore whether liraglutide , a human P0C6A0 analogue , protects beta cells via AMPK / P42345 signaling . We evaluated P01308 - 1 beta - cell line proliferation using the Cell Counting Kit - 8 , and examined the effect of P0C6A0 on cellular DB00171 levels using an DB00171 assay kit . P42345 pathway protein expression levels were tested by Western blotting and glucolipotoxicity - induced cell apoptosis was evaluated by flow cytometry . DB06655 increased beta - cell viability at an optimum concentration of 100 nmol / L in the presence of 11 . 1 or 30 mmol / L glucose . DB06655 ( 100 nmol / L ) activated P42345 and its downstream effectors , 70 - kDa ribosomal protein S6 kinase and P06730 - binding protein - 1 , in P01308 - 1 cells . This effect was abated by pathway blockers : the AMPK activator AICAR and the P42345 inhibitor rapamycin . Furthermore , the effect of liraglutide on beta - cell proliferation was inhibited by AICAR and rapamycin . DB06655 increased cellular DB00171 levels . In addition , liraglutide protected beta cells from glucolipotoxicity - induced apoptosis . This response was also prevented by rapamycin treatment . These results suggest that the enhancement of beta - cell proliferation by that P43220 agonist liraglutide is mediated , at least in part , by AMPK / P42345 signaling . DB06655 also prevents beta - cell glucolipotoxicity by activating P42345 .", "The P43220 agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis , plaque stability and endothelial function in an ApoE (-/-) mouse model . DB06655 , a once - daily glucagon - like peptide - 1 receptor ( P43220 ) agonist , has been approved as a new treatment for type 2 diabetes and is the subject of a clinical trial programme to evaluate the effects on cardiovascular disease and safety . The current study aimed to determine the in vivo effect of liraglutide on progression of atherosclerotic vascular disease in the apolipoprotein E - deficient ( ApoE (-/-) ) mouse model and identify underlying mechanisms responsible . DB06655 treatment inhibited progression of early onset , low - burden atherosclerotic disease in a partially P43220 - dependent manner in the ApoE (-/-) mouse model . In addition , liraglutide treatment inhibited progression of atherosclerotic plaque formation and enhanced plaque stability , again in a partially P43220 - dependent manner . No significant effect of liraglutide on progression of late onset , high - burden atherosclerotic disease was observed . In addition , no significant endothelial cell dysfunction was identified in ApoE (-/-) mice with early onset , low - burden atherosclerotic disease , although significant prevention of weight gain was observed in liraglutide - treated mice using this dietary protocol . Taken together , these results suggest a potential role for liraglutide in the prevention and stabilisation of atherosclerotic vascular disease together with possible protection against major cardiovascular events .", "DB06655 : short - lived effect on gastric emptying -- long lasting effects on body weight . AIM : Previous studies with the novel once daily glucagon - like peptide - 1 ( P0C6A0 ) analogue liraglutide and the P43220 agonist exenatide have revealed profound insulinotrophic and antidiabetic effects , but also potent effects on gastric emptying ( GE ) and long - term and lasting reductions in body weight . In this study , we examined the acute and chronic effects of two different P0C6A0 analogues with different pharmacokinetic profiles on GE , food intake and body weight . METHODS : On the basis of a series of dose - finding studies , the doses of exenatide and liraglutide with similar acute anorectic effects were identified . GE was assessed using a standard acetaminophen release assay . After the acute test , rats were dosed bi - daily for 14 days in which period food intake and body weight was monitored . On day 14 , the GE rate was reassessed . RESULTS : While both compounds exerted robust acute reductions in GE , the effect was markedly diminished following 14 days of dosing with liraglutide . In contrast , exenatide - treated rats still displayed a profound reduction in GE at the 14 - day time - point . Both compounds exerted similar effects on body weight . CONCLUSION : The data suggest that the ' gastric inhibitory ' P0C6A0 receptors in rats are subject to desensitization / tachyphylaxis but that this effect is dependent on full 24 - h exposure as obtained by liraglutide . The body weight - lowering effects of P43220 stimulation are not subject to desensitization . These data indicate that regulation of appetite signals in the brain , and not GE , is the main mechanism for liraglutide - induced weight loss .", "Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .", "Exendin - 4 attenuates lipopolysaccharides induced inflammatory response but does not protects H9c2 cells from apoptosis . BACKGROUND : Glucagon - like peptide - 1 ( P0C6A0 ) and its analogues are reported to exert wide - ranging cardiovascular actions in preclinical and clinical studies . We thus investigated whether the P43220 agonist , exendin - 4 , has inhibitory effects on LPS - stimulated inflammatory response in cardiomyoblasts . METHODS : H9c2 cardiomyoblasts were exposed to LPS and treated with exendin - 4 . Expressions of proinflammatory mediators were assessed using quantitative real - time PCR . Nuclear localization of NF - κB was examined using immunoblotting . mRNA expression of inducible nitric oxide synthase ( P35228 ) and nitric oxide ( NO ) production were evaluated by q PCR and NO assay . Furthermore , anti - apoptotic effect of exendin - 4 in LPS - stimulated H9c2 cells was determined using qPCR and immunoblot . RESULTS : Exposure to LPS increased mRNA expressions of P01375 - α , P35354 and P14780 in H9c2 cells . It also caused increases in P35228 mRNA expression and NF - κB nuclear translocation . Exendin - 4 dose - dependently downregulated mRNA levels of P01375 - α , P35354 and P14780 in LPS - stimulated H9c2 cells . It also reduced NF - κB nuclear translocation . Treatment with exendin - 4 showed no effect on LPS - induced apoptosis in H9c2 cells . CONCLUSIONS : Exendin - 4 exerts an effect on cardiomyoblast exposed to LPS by inhibiting mRNA expression of inflammatory mediators and suppressing NF - κB activation . These effects are consistent with some of the observed anti - inflammatory properties of exendin - 4 , as well as its beneficial actions on the cardiovascular system .", "DB06655 suppresses the plasma levels of active and des - acyl ghrelin independently of active glucagon - like Peptide - 1 levels in mice . Glucagon - like peptide - 1 ( P0C6A0 ) , an insulinotropic gastrointestinal peptide that is primarily produced by intestinal endocrine L - cells , stimulates satiety . Ghrelin , a hormone that is produced predominantly by the stomach stimulates hunger . There are two forms of ghrelin : active ghrelin and inactive des - acyl ghrelin . After depriving mice of food for 24 h , we demonstrated that the systemic administration of liraglutide ( 100 μ g / kg ) , a human P0C6A0 analog that binds to the P43220 , increased ( 1 . 4 - fold ) the plasma levels of active P0C6A0 and suppressed the plasma levels of active and des - acyl ghrelin after 1 h . Despite the elevated plasma levels of active P0C6A0 ( 11 - fold ) , liraglutide had no effect on the plasma levels of active or des - acyl ghrelin after 12 h . These findings demonstrated that liraglutide suppresses the plasma levels of active and des - acyl ghrelin independently of active P0C6A0 levels in fasted mice , suggesting a novel in vivo biological effect of liraglutide beyond regulating plasma P0C6A0 .", "Neuroprotective and anti - apoptotic effects of liraglutide on SH - SY5Y cells exposed to methylglyoxal stress . Glucagon - like peptide 1 ( P0C6A0 ) is a growth factor that has demonstrated neuroprotective properties in a range of studies . In an APPswe / P49768 ΔE9 mouse model of Alzheimer ' s disease ( AD ) , we previously found protective effects on memory formation , synaptic plasticity , synapse survival and a reduction of amyloid synthesis and plaque load in the brain . Here , we analyse the neuroprotective properties of the P0C6A0 analogue liraglutide in human neuroblastoma cell line SH - SY5Y during methyl glyoxal stress . We show for the first time that cell viability was enhanced by liraglutide ( XTT assay ) in a dose - dependent way , while cytotoxicity ( LDH assay ) and apoptosis were reduced . Expression of the pro - survival Mcl1 signaling protein was increased , as was activation of cell survival kinases Akt , Q02750 / 2 and the transcription factor p90RSK . DB06655 also decreased pro - apoptotic Bax and Bik expression . In addition , the membrane potential and the influx of calcium into the cell were enhanced by liraglutide . P43220 expression was also increased by the drug . The results demonstrate a range of growth factor - related cytoprotective processes induced by liraglutide , which is currently on the market as a treatment for type 2 diabetes ( DB06655 ® ) . It is also tested in clinical trials in patients with Alzheimer disease .", "DB06655 , a long - acting P0C6A0 mimetic , and its metabolite attenuate inflammation after intracerebral hemorrhage . The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage ( ICH ) . Glucagon - like - peptide - 1 ( P0C6A0 ) is a hormone with antidiabetic effect and may also have antiinflammatory properties . Despite consensus that the glucoregulatory action is mediated by the P43220 ( P43220 ) , mechanisms in the brain remain unclear . We investigated the effect of a long - acting P0C6A0 analog , liraglutide , and its truncated metabolite , P0C6A0 ( 9 - 36 ) a from dipeptidyl peptidase - 4 ( DPP - 4 ) cleavage in ICH - induced brain injury . Primary outcomes were cerebral edema formation , neurobehavior , and inflammatory parameters . P0C6A0 ( 9 - 36 ) a , P43220 inhibitor , adenosine monophosphate - activated protein kinase ( AMPK ) phosphorylation inhibitor and DPP - 4 inhibitor were administered to examine the mechanisms of action . DB06655 suppressed neuroinflammation , prevented brain edema and neurologic deficit following ICH , which were partially reversed by P43220 inhibitor and AMPK phosphorylation inhibitor . DB06655 - mediated AMPK phosphorylation was unaffected by P43220 inhibitor , and was found to be induced by P0C6A0 ( 9 - 36 ) a . P0C6A0 ( 9 - 36 ) a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by P43220 inhibitor . DB06655 and DPP - 4 inhibitor co - administration reversed liraglutide - mediated AMPK phosphorylation and antiinflammatory effects . DB06655 exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK - dependent manner . Therapies that inhibit P0C6A0 degradation may weaken the metabolite - mediated effects .", "The future use of liraglutide : implications of the LEAD - 2 study for treatment guidelines in type 2 diabetes . The effective identification and management of type 2 diabetes ( T2D ) in primary care is a healthcare priority . New antidiabetic agents , including glucagon - like peptide ( GLP ) - 1 receptor agonists , may help overcome drawbacks with current treatments . These new agents have been reviewed in the updated National Institute for Health and Clinical Excellence ( NICE ) guidelines for the treatment of T2D . DB06655 , a P43220 agonist , was licensed for use in patients with T2D after the development of the NICE guidelines . Data from Phase III trials evaluating liraglutide are presented here in the context of the role of P43220 agonists in NICE guidelines .", "P0C6A0 treatment reduces endogenous insulin resistance via activation of central P0C6A0 receptors in mice fed a high - fat diet . Glucagon - like peptide - 1 ( P0C6A0 ) improves insulin sensitivity in humans and rodents . It is currently unknown to what extent the ( metabolic ) effects of P0C6A0 treatment are mediated by central P0C6A0 receptors . We studied the impact of central P43220 ( P43220 ) antagonism on the metabolic effects of peripheral P0C6A0 administration in mice . High - fat - fed insulin - resistant C57Bl / 6 mice were treated with continuous subcutaneous infusion of P0C6A0 or saline ( PBS ) for 2 wk , whereas the P43220 antagonist exendin - 9 ( EX - 9 ) and cerebrospinal fluid ( P04141 ) were simultaneously infused in the left lateral cerebral ventricle ( icv ) . DB09341 and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp . VLDL - triglyceride ( VLDL - TG ) production was determined in hyperinsulinemic conditions . Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by P0C6A0 . Simultaneous icv infusion of EX - 9 diminished this effect by 62 % . The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by P0C6A0 . Simultaneous icv infusion of EX - 9 significantly diminished the latter effect . Central P43220 antagonism alone did not affect glucose metabolism . Also , P0C6A0 treatment reinforced the inhibitory action of insulin on VLDL - TG production . In conclusion , peripheral administration of P0C6A0 reinforces the ability of insulin to suppress endogenous glucose and VLDL - TG production ( but not lipolysis ) and boosts its capacity to stimulate glucose disposal in high - fat - fed C57Bl / 6 mice . Activation of central GLP - 1Rs contributes substantially to the inhibition of endogenous glucose production by P0C6A0 treatment in this animal model ." ]

[ "___MASK22___", "___MASK31___", "___MASK3___", "___MASK59___", "___MASK60___", "___MASK63___", "___MASK74___", "___MASK82___", "___MASK94___" ]

[ "Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK10___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK10___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK10___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .", "A new clinical evidence - based gene - environment interaction model of depression . In our current understanding of mood disorders , the role of genes is diverse including the mediation of the effects of provoking and protective factors . Different or partially overlapping gene sets play a major role in the development of personality traits including also affective temperaments , in the mediation of the effects of environmental factors , and in the interaction of these elements in the development of depression . Certain genes are associated with personality traits and temperaments including e . g . , neuroticism , impulsivity , openness , rumination and extroversion . Environmental factors consist of external ( early and provoking life events , seasonal changes , social support etc . ) and internal factors ( hormones , biological rhythm generators , comorbid disorders etc ) . Some of these environmental factors , such as early life events and some prenatal events directly influence the development of personality traits and temperaments . In the NEWMOOD cohort polymorphisms of the genes of the serotonin transporter , P08908 , P28222 and 5 - Q13049 and endocannabinoid P21554 receptors , tryptophan hydroxylase , P16220 , P23560 and GIRK provide evidence for the involvement of these genes in the development of depression . Based on their role in this process they could be assigned to different gene sets . The role of certain genes , such as promoter polymorphisms of the serotonin transporter ( 5 - HTTLPR ) and P21554 receptor has been shown in more than one of the above factors . Furthermore , gene - gene interactions of these promoters associated with anxiety suggest the application of these polymorphisms in personalized medicine . In this review we introduce a new model including environmental factors , genes , trait and temperament markers based on human genetic studies .", "Characterisation of the contractile activity of eletriptan at the canine vascular P28222 receptor . The functional activity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1 H - indole ) at the contractile serotonin ( 5 - hydroxytryptamine ; 5 - HT ) ' 1B - like ' receptor in dog isolated saphenous vein and basilar artery was investigated . DB00216 , like 5 - HT and sumatriptan potently contracted saphenous vein ( pEC50 : 6 . 3 , 6 . 9 and 6 . 1 , respectively ) and basilar artery ( pEC50 7 . 2 , 7 . 5 and 6 . 8 , respectively ) . The maximum responses evoked by eletriptan was , unlike sumatriptan , significantly lower than that to 5 - HT ( intrinsic activity saphenous vein : eletriptan 0 . 57 , 5 - HT 1 . 0 , sumatriptan 0 . 85 ; basilar artery : eletriptan 0 . 77 , 5 - HT 0 . 98 , sumatriptan 0 . 89 ) . Contractions evoked by eletriptan were antagonised by the P28222 / 1D receptor antagonist GR125743 ( N - [ 4 - methoxy - 3 - ( 4 - methyl piperazin - 1 - yl ) phenyl ] - 3 - methyl - 4 -( 4 - pyridyl ) benzamide ) with pA2 values of 9 . 1 in saphenous vein and 9 . 4 in basilar artery . Affinity estimates ( pKA ) for 5 - HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6 . 6 and 6 . 3 , respectively , compared to the apparent equilibrium dissociation constant ( pKp ) for eletriptan of 6 . 8 . The rank order of relative intrinsic efficacies ( epsilon ) was 5 - HT > sumatriptan > eletriptan . Thus , eletriptan required greater receptor occupancy ( 4 . 4 - fold ) to evoke an equivalent contraction to 5 - HT and sumatriptan in dog isolated saphenous vein . These data demonstrate that eletriptan is a potent partial agonist at the canine vascular P28222 receptor .", "Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK88___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK88___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .", "Neurokinin - 1 receptor antagonism in a rat model of subarachnoid hemorrhage : prevention of upregulation of contractile ETB and P28222 receptors and cerebral blood flow reduction . OBJECT : Cerebral vasospasm following subarachnoid hemorrhage ( Q53FZ2 ) leads to reduced cerebral blood flow ( Q03701 ) and to cerebral ischemia , in some cases even producing infarction and long - term disability . The goal of the present study was to investigate the hypothesis that inhibition of neurokinin - 1 receptors ( NK1Rs ) by administration of L - 822429 blunts the decrease in Q03701 as well as cerebrovascular receptor upregulation in an animal model of Q53FZ2 . METHODS : Subarachnoid hemorrhage was induced in rats by injection of 250 microl of blood into the prechiasmatic cistern . The P25103 inhibitor L - 822429 was injected intracisternally 30 minutes and 24 hours after the induction of Q53FZ2 . Two days after Q53FZ2 induction , the basilar arteries were harvested , and contractile responses to endothelin - 1 ( ET - I , an P25101 - and ETB - receptor agonist ) and 5 - carboxamidotryptamine ( a 5 - hydroxytryptamine - I1 [ 5 - HT1 ] - receptor agonist ) were investigated using sensitive myographs . To determine whether Q8TDQ1 inhibition had an influence on local Q03701 after post - Q53FZ2 , a quantitative autoradiographic technique was used . After Q53FZ2 , the vascular receptor phenotype was changed in cerebral arteries through upregulation of contractile ET , and P28222 receptors , while regional and total Q03701 were markedly reduced . Treatment with the selective P25103 inhibitor L - 822429 prevented both the receptor upregulation and the reduction in regional and global Q03701 . CONCLUSIONS : The data reveal the coregulation of vascular receptor changes and blood flow effects , and also show that interaction with a small - molecule P25103 antagonist is a promising area of focus for the development of specific treatments for Q53FZ2 .", "Differential radiosensitisation by ZD1839 ( ___MASK86___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK86___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .", "Efficacy , safety and tolerability of oral eletriptan in the acute treatment of migraine : results of a phase III , multicentre , placebo - controlled study across three attacks . The efficacy , safety and tolerability of the P28222 / D receptor agonist eletriptan ( 40 mg and 80 mg ) in acute treatment of migraine was evaluated in a multinational , randomized , double - blind , parallel - group , placebo - controlled , three - attack study treating 1153 patients . In the initial attack , significantly more eletriptan patients reported headache relief and complete pain relief at 2 h vs . placebo ( 40 mg 62 % and 32 % , 80 mg 65 % and 34 % , placebo 19 % and 3 % ; P < 0 . 0001 ) . Headache relief occurred faster after eletriptan , with more patients at both doses reporting relief 30 min ( P < 0 . 01 ) and 1 h ( P < 0 . 0001 ) after treatment than after placebo . There was a significantly lower recurrence rate with eletriptan 80 mg compared with placebo ( P < 0 . 01 ) . Adverse events for all treatments were generally mild or moderate and self - limiting . DB00216 40 mg and eletriptan 80 mg both appear to be effective and well - tolerated acute migraine treatments .", "Characterisation of the 5 - HT receptor binding profile of eletriptan and kinetics of [ 3H ] eletriptan binding at human P28222 and P28221 receptors . The affinity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1H - indole ) for a range of 5 - HT receptors was compared to values obtained for other P28222 / 1D receptor agonists known to be effective in the treatment of migraine . DB00216 , like sumatriptan , zolmitriptan , naratriptan and rizatriptan had highest affinity for the human P28222 , P28221 and putative 5 - ht1f receptor . Kinetic studies comparing the binding of [ 3H ] eletriptan and [ 3H ] sumatriptan to the human recombinant P28222 and P28221 receptors expressed in HeLa cells revealed that both radioligands bound with high specificity ( > 90 % ) and reached equilibrium within 10 - 15 min . However , [ 3H ] eletriptan had over 6 - fold higher affinity than [ 3H ] sumatriptan at the P28221 receptor ( K ( D ) ) : 0 . 92 and 6 . 58 nM , respectively ) and over 3 - fold higher affinity than [ 3H ] sumatriptan at the P28222 receptor ( K ( D ) : 3 . 14 and 11 . 07 nM , respectively ) . Association and dissociation rates for both radioligands could only be accurately determined at the P28221 receptor and then only at 4 degrees C . At this temperature , [ 3H ] eletriptan had a significantly ( P < 0 . 05 ) faster association rate ( K ( on ) 0 . 249 min (- 1 ) nM (- 1 ) ) than [ 3H ] sumatriptan ( K ( on ) 0 . 024 min (- 1 ) nM (- 1 ) ) and a significantly ( P < 0 . 05 ) slower off - rate ( K ( off ) 0 . 027 min (- 1 ) compared to 0 . 037 min (- 1 ) for [ 3H ] sumatriptan ) . These data indicate that eletriptan is a potent ligand at the human P28222 , P28221 , and 5 - ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache .", "DNA repair enzyme , O6 - methylguanine DNA methyltransferase , modulates cytotoxicity of camptothecin - derived topoisomerase I inhibitors . Two camptothecin - resistant cell lines , CPT30 and KB100 , were established and characterized previously in our laboratory . Because enhanced sensitivity to 1 , 3 - bis ( 2 - chloroethyl )- 1 - nitrosourea ( DB00262 ) and decreased expression of O ( 6 )- methylguanine - DNA methyltransferase ( P16455 ) protein were observed in these lines , we hypothesized that P16455 may be a determinant of cytotoxicity associated with camptothecin - derived P11387 inhibitors ( CPTs ) . We used the Tet - On system to induce expression of P16455 in Chinese hamster ovary ( CHO ) cells and RNA interference to knock down P16455 expression in human nasopharyngeal carcinoma HONE - 1 cells in order to identify any correlations between P16455 expression and CPTs cytotoxicity . CHO - derived Tet - On - inducible cells ( P28222 + ) showed P16455 overexpression and statistically significant more resistance to DB00262 , camptothecin , 7 - ethyl - 10 - hydrocamptothecin ( SN38 ) , and topotecan than parental CHO cells ( p < 0 . 05 ) , but there was less resistance to CPTs than to DB00262 . Knockdown of P16455 expression with small interfering RNA in HONE - 1 cells conferred increased sensitivity to DB00262 and CPTs compared with mock control . Furthermore , alteration of P16455 expression coincides with CPT - induced cell death and poly ( ADP - ribose ) polymerase cleavage . There were no differences in protein levels and catalytic activity of topoisomerase I between P16455 - proficient and P16455 - deficient cells from the Tet - On - inducible and small interfering RNA ( siRNA ) systems . Resistance to CPTs coincided with decreased amounts of protein - linked DNA breaks generated by CPTs in P16455 - proficient cells and vice versa in P16455 - deficient cells . Our data indicate that P16455 can modulate cytotoxicity of CPT - derived topoisomerase I inhibitors .", "Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .", "Disabling the mitotic spindle and tumor growth by targeting a cavity - induced allosteric site of survivin . Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis . Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy . P00533 and Her / neu - transformed human tumors in particular exhibit high levels of survivin . The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein . We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces . P28222 , a lead compound identified in the screen , can bind to the survivin protein at the intended target site . Moreover , P28222 alters spindle formation , causing mitotic arrest and cell death , and inhibits tumor growth in vitro and in vivo . Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity . Thus , the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers .", "P10275 and calcitonin gene - related peptide in neurons of the genitofemoral nerve during testicular descent induced with human chorionic gonadotropin . BACKGROUND : Low levels of circulating testosterone during testis descent cause cryptorchidism in humans and rats . Treatment with human chorionic gonadotrophin ( hCG ) induces testis descent by stimulating production of testosterone ( T ) . Neurons of genitofemoral nerve ( GFN ) , which innervate testicular gubernaculum , may play a role in testis descent . METHODS : In the current study , putative correlations were made between T and GFN motor and sensory neuron activity during inguinoscrotal testis descent . Cryptorchidism was provoked in prepuberal rats with estradiol . Rats with testicular descent induced with hCG and cryptorchid controls were used . Cells of spinal cord and dorsal root ganglia were labeled by retrograde staining with fast - blue . Expression of androgen receptor ( AR ) and calcitonin gene - related peptide ( P80511 ) were detected with indirect immunofluorescence . RESULTS : Neurons labeled with fast - blue were found in the center of motor horn and dorsal root ganglia at levels Q9NUQ9 and Q401N2 . While number of motor neurons expressing AR was significantly higher in the group treated with hCG , number expressing P80511 was higher in controls . In dorsal root ganglion , number of cells immunostained with P80511 antibody was similar in both groups but AR was not detected . CONCLUSIONS : Present results support the hypothesis that motor nucleus of the GFN is a direct target of testosterone and that regulation of P80511 in sensory nucleus may be involved in testicular descent .", "[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK69___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .", "Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .", "Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK11___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK11___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK11___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .", "Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion , and on the expression of c - fos and c - jun in the trigeminal complex of the rat in an experimental migraine model . Nociceptive axons and terminals in the supratentorial cerebral dura mater display an intense calcitonin gene - related peptide ( P80511 ) immunoreactivity . In an experimental migraine model , it has been shown that electrical stimulation of the rat trigeminal ganglion induced an increase in the lengths of P80511 - immunoreactive axons , increased size and number of pleomorphic axonal varicosities in the dura mater , and an increased number of c - jun and c - fos protein - expressing nerve cells in the trigeminal complex . We demonstrate the effect of the highly specific and moderately lipophilic serotonin agonist eletriptan ( Pfizer ) which prevents the effects of electrical stimulation in the dura mater . DB00216 also affected the caudal trigeminal complex ; it markedly reduced the numbers of the oncoprotein - expressing cells , mainly after stimulation and to some extent also in nonstimulated animals . DB00216 also affected expression of P80511 in perikarya of trigeminal ganglion cells , insofar as the number of small nerve cells exhibiting a compact P80511 immunoreaction was decreased to one quarter of the original value . In all these respects , eletriptan acted in a similar way to sumatriptan , with the notable exception that eletriptan also blocked the stimulation - induced effects in the nucleus caudalis trigemini and the upper cervical spinal cord ( trigeminal complex ) , whereas sumatriptan did not . It is concluded that eletriptan , acting on perikarya and both the peripheral and the central axon terminals of primary sensory neurons , exerts its antimigraine effect by an agonist action on P28222 / 1D receptors throughout the entire trigeminal system , probably by passing the blood - brain - barrier because of its lipophilic character .", "Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK59___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .", "DB00216 Pfizer . Pfizer has developed and launched eletriptan , a P28222 / 1D agonist , for the potential treatment of migraine with and without aura . DB00216 has 6 - fold greater affinity for the P28221 receptor than sumatriptan , and a 3 - fold greater affinity for the P28222 receptor [ 249570 ] . DB00216 pharmacology has also been evaluated in vitro in comparison with zolmitriptan ( AstraZeneca plc ) and naratriptan ( GlaxoSmithKline plc ) [ 290116 ] .", "Porcine carotid vascular effects of eletriptan ( UK - 116 , 044 ) : a new P28222 / 1D receptor agonist with anti - migraine activity . It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine . Indeed , a number of acutely acting anti - migraine drugs , including the ergot alkaloids and sumatriptan , constrict porcine carotid arteriovenous anastomoses . In this study , using pentobarbital anaesthetised pigs , we investigated the effects of eletriptan , a close structural analogue of sumatriptan , on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient ( capillary ) fractions . DB00216 ( 10 , 30 , 100 , 300 and 1000 microg kg (- 1 ) , i . v . ) decreased the total carotid blood flow , exclusively by decreasing cephalic arteriovenous anastomotic blood flow ; nutrient blood flow , particularly to the ear , skin and fat , was significantly increased . The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50 % ( ED50 ) were , respectively , 117 +/- 21 microg kg (- 1 ) ( 251 +/- 45 nmol kg (- 1 ) ) and 184 +/- 42 microg kg (- 1 ) ( 396 +/- 91 nmol kg (- 1 ) ) ; the highest dose caused reductions of 84 +/- 3 % and 77 +/- 4 % , respectively . The eletriptan - induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective P28222 / 1D receptor antagonist GR127935 ( 0 . 5 mg kg (- 1 ) ) . On the basis of these results , we conclude that ( 1 ) the eletriptan - induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by P28222 / 1D receptors , and ( 2 ) eletriptan should be effective in aborting migraine headache . Clinical studies have already demonstrated its therapeutic action in migraine patients .", "5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK59___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .", "Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .", "Lessons learned from the irinotecan metabolic pathway . ___MASK69___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK69___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK69___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .", "Differential innate immune responses of a living skin equivalent model colonized by Staphylococcus epidermidis or Staphylococcus aureus . Staphylococcus epidermidis is a commensal on skin , whereas Staphylococcus aureus is a transient pathogen . The aim was to determine whether the skin ' s innate defence systems responded differently to these microorganisms . Differential gene expression of a human skin equivalent ( SE ) model was assessed by microarray technology , in response to colonization by S . epidermidis or S . aureus . Only a small number of transcripts were significantly ( P < 0 . 0001 ) increased ( 12 ) or decreased ( 35 ) with gene expression changes of > 2 - fold on SEs colonized with S . epidermidis compared with controls ( no colonization ) . Expression of one innate defence gene , pentraxin 3 ( PTX3 ) , was upregulated , while psoriasin , P80511 , S100A15 , beta defensin 4 , beta defensin 3 , lipocalin 2 and peptidoglycan recognition protein 2 were downregulated . In contrast , large numbers of transcripts were significantly increased ( 480 ) or decreased ( 397 ) with gene expression changes of > 2 - fold on SEs colonized with S . aureus compared with controls . There was upregulation in gene expression of many skin defence factors including O60603 , beta defensin 4 , properdin , PTX3 , proinflammatory cytokines tumour necrosis factor - alpha , P01583 , P01584 , Q9P0M4 , IL - 20 , IL - 23A and chemokines P10145 , P13236 , P13501 , P78556 and Q9Y4X3 . These differences may partly explain why S . epidermidis is a normal skin resident and S . aureus is not .", "P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK100___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .", "Antibody to ras proteins in patients with colon cancer . The current study examined sera from 160 colon cancer patients and 60 normal individuals to determine whether antibody to mutated P38936 ras protein was present . Studies focused on the aspartic acid substitution at amino acid position 12 ( denoted D12 ) , one of the most common mutations in colon adenocarcinoma . IgA antibodies directed against mutated P38936 ras - D12 protein were detected in 51 ( 32 % ) of 160 colon cancer patients , but only in 1 ( 2 . 5 % ) of 40 normal individuals . The greater incidence of antibody in cancer patients provides presumptive evidence that immunization to the ras proteins occurred as a result of the malignancy . Examination of sera for antibody reactivity to wild - type P38936 ras protein ( denoted P38936 ras - G12 ) as well as P38936 ras proteins bearing the D12 , V12 , P28222 , or L61 mutations showed that antibody detected was largely to normal segments of the P38936 ras protein . Epitope mapping , using peptide neutralization assays with mutated or normal ras peptides as competitors , demonstrated that in 10 ( 67 % ) of 15 sera examined the antibody reactivity to P38936 ras - G12 protein was neutralized by peptides near the carboxyl terminus of P38936 ras protein , but not by peptides spanning the specific point mutation region . Antibody reactivities correlated with peripheral blood lymphocyte count , but did not correlate with patient age , sex , histology , stage , tumor locus , lymph node metastasis , or serum carcinoembryonic antigen .", "Peptides encoded by the calcitonin gene inhibit macrophage function . Neuropeptides are considered to play an important role in the modulation of a number of immune functions . P01258 gene - related peptide ( P80511 ) , one of the neuropeptides , was found to profoundly inhibit the ability of macrophages to produce H2O2 in response to P01579 or to act as P25054 . For the inhibition of H2O2 production to occur , preincubation of the macrophages with P80511 was required . Among neuropeptides that are similar in size , calcitonin also prevented macrophage activation but adrenocorticotropic hormone did not . These findings suggest that P80511 and calcitonin play an important role in modulating the ability of macrophages to present Ag and to respond to activating factors .", "Anandamide regulates neuropeptide release from capsaicin - sensitive primary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro . The effect of anandamide , which activates both the cannabinoid 1 ( P21554 ) receptor and the vanilloid receptor 1 ( Q8NER1 ) , was studied on calcitonin gene - related peptide ( P80511 ) release from cultured primary sensory neurons , the majority of which coexpress the P21554 receptor and Q8NER1 . Concentrations of anandamide < 1 micro m produced a small but significant P21554 receptor - mediated inhibition of basal P80511 release while higher concentrations induced Q8NER1 - mediated P80511 release . The excitatory effect of anandamide was potentiated by the P21554 receptor antagonist SR141716A . In the presence of SR141716A at concentrations < 100 nm , anandamide was equipotent with capsaicin in stimulating P80511 release . However , at higher concentrations anandamide produced more P80511 release than equimolar concentrations of capsaicin . Three and ten nanomolar anandamide inhibited the capsaicin - evoked P80511 release . In the presence of SR141716A , treatments which activated protein kinase A , protein kinase C and phospholipase C significantly potentiated the anandamide - evoked P80511 release at all anandamide concentrations . Although this potentiation was reduced when the P21554 receptor antagonist was omitted from the buffer , the P80511 release evoked by 300 nm and 1 micro m anandamide was still significantly larger than that seen with nonpotentiated cells . These data indicate that anandamide may regulate P80511 release from capsaicin - sensitive primary sensory neurons in vivo , and that the net effect of anandamide on transmitter release from capsaicin - sensitive primary sensory neurons depends on the concentration of anandamide and the state of the P21554 receptor and Q8NER1 . These findings also suggest that anandamide could be one of the molecules responsible for the development of inflammatory heat hyperalgesia .", "The ( pro ) renin receptor blocker handle region peptide upregulates endothelium - derived contractile factors in aliskiren - treated diabetic transgenic ( mREN2 ) 27 rats . BACKGROUND : Elevated prorenin levels associate with microvascular complications in patients with diabetes mellitus , possibly because prorenin affects vascular function in diabetes mellitus , for example by generating angiotensins following its binding to the ( pro ) renin receptor [ ( P ) RR ] . Here we evaluated whether the renin inhibitor aliskiren , with or without the putative ( P ) RR antagonist handle region peptide ( HRP ) improved the disturbed vascular function in diabetic TGR ( mREN2 ) 27 rats , a high - prorenin , high -( P ) RR hypertensive model . METHODS : Telemetry transmitters were implanted to monitor blood pressure . After 3 weeks of treatment , rats were sacrificed , and iliac and mesenteric arteries were removed to evaluate vascular reactivity . RESULTS : Diabetes mellitus enhanced the contractile response to nitric oxide synthase ( NOS ) blockade , potentiated the response to phenylephrine , diminished the effectiveness of endothelin type A ( P25101 ) receptor blockade and allowed acetylcholine to display constrictor , cyclo - oxygenase - 2 mediated , endothelium - dependent responses in the presence of NOS inhibition and blockers of endothelium - derived hyperpolarizing factors . ___MASK8___ normalized blood pressure , suppressed renin activity , and reversed the above vascular effects , with the exception of the altered effectiveness of P25101 receptor blockade . Remarkably , when adding HRP on top of aliskiren , its beneficial vascular effects either disappeared or were greatly diminished , although HRP did not alter the effect of aliskiren on blood pressure and renin activity . CONCLUSIONS : P00797 inhibition improves vascular dysfunction in diabetic hypertensive rats , and HRP counteracts this effect independently of blood pressure and angiotensin . ( P ) RR blockade therefore is unlikely to be a new tool to further suppress the renin - angiotensin system ( DB01367 ) on top of existing DB01367 blockers .", "P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK8___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK8___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .", "Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .", "Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK77___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK77___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK77___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK77___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK77___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK77___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK77___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK77___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK77___ in the treatment of changes in hypervigilance following severe stress .", "Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 - binding cassette transporters ( ABCs ) in one of the most drug - resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical - pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real - time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high - resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical - pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up - regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up - regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down - regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC .", "K ( DB00171 ) channel openers in the trigeminovascular system . BACKGROUND : The DB00171 - sensitive K (+) ( K ( DB00171 ) ) channel openers levcromakalim and pinacidil are vasodilators that induce headache in healthy people . The neuropeptide calcitonin gene - related peptide ( P80511 ) induces headache in healthy people and migraine in migraineurs , potentially through a mechanism that involves opening of vascular or neuronal K ( DB00171 ) channels and mast cell degranulation . Using rat as a model , we studied the molecular presence of K ( DB00171 ) channels in the trigeminovascular system . Furthermore , we examined whether K ( DB00171 ) channel openers stimulate the in vitro release of P80511 and whether they degranulate dural mast cells . METHODS : mRNA and protein expression of K ( DB00171 ) channel subunits were studied in the trigeminal ganglion ( TG ) and trigeminal nucleus caudalis ( P24821 ) by qPCR and western blotting . In vitro P80511 release was studied after application of levcromakalim ( 1 µM ) and diazoxide ( 10 µM ) to freshly isolated rat dura mater , TG and P24821 . Rat dural mast cells were challenged in situ with levcromakalim ( 10 (- 5 ) M ) to study its potential degranulation effect . RESULTS : mRNA and protein of K ( DB00171 ) channel subunits Kir6 . 1 , Kir6 . 2 , Q09428 and SUR2B were identified in the TG and P24821 . K ( DB00171 ) channel openers did not release or inhibit capsaicin - induced P80511 release from dura mater , TG or P24821 . They did also not induce dural mast cell degranulation . CONCLUSIONS : K ( DB00171 ) channel openers do not interact with P80511 release or mast cell degranulation . Activation of these channels in the CNS is antinociceptive and therefore can not explain the headache induced by K ( DB00171 ) channel openers . Thus , they are likely to induce headache by interaction with extracerebral K ( DB00171 ) channels , probably the SUR2B isoforms .", "A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis . BACKGROUND : DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis . Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors . METHODS : Genome - wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I ( Illumina , Inc . ) . All clinical stages of disease were considered . RESULTS : We found 41 genes hypermethylated in more than 20 % of the tumors analyzed ( P < 0 . 01 ) . Of these , we newly identified P28161 and P01210 as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40 . 9 % of the tumors analyzed . We also identified panels of genes that are more frequently methylated in tumor samples with clinico - pathological indicators of poor prognosis : a high Gleason score , elevated Ki - 67 , and advanced disease . Of these , we found simultaneous hypermethylation of P13569 and P28222 to be common in patients with a high Gleason score and high Ki - 67 levels ; this might indicate the population at higher risk of therapeutic failure . The DNA hypermethylation profile was associated with cancer - specific mortality ( log - rank test , P = 0 . 007 ) and biochemical recurrence - free survival ( log - rank test , P = 0 . 0008 ) . CONCLUSIONS : Our findings strongly indicate that epigenetic silencing of P28161 and P01210 is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis . In addition , simultaneous P28222 and P13569 hypermethylation could help discriminate aggressive from indolent prostate tumors ." ]

[ "___MASK100___", "___MASK10___", "___MASK11___", "___MASK59___", "___MASK69___", "___MASK77___", "___MASK86___", "___MASK88___", "___MASK8___" ]

[ "___MASK15___ sulfate suppresses the expressions of urokinase plasminogen activator and inhibitor and gelatinases during the early stage of osteoarthritis . BACKGROUND : ___MASK15___ sulfate may have an ex vivo inhibitory effect on the plasminogen activator ( PA ) / plasmin system and gelatinases expression during the early development of osteoarthritis ( OA ) . METHODS : We compared the levels of urokinase - type PA ( u - PA ) , PA inhibitor - 1 ( P05121 ) and gelatinases ( matrix metalloproteinase - 2 and - 9 [ P08253 and - 9 ] ) in a series of chondral , meniscal , and synovial cultures of early OA after treatment with or without glucosamine sulfate . RESULTS : Gelatin zymography revealed that glucosamine sulfate could suppress P08253 secretion in chondral , meniscal and synovial cultures and also decrease P14780 production in synovial and meniscal cultures . ELISA data also showed the suppressive effects of glucosamine sulfate on u - PA and P05121 production in synovial cultures at 48 h . CONCLUSIONS : Our data suggest that one of the therapeutic effects of glucosamine sulfate is to down - regulate the expressions of u - PA , P05121 , P08253 and P14780 that underlie the destruction of articular cartilage in the early stage of OA , and therefore to delay the joint failure .", "Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy . Sustained cardiac pressure overload induces hypertrophy and pathological remodeling , frequently leading to heart failure . Genetically engineered hyperstimulation of guanosine 3 ', 5 '- cyclic monophosphate ( cGMP ) synthesis counters this response . Here , we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase - 5A ( O76074 ) inhibitor ( sildenafil ) suppresses chamber and myocyte hypertrophy , and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction . ___MASK100___ also reverses pre - established hypertrophy induced by pressure load while restoring chamber function to normal . cGMP catabolism by O76074 increases in pressure - loaded hearts , leading to activation of cGMP - dependent protein kinase with inhibition of O76074 . O76074 inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load ( the calcineurin / NFAT , phosphoinositide - 3 kinase ( PI3K ) / Akt , and P27361 / 2 signaling pathways ) . But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo , suggesting upstream targeting of these pathways . O76074 inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling .", "The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .", "Oral administration of an angiotensin - converting enzyme 2 activator ameliorates diabetes - induced cardiac dysfunction . We evaluated the hypothesis that activation of endogenous angiotensin - converting enzyme ( P12821 ) 2 would improve cardiac dysfunction induced by diabetes . Ten days after diabetes induction ( streptozotocin , 50 mg / kg , i . v . ) , male Wistar rats were treated with the Q9BYF1 activator 1 -[[ 2 -( dimethylamino ) ethyl ] amino ]- 4 -( hydroxymethyl )- 7 -[[( 4 - methylphenyl ) sulfonyl ] oxy ]- 9H - xanthen - 9 - one ( XNT , 1 mg / kg / day , gavage ) or saline ( control ) for 30 days . Echocardiography was performed to analyze the cardiac function and kinetic fluorogenic assays were used to determine cardiac P12821 and Q9BYF1 activities . Cardiac Q9BYF1 , P12821 , Mas receptor , AT ( 1 ) receptor , AT ( 2 ) receptor and collagen types I and III mRNA and Q9BYF1 , P12821 , Mas , AT ( 1 ) receptor , AT ( 2 ) receptor , P27361 / 2 , Akt , AMPK - α and AMPK - β ( 1 ) protein were measured by qRT - PCR and western blotting techniques , respectively . Histological sections of hearts were analyzed to evaluate the presence of hypertrophy and fibrosis . Diabetic animals presented hyperglycemia and diastolic dysfunction along with cardiac hypertrophy and fibrosis . XNT treatment prevented further increase in glycemia and improved the cardiac function , as well as the hypertrophy and fibrosis . These effects were associated with increases in cardiac Q9BYF1 / P12821 ratios ( activity : ~ 26 % ; mRNA : ~ 113 % ; and protein : ~ 188 % ) and with a decrease in AT ( 1 ) receptor expression . Additionally , XNT inhibited P27361 / 2 phosphorylation and prevented changes in AMPK - α and AMPK - β ( 1 ) expressions . XNT treatment did not induce any significant change in AT ( 2 ) receptor and Akt expression . These results indicate that activation of intrinsic cardiac Q9BYF1 by oral XNT treatment protects the heart against diabetes - induced dysfunction through mechanisms involving P12821 , Q9BYF1 , P27361 / 2 , AMPK - α and AMPK - β ( 1 ) modulations .", "DB01169 ( ATO ) and Q02750 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells . Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras - mitogen - activated protein kinase ( MAPK ) can confer an aggressive , apoptosis - resistant phenotype to leukemia cells . In this study , we report that acute promyelocytic leukemia ( APL ) cells exploit the Ras - MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad , delaying arsenic trioxide ( ATO ) - induced apoptosis . Both in APL cell line NB4 and in APL primary blasts , the inhibition of extracellular signal - regulated kinases 1 / 2 ( P27361 / 2 ) and Bad phosphorylation by Q02750 inhibitors enhanced apoptosis in ATO - treated cells . We isolated an arsenic - resistant NB4 subline ( NB4 - As ( R ) ) , which showed stronger P27361 / 2 activity ( 2 . 7 - fold increase ) and Bad phosphorylation ( 2 . 4 - fold increase ) compared to parental NB4 cells in response to ATO treatment . Upon ATO exposure , both NB4 and NB4 - As ( R ) cell lines doubled protein levels of the death antagonist Bcl - xL , but the amount of free Bcl - xL that did not heterodimerize with Bad was 1 . 8 - fold greater in NB4 - As ( R ) than in the parental line . Q02750 inhibitors dephosphorylated Bad and inhibited the ATO - induced increase of Bcl - xL , overcoming ATO resistance in NB4 - As ( R ) . These results may provide a rationale to develop combined or sequential Q02750 inhibitors plus ATO therapy in this clinical setting .", "Counteraction between angiotensin II and angiotensin -( 1 - 7 ) via activating angiotensin type I and Mas receptor on rat renal mesangial cells . In the updated concept of renin - angiotensin system ( DB01367 ) , it contains the angiotensin converting enzyme ( P12821 ) - angiotensin ( Ang ) II - angtiogensin type 1 receptor ( AT1 ) axis and the angiotensin - converting enzyme - related carboxypeptidase ( Q9BYF1 ) - Ang -( 1 - 7 )- Mas axis . The former axis has been well demonstrated performing the vasoconstrictive , proliferative and pro - inflammatory functions by activation of AT1 receptors , while the later new identified axis is considered counterbalancing the effects of the former . The present study is aimed at observing the interaction between Ang -( 1 - 7 ) and Ang II on cultured rat renal mesangial cells ( MCs ) . RT - PCR , Western blot and immunofluorescent staining and confocal microscopy results showed that both AT1 and Mas receptor were co - distributed in rat renal MCs . Ang -( 1 - 7 ) showed similar effects on Ang II in cultured MCs that stimulated phosphorylated extracellular signal - regulated kinase ( P29323 ) 1 / 2 phosphorylation and transforms growth factor - β1 synthesis , and cell proliferation and extracellular matrix synthesis . Co - treatment of the cell with Ang -( 1 - 7 ) and Ang II , Ang -( 1 - 7 ) counteracted AngII - induced effects in a concentration dependent manner , but failed to alter the changes induced by endothelin - 1 . The stimulating effect of Ang II was mediated by AT1 receptor while all the effects of Ang -( 1 - 7 ) were blocked by Mas receptor antagonist A - 779 , but not by AT1 receptor antagonist losartan or P50052 receptor antagonist PD123319 . These results suggest that Ang -( 1 - 7 ) and Ang II specifically interact with each other on rat renal MCs via activation of their specific receptors , Mas and AT1 receptor respectively .", "Multiple antigenic polypeptide composed of heparanase B ‑ cell epitopes shrinks human hepatocellular carcinoma in mice . The purpose of this study was to evaluate the anti ‑ growth effect of the self ‑ designed multiple antigenic polypeptide ( Q96HU1 ) vaccine comprising B ‑ cell epitopes of heparanase ( Q9Y251 ) on HCC97 ‑ H hepatocellular carcinoma ( HCC ) in mice . The polyclonal antibodies against the B ‑ cell epitopes of Q9Y251 were prepared by immunizing rabbits with freshly synthesized Q96HU1 vaccine . HCC ‑ bearing models were constructed on BALB / c nude mice . Anti ‑ Q96HU1 antibodies were administrered to the models to assess the effects on Q9Y251 activity , HCC growth , the expression of P15692 / P09038 and the value of micro ‑ vessel density ( P53602 ) . The anti ‑ Q96HU1 antibodies were harvested , purified and identified . These antibodies were able to specifically bind with the dominant epitopes of the precursor protein and large subunit monomer of Q9Y251 , decrease Q9Y251 activity , suppress the expressions of P15692 and P09038 , reduce the P53602 , and markedly shrink the HCC volume . Based on these findings , Q96HU1 vaccine based on the B ‑ cell epitopes of Q9Y251 seemed to provide theoretical evidence for further study of the synthesized Q9Y251 Q96HU1 vaccine in the treatment of HCC .", "P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .", "SnoN / SkiL expression is modulated via arsenic trioxide - induced activation of the PI3K / AKT pathway in ovarian cancer cells . SnoN / SkiL ( TGFβ regulator ) is dysregulated in ovarian cancer , a disease associated with acquired drug - resistance . DB01169 ( As₂O₃ , used in treating APL ) induces SnoN to oppose the apoptotic response in ovarian cancer cells . We now report that As₂O₃ increases phosphorylation of P00533 / p66ShcA and P00533 degradation . As₂O₃ activates Src ( Y416 ) whose activity ( inhibited by Q99463 ) modulates P00533 activation , its interaction with Shc / Grb2 , and p - AKT . Inhibition of PI3K reduces SnoN and cell survival . Although P00533 or P28482 siRNA did not alter SnoN expression , As₂O₃ - induced cleaved PARP was reduced together with increased P98170 . Collectively , As₂O₃ mediates an initial rise in pY - Src ( 416 ) to regulate the PI3K / AKT pathway which increases SnoN and cell survival ; these early events may counter the cell death response associated with increased pY - P00533 / MAPK activation .", "C . elegans vulval development as a model system to study the cancer biology of P00533 signaling . Molecular genetic studies of C . elegans vulval development have helped to define an evolutionarily conserved signaling pathway from an P01133 - like ligand through P01133 - receptor , Ras and Q96HU1 kinase to the nucleus . Further studies have identified novel positive regulators such as Q8IVT5 - 1 and Q09428 - 8 / Q5T124 - 2 and negative regulators such as cbl / SLI - 1 . The many negative regulatory proteins might serve to prevent inappropriate signaling , and thus are analogous to tumor suppressor genes .", "___MASK73___ reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin - converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU / ml ) , tissue plasminogen activator ( t - PA ) antigen ( ng / ml ) , and serum P12821 activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37 . 5 mg daily ) and compared them with the values in 15 placebo - treated patients chosen at random . Blood sampling was performed at 07 . 00 h . In the captopril - treated group , serum P12821 activity decreased significantly , from 14 . 0 +/- 0 . 8 to 11 . 5 +/- 1 . 2 IU / L 24 h after captopril therapy ( p < 0 . 01 ) , and those of P05121 activity and t - PA antigen also decreased significantly - from 11 . 9 +/- 2 . 8 to 5 . 5 +/- 2 . 2 IU / ml ( p < 0 . 02 ) and from 9 . 9 +/- 1 . 0 to 7 . 5 +/- 0 . 9 ng / ml ( p < 0 . 05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t - PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .", "Systematic review : diet - gene interactions and the risk of colorectal cancer . BACKGROUND : Diet contributes significantly to colorectal cancer ( CRC ) aetiology and may be potentially modifiable . AIM : To review diet - gene interactions , aiming to further the understanding of the underlying biological pathways in CRC development . METHODS : The PubMed and Medline were systematically searched for prospective studies in relation to diet , colorectal cancer and genetics . RESULTS : In a meta - analysis , no interaction between NAT1 phenotypes and meat intake in relation to risk of CRC was found ( P - value for interaction 0 . 95 ) . We found a trend towards interaction between NAT2 phenotypes and meat intake in relation to risk of CRC . High meat intake was not associated with risk of CRC among carriers of the slow NAT2 phenotype , whereas NAT2 fast acetylators with high meat intake were at increased risk of CRC ( OR = 1 . 25 ; 95 % confidence interval ( CI ) : 0 . 92 - 2 . 01 ) compared with slow acetylators with low meat intake ( reference ) , P - value for interaction = 0 . 07 . Low meat intake in the studied populations may influence the result . Interactions between meat , cruciferous vegetables , fibres , calcium , vitamins , and alcohol and P08183 , P19838 , P09488 , P30711 , P24385 , P11473 , MGTM , P22301 and P37231 are suggested . CONCLUSIONS : A number of interactions between genetic variation and diet are suggested , but the findings need replication in independent , prospective , and well - characterised cohorts before conclusions regarding the underlying biological mechanisms can be reached . When the above criteria are met , studies on diet - gene interactions may contribute valuable insight into the biological mechanisms underlying the role of various dietary items in colorectal carcinogenesis .", "[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK73___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .", "Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK31___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .", "DB01169 induces apoptosis through JNK and P29323 in human mesothelioma cells . Malignant mesothelioma is an aggressive tumor of serosal surfaces , which is refractory to current treatment options . DB01169 ( As2O3 ) is used clinically to treat acute promyelocytic leukemia , and also to inhibit proliferation of several solid tumors including hepatoma , esophageal , and gastric cancer in vitro . Here we found that As2O3 inhibited cell viability of a mesothelioma cell line , NCI - H2052 . As2O3 induced apoptosis of NCI - H2052 cells , which was accompanied by activation of c - Jun NH2 - terminal kinase ( JNK ) 1 / 2 , extracellular signal - regulated kinase ( P29323 ) 1 / 2 , and caspase - 3 . zVAD - fmk , a broad - spectrum caspase inhibitor , inhibited As2O3 - induced apoptosis and activation of caspase - 3 , but not that of P45983 / 2 and P27361 / 2 . Small interfering RNAs ( siRNAs ) targeting P45983 / 2 suppressed As2O3 - induced caspase - 3 activation and apoptosis , indicating that P45983 / 2 regulate As2O3 - induced apoptosis though caspase cascade . Furthermore , P45983 siRNA abrogated As2O3 - induced P45984 phosphorylation and P45984 siRNA abrogated As2O3 - induced P45983 phosphorylation , suggesting that P45983 and P45984 interact with each other . Moreover , P45983 siRNA , but not P45984 siRNA , abrogated As2O3 - induced P27361 / 2 phosphorylation . P45984 siRNA together with PD98059 , a specific MAPK / P29323 kinase inhibitor , suppressed As2O3 - induced apoptosis more significantly than P45984 siRNA alone . These results indicated that As2O3 induces apoptosis of NCI - H2052 cells mainly through P45983 / 2 activation , and that P27361 / 2 is involved in As2O3 - induced apoptosis when P45983 / 2 are inactivated .", "An absolute role of the PKC - dependent NF - kappaB activation for induction of P14780 in hepatocellular carcinoma cells . Matrix metalloproteinases ( MMPs ) play an important role in inflammation , tumor cell invasion , and metastasis . We found that phorbol - 12 - myristate - 13 - acetate ( PMA ) - stimulated invasion of the hepatocellular carcinoma ( HCC ) SNU - 387 and SNU - 398 cells and that PMA induced the secretion of P14780 in the cells , but did not induce the secretion of P08253 . The PMA - induced P14780 secretion was abolished by treatment of a pan - protein kinase C ( PKC ) inhibitor , GF109203X , and an inhibitor of NF - kappaB activation , sulfasalazine , and partly inhibited by treatment of inhibitors of P29323 pathway , PD98059 and U0126 . In addition , the PMA - stimulated activation of the P14780 promoter was completely inhibited by a mutation of the NF - kappaB site within the P14780 promoter , but not completely by mutations of two AP - 1 sites . Moreover , the P14780 induction by P14210 and P01375 was also completely inhibited by GF109203X and sulfasalazine , but not by PD98059 and U0126 . These data demonstrate that the PKC - dependent NF - kappaB activation is absolute for P14780 induction and that the PKC - dependent P29323 activation devotes to increase the expression level of P14780 , in HCC cells .", "A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor - mediated signal transduction . P14324 ( FPPS ) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways . Here we describe a novel role for this enzyme in fibroblast growth factor ( FGF ) - mediated signalling . We demonstrate the binding of FPPS to FGF receptors ( FGFRs ) using the yeast two - hybrid assay , pull - down assays and co - immunoprecipitation . The interaction between FPPS and FGFR is regulated by the cellular metabolic state and by treatment with P09038 . Overexpression of FPPS inhibits P09038 - induced cell proliferation , accompanied by a failure of the P09038 - mediated induction of cyclins D1 and E . Overexpression of FPPS in fibroblasts also promotes increased farnesylation of Ras , and temporally extends P09038 - stimulated activation of the Ras / P29323 ( extracellular - signal - regulated kinase ) cascade . These data suggest that , in addition to its role in isoprenoid biosynthesis , FPPS may function as a modulator of the cellular response to FGF treatment .", "DB01169 - mediated antiplatelet activity : pivotal role of the phospholipase C gamma 2 - protein kinase C - p38 MAPK cascade . DB01169 produces high rates of complete clinical remission in patients with relapsed / refractory acute promyelocytic leukemia . Platelet activation is relevant in a variety of acute thrombotic events and coronary heart diseases . Few studies have examined the effects of arsenic trioxide on platelets , and the mechanisms underlying the signaling pathways remain obscure . The aim of this study was to examine systematically the detailed mechanisms of arsenic trioxide in preventing platelet activation . DB01169 ( 5 micromol / L ) exhibited more potent activity at inhibiting collagen ( 1 microg / mL ) - induced platelet aggregation than other agonists . DB01169 ( 15 and 25 micromol / L ) inhibited collagen - induced platelet activation accompanied by [ Ca (+ 2 )] i mobilization , thromboxane A ( 2 ) ( TxA ( 2 ) ) formation , phospholipase C ( P98160 ) gamma 2 phosphorylation , and protein kinase C ( PKC ) activation . DB01169 ( 15 and 25 micromol / L ) did not significantly affect cyclic nucleotide - induced vasodilator - stimulated phosphoprotein phosphorylation . Moreover , arsenic trioxide markedly inhibited p38 mitogen - activated protein kinase ( MAPK ) but not P45983 / 2 or P28482 phosphorylation in washed platelets . DB01169 also markedly reduced hydroxyl radical ( OH (.) ) formation in the erythrocyte sedimentation rate ( P03372 ) study . The most important findings of this study suggest that the inhibitory effect of arsenic trioxide possibly involves inhibition of the P98160 gamma 2 - PKC - p38 MAPK cascade , thereby leading to inhibition of [ Ca (+ 2 )] i or free radical formation , and finally the inhibition of platelet aggregation .", "Molecular targeting therapy against promyelocytic leukemia protein using arsenic acids in experimental intracranial medulloblastoma . Our previous study using human Daoy medulloblastoma cells showed that the promyelocytic leukemia ( P29590 ) gene was significantly upregulated ( 2 . 5 - fold ) in cells positive to prominin - 1 antigen ( CD133 ) , a possible marker for cancer initiating cells . DB01169 ( As ( 2 ) O ( 3 ) ) is known to degrade P29590 protein and has been used for the treatment of patients with acute P29590 . In the present study , the effect of P29590 targeting therapy with As ( 2 ) O ( 3 ) and cytarabine ( DB00987 ) on Daoy medulloblastoma cell proliferation was investigated . Daoy cells were pretreated with As ( 2 ) O ( 3 ) for 6 weeks . The As ( 2 ) O ( 3 )- pretreated Daoy cells were cultured in medium containing DB00987 and cell viability was examined . Next , the As ( 2 ) O ( 3 )- pretreated Daoy cells were inoculated into the nude mouse brain and the effect of DB00987 on the tumor size was evaluated . A significant increase in chemosensitivity to DB00987 was observed in the As ( 2 ) O ( 3 )- pretreated Daoy cells in both in vitro and in vivo conditions . P29590 and P24385 ( cyclin D1 ) protein expression of Daoy medulloblastoma cells was downregulated by As ( 2 ) O ( 3 ) treatment . P29590 has been proposed as a novel therapeutic target to eradicate quiescent leukemia - initiating cells , and P29590 - expressing CD133 - positive cells are similarly a potential therapeutic target of treatment for medulloblastoma .", "DB01169 concentration determines the fate of Ewing ' s sarcoma family tumors and neuroblastoma cells in vitro . DB01169 ( As ( 2 ) O ( 3 ) ) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner . We assessed the effects of As ( 2 ) O ( 3 ) in CADO - ES Ewing ' s sarcoma ( ES ) , JK - GMS peripheral primitive neuroectodermal tumor ( PNET ) , and SH - SY5Y neuroblastoma cells , as they share common histogenetic backgrounds . As ( 2 ) O ( 3 ) at low concentrations ( 0 . 1 - 1 microM ) induced SH - SY5Y differentiation , and whereas PNET cells acquired a slightly differentiated phenotype , change was minimal in ES cells . P28482 ( P28482 ) was activated at low As ( 2 ) O ( 3 ) concentrations , and PD98059 , an inhibitor of MEK - 1 , blocked SH - SY5Y cell differentiation by As ( 2 ) O ( 3 ) . High concentrations ( 2 - 10 microM ) of As ( 2 ) O ( 3 ) induced the apoptosis in all three cell lines , and this was accompanied by the activation of c - jun N - terminal kinase . The generation of H ( 2 ) O ( 2 ) and activation of caspase 3 were identified as critical components of As ( 2 ) O ( 3 )- induced apoptosis in all of the above cell lines . P09038 enhanced As ( 2 ) O ( 3 )- induced apoptosis in JK - GMS cells . The overall effects of As ( 2 ) O ( 3 ) strongly suggest that it has therapeutic potential for the treatment of ES / PNET .", "O75915 is required for arsenic trioxide induced apoptosis in HeLa and MCF - 7 cells via reactive oxygen species and mitochondria linked signal pathway . DB01169 , emerging as a standard therapy for refractory acute promyelocytic leukemia , induces apoptosis in a variety of malignant cell lines . O75915 , a novel retinoic acid - inducible gene , is known to be involved in apoptosis induced by various agents , for example , 12 - O - tetradecanoylphorbol 13 - acetate , N - 4 - hydroxy - phenyl - retinamide and arsenic trioxide . However , the molecular mechanisms underlying how O75915 gene is functionally involved in apoptosis remain largely unknown . Herein , our studies demonstrated that treatment of arsenic trioxide produced apoptosis in HeLa and MCF - 7 cells in a dose - dependent manner and paralleled with increased O75915 expression . O75915 expression was dependent upon generation of intracellular reactive oxygen species induced by arsenic trioxide . Knockdown of O75915 attenuated arsenic trioxide induced apoptosis , and was accompanied by significantly reduced activity of caspase - 9 , enhanced Bad phosphorylation and inhibited Q02750 / 2 , P27361 / 2 and JNK phosphorylations . DB01169 induced loss of mitochondrial transmembrane potential was O75915 - dependent . These findings suggest that O75915 may serve as a pro - apoptotic molecule to mediate arsenic trioxide triggered apoptosis via a reactive oxygen species and mitochondria - associated signal pathway .", "___MASK43___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK43___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK43___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK43___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .", "[ Quality of life and psychosocial factors during treatment with antihypertensive drugs . A comparison of captopril and quinapril in geriatric patients ] . BACKGROUND : There is an increasing prevalence of older adults ( > 65 years ) with hypertension and the need for antihypertensive medication . It is well established that elderly hypertensive patients benefit from drug treatment with regards to cardiovascular morbidity and mortality . Due to the comorbidity and reduced quality of life ( QOL ) in the elderly , drug - induced changes of well - being and QOL are especially important to maintain compliance and social abilities . Whereas in most studies different antihypertensive agents exerted similar influences on QOL , ___MASK73___ was found to be superior to other antihypertensives in some trials . PATIENTS AND METHOD : In this controlled non - randomized study 100 elderly hypertensive patients ( mean age 75 . 4 +/- 7 . 2 years ; 56 % female ) were treated with ___MASK73___ ( 25 - 50 mg twice daily ) or the newer P12821 - inhibitor Quinapril ( 5 - 20 mg per day ) . Blood pressure and QOL were recorded initially and after 6 months , assessment of QOL was based on a validated questionnaire ( P98160 ) . RESULTS : Blood pressure fell from 153 / 82 mm Hg to 142 / 80 mm Hg with ___MASK73___ and 154 / 82 to 142 / 80 mm Hg [ corrected ] with Quinapril . An improvement of QOL was only seen with Quinapril , mainly due to better mood and lower depression scores . Analysis of underlying psychosocial factors on QOL found lack of social support , female sex and a current life event as additional significant negative influences on QOL . CONCLUSION : A favorable antidepressive effect of Quinapril in elderly hypertensive patients is concluded and should be studied in further investigations .", "Identification of B cells participated in the mechanism of postmenopausal women osteoporosis using microarray analysis . To further understand the molecular mechanism of lymphocytes B cells in postmenopausal women osteoporosis . Microarray data ( GSE7429 ) were downloaded from Gene Expression Omnibus , in which B cells were separated from the whole blood of postmenopausal women , including 10 with high bone mineral density ( BMD ) and 10 with low BMD . Differentially expressed genes ( DEGs ) between high and low BMD women were identified by Student ' s t - test , and P < 0 . 01 was used as the significant criterion . Functional enrichment analysis was performed for up - and down - regulated DEGs using KEGG , REACTOME , and Gene Ontology ( GO ) databases . Protein - protein interaction network ( PPI ) of up - and down - regulated DEGs was respectively constructed by Cytoscape software using the STRING data . Total of 169 up - regulated and 69 down - regulated DEGs were identified . Functional enrichment analysis indicated that the genes ( Q9BY32 , P31939 , P11172 , P00492 , Q12887 and Q7KZN9 ) might participate in metabolic pathways , Q02779 and P80192 might participate in the activation of P45985 activity , Q12887 and Q7KZN9 might involve in mitochondrial electron transport , and P31939 , P11172 and P00492 might involve in transferase activity . P27361 , Q9BY32 , P31939 , P11172 and P00492 with a higher degree in PPI network were identified . P27361 , Q02779 , P80192 , Q12887 , Q7KZN9 , P31939 , P11172 and P00492 might participate in the pathogenesis of osteoporosis .", "Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells . Q9Y251 is a heparan sulfate - degrading endoglycosidase expressed by mature monocytes and myeloid cells , but not by immature hematopoietic progenitors . Q9Y251 gene expression is upregulated during differentiation of immature myeloid cells . P29590 - RARalpha and Q05516 - RARalpha fusion gene products associated with acute promyelocytic leukemia abrogate myeloid differentiation and heparanase expression . AML - Eto , a translocation product associated with AML FAB M2 , also downregulates heparanase gene expression . The common mechanism that underlines the activity of these three fusion gene products involves the recruitment of histone deacetylase complexes to specific locations within the DNA . We found that retinoic acid that dissociates P29590 - RARalpha from the DNA , and which is used to treat acute promyelocytic leukemia patients , restores heparanase expression to normal levels in an acute promyelocytic leukemia cell line . The retinoic acid effects were also observed in primary acute promyelocytic leukemia cells and in a retinoic acid - treated acute promyelocytic leukemia patient . Histone deacetylase inhibitor reverses the downregulation of heparanase expression induced by the AML - Eto fusion gene product in M2 type AML . In summary , we have characterized a link between leukomogenic factors and the downregulation of heparanase in myeloid leukemic cells .", "OSU - 03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood - Brain Barrier : Implications for Anti - Cancer Therapies . We examined the interaction between OSU - 03012 ( also called AR - 12 ) with phosphodiesterase 5 ( O76074 ) inhibitors to determine the role of the chaperone glucose - regulated protein ( P11021 ) / P11021 / P11021 in the cellular response . ___MASK100___ ( Viagra ) interacted in a greater than additive fashion with OSU - 03012 to kill stem - like GBM cells . Treatment of cells with OSU - 03012 / sildenafil : abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of P11021 and other HSP70 and HSP90 family chaperone proteins . Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced Q9NZJ5 - eIF2α - P18848 - P35638 signaling and was blocked by P11021 over - expression . In vivo OSU - 03012 / sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of P08183 and Q9UNQ0 in the normal brain . The combination of OSU - 03012 / sildenafil synergized with low concentrations of sorafenib to kill tumor cells , and with lapatinib to kill P00533 over - expressing tumor cells . In multiplex assays on plasma and human tumor tissue from an OSU - 03012 / sildenafil treated mouse , we noted a profound reduction in uPA signaling and identified FGF and P23458 / 2 as response biomarkers for potentially suppressing the killing response . Inhibition of FGFR signaling and to a lesser extent P23458 / 2 signaling profoundly enhanced OSU - 03012 / sildenafil lethality .", "Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .", "DB01169 phosphorylates c - Fos to transactivate P38936 ( P38936 / CIP1 ) expression . An infamous poison , arsenic also has been used as a drug for nearly 2400 years ; in recently years , arsenic has been effective in the treatment of acute promyelocytic leukemia . Increasing evidence suggests that opposite effects of arsenic trioxide ( ATO ) on tumors depend on its concentrations . For this reason , the mechanisms of action of the drug should be elucidated , and it should be used therapeutically only with extreme caution . Previously , we demonstrated the opposing effects of P27361 / 2 and JNK on P38936 ( P38936 / CIP1 ) ( P38936 ) expression in response to ATO in A431 cells . In addition , JNK phosphorylates c - Jun ( DB00133 ( 63 / 73 ) ) to recruit Q15583 / Q13547 to suppress P38936 gene expression . Presently , we demonstrated that a high concentration of ATO sustains P27361 / 2 phosphorylation , and increases c - Fos biosynthesis and stability , which enhances P38936 gene expression . Using site - directed mutagenesis , a DNA affinity precipitation assay , and functional assays , we demonstrated that phosphorylation of the C - terminus of c - Fos ( DB00156 ( 232 ) , DB00156 ( 325 ) , DB00156 ( 331 ) , and DB00133 ( 374 ) ) plays an important role in its binding to the P38936 promoter , and in conjunction with N - terminus phosphorylation of c - Fos ( DB00133 ( 70 ) ) to transactivate P38936 promoter expression . In conclusion , a high concentration of ATO can sustain P27361 / 2 activation to enhance c - Fos expression , then dimerize with dephosphorylated c - Jun ( DB00133 ( 63 / 73 ) ) and recruit p300 / CBP to the Sp1 sites ( - 84 /- 64 ) to activate P38936 gene expression in A431 cells .", "p38 Mitogen - activated protein kinase is required for glucosamine - induced endothelial nitric oxide synthase uncoupling and plasminogen - activator inhibitor expression . BACKGROUND : Hexosamine biosynthetic pathway ( HBP ) is implicated in increased plasminogen activator inhibitor - 1 ( P05121 ) , and endothelial nitric oxide synthase ( P29474 ) dysfunction in diabetes . ___MASK15___ ( GlcN ) that directly activates HBP is a dietary supplement and is clinically used to treat osteoarthritis despite uncertain efficacy and adverse cardiovascular effects observed in animal models . p38 mitogen - activated protein kinase ( p38mapk ) has been shown to be involved in HBP - mediated biological processes . The aim of the present study was to investigate the role of p38mapk in GlcN - induced endothelial P05121 expression and P29474 dysfunction . METHODS AND RESULTS : In cultured human endothelial cells , GlcN time - and concentration - dependently increased P05121 protein level that was further enhanced by tumor necrosis factor ( P01375 ) - α , which was accompanied by a transient synergistic activation of p38mapk . The stimulation of P05121 by GlcN alone or by GlcN and P01375 - α in combination was inhibited by the specific inhibitor of p38mapk , but not that of JNK or P27361 / 2 . Moreover , in isolated mouse aortas , GlcN caused P29474 uncoupling resulting in enhanced superoxide and decreased NO production , as well as impaired endothelium - dependent relaxations , which were also fully prevented by the p38mapk inhibitor . CONCLUSIONS : HBP activated by GlcN increases P05121 expression and P29474 uncoupling depending on p38mapk , which not only explains hyperglycemic vascular complications , but also may bring into question the clinical use of GlcN . The present results , support currently ongoing clinical application of p38mapk inhibitor in patients with cardiovascular disease .", "DB01169 inhibits osteosarcoma cell invasiveness via MAPK signaling pathway . DB01169 ( As ( 2 ) O ( 3 ) ) is an active ingredient in traditional Chinese medicine . Recent studies showed that it causes apoptosis in several cancer cells . However , research of As ( 2 ) O ( 3 ) in osteosarcoma is sparse . In our present study , an inhibitory effect of As ( 2 ) O ( 3 ) on osteosarcoma cell adhesion and metastasis was observed with a cell adhesion , migration and invasion test . The impact of As ( 2 ) O ( 3 ) on the activities of P14780 and MAPK pathway - related downstream factors was analyzed by western blotting . Our results showed that As ( 2 ) O ( 3 ) significantly inhibited motility , migration and invasion in Q9UKB1 and MNNG cells in a concentration - dependent manner at concentrations ranging from 0 . 5 - 2 μM , and led to cytoskeletal rearrangements . As ( 2 ) O ( 3 ) exerted an inhibitory effect on the phosphorylation of P27361 / 2 and MEK , which are the members of the MAPK family . Additionally , treatment with As ( 2 ) O ( 3 ) in combination with inhibitors specific for MEK ( U0126 ) in Q9UKB1 and MNNG cells resulted in a marked inhibition of cell invasion and As ( 2 ) O ( 3 ) could significantly reduce PMA - induced invasion . In conclusion , we demonstrate the inhibitory effects of As ( 2 ) O ( 3 ) on the invasiveness of Q9UKB1 and MNNG cells , which may be due at least partly to inactivation of the MAPK signaling pathway .", "Activation of a mitogen - activated protein kinase ( P28482 ) by the 5 - hydroxytryptamine1A receptor is sensitive not only to inhibitors of phosphatidylinositol 3 - kinase , but to an inhibitor of phosphatidylcholine hydrolysis . A variety of receptors coupled to GTP - binding regulatory proteins ( G proteins ) initiate signals that culminate in activation of the mitogen - activated protein kinases P27361 and P28482 . We demonstrate here that the human P08908 receptor expressed in Chinese hamster ovary cells similarly promotes activation of P27361 and P28482 , but that the pathway used does not conform entirely to those proposed previously for G protein - coupled receptors . Activation of P28482 by the P08908 receptor - selective agonist 8 - hydroxy - N , N - dipropyl - 2 - aminotetralin hydrobromide ( 8 - OH - DPAT ) was inhibited completely by pertussis toxin and substantially by prolonged treatment of cells with phorbol 12 - myristate 13 - acetate . The implied requirement for protein kinase C , however , was negated in studies with bisindolylmaleimide and Ro - 31 - 8220 , which , although completely inhibiting activation of P28482 by phorbol ester , had no impact on activation by 8 - OH - DPAT . The anticipated inhibition by the tyrosine kinase inhibitors genistein and herbimycin A , moreover , was marginal at best . As expected for a Gi - coupled receptor , the inhibitors of phosphatidylinositol 3 - kinase wortmannin and LY294002 inhibited activation of P28482 , albeit only partly ( 70 % ) . Of significance , an inhibitor of a phosphatidylcholine - specific phospholipase C , tricyclodecan - 9 - yl - xanthogenate ( D609 ) , caused a similar degree of inhibition . When the two types of inhibitors were combined , an almost complete inhibition was achieved . Our data suggest that phosphatidylinositol 3 - kinase and phosphatidylcholine - specific phospholipase C represent components of different , but partly overlapping pathways that can account almost entirely for the activation of P28482 by the P08908 receptor .", "Accumulation of biglycan and perlecan , but not versican , in lesions of murine models of atherosclerosis . Proteoglycan accumulation within the arterial intima has been implicated in lipoprotein retention and in atherosclerosis progression in humans . Two commonly studied murine models of atherosclerosis , the apolipoprotein E ( apoE ) - deficient ( apoE -/- ) mouse and the low density lipoprotein receptor - deficient ( P01130 -/- ) mouse , develop arterial lesions similar to those of human atherosclerosis . However , specific proteoglycan classes that accumulate in lesions of these mice and their relation to the retention of specific apolipoproteins have not been previously determined . In this report , we characterized the distribution of proteoglycans ( versican , biglycan , and perlecan ) and apolipoproteins ( apoB , apoA - I , and apoE ) in proximal aortic lesions of chow - fed apoE -/- and P01130 -/- mice at 10 , 52 , and 73 weeks of age . We observed that similar to the apoE -/- mice , the P01130 -/- mice develop intermediate and advanced plaques within 52 weeks of age . P98160 and biglycan ( both are proteoglycans ) appeared early in lesion development with distinct expression patterns as the plaques advanced . Versican , a major proteoglycan detected in human plaques , was mostly absent in both strains . P02647 and apoB were detected in early through advanced lesions in regions of proteoglycan accumulation in both strains . Our results indicate that proteoglycans may contribute to the retention of lipoproteins at the earliest stage of atherosclerosis in murine models of atherosclerosis .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK28___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .", "___MASK15___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK15___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .", "Inhibition of P78536 reduces hypoxia - induced brain tumor cell invasiveness . The membrane - anchored metalloproteinase tumor necrosis factor - alpha - converting enzyme ( P78536 / a disintegrin and metalloproteinase [ ADAM ] 17 ) is key in proteolytic ectodomain shedding of several membrane - bound growth factors , cytokines and receptors . The expression and activity of P78536 increases under some pathological conditions including stroke , and promotes neural progenitor cell migration and contributes to stroke - induced neurogenesis . Hypoxia initiates cellular invasive processes that occur under both physiological and pathological conditions such as invasion and metastasis of some tumors . In the present study , we sought to elucidate whether P78536 contributes to brain tumor invasion . To this end , we examined the role of P78536 in the invasiveness of two different brain tumor cell lines , 9L rat gliosarcoma and U87 human glioma , under normoxic and hypoxic conditions . Additionally , we tested the effects of P78536 suppression on in vitro tumor cell invasion by means of P78536 proteolytic inhibitors and specific small interfering RNA . We found that tumor cells upregulated P78536 expression under hypoxia , and that P78536 activity correlated with increased tumor cell invasion . Conversely , suppression of P78536 proteolysis decreased invasiveness induced by hypoxia in 9L and U87 cells . Furthermore , the contribution of P78536 to tumor invasion was independent of matrix metalloproteinase ( MMP ) - 2 and P14780 activity . P78536 was also found to activate the epidermal growth factor / phosphoinositide - 3 kinase / serine / threonine kinase signal transduction pathway . Our data suggest that hypoxia - induced P78536 contributes to glioma cell invasiveness through activation of the P00533 signal pathway .", "Synergistic inhibition of colon carcinoma cell growth by Hedgehog - Gli1 inhibitor arsenic trioxide and phosphoinositide 3 - kinase inhibitor LY294002 . The Hedgehog ( Hh ) signaling pathway not only plays important roles in embryogenesis and adult tissue homeostasis , but also in tumorigenesis . Aberrant Hh pathway activation has been reported in a variety of malignant tumors including colon carcinoma . Here , we sought to investigate the regulation of the Hh pathway transcription factor Gli1 by arsenic trioxide and phosphoinositide 3 - kinase ( PI3K ) inhibitor LY294002 in colon carcinoma cells . We transfected cells with siGli1 and observed a significant reduction of Gli1 expression in HCT116 and HT29 cells , which was confirmed by quantitative real - time polymerase chain reaction and Western blots . Knocking down endogenous Gli1 reduced colon carcinoma cell viability through inducing cell apoptosis . Similarly , knocking down Gli2 using short interfering RNA impaired colon carcinoma cell growth in vitro . To elucidate the regulation of Gli1 expression , we found that both Gli inhibitor arsenic trioxide and PI3K inhibitor LY294002 significantly reduced Gli1 protein expression and colon carcinoma cell proliferation . DB01169 treatment also reduced Gli1 downstream target gene expression , such as Bcl2 and P24385 . More importantly , the inhibition of Hedgehog - Gli1 by arsenic trioxide showed synergistic anticancer effect with the PI3K inhibitor LY294002 in colon carcinoma cells . Our findings suggest that the Hh pathway transcription factor Gli1 is involved in the regulation of colon carcinoma cell viability . Inhibition of Hedgehog - Gli1 expression by arsenic trioxide and PI3K inhibitor synergistically reduces colon cancer cell proliferation , indicating that they could be used as an effective anti - colon cancer combination therapy .", "EVI1 abrogates interferon - alpha response by selectively blocking P29590 induction . EVI1 is an oncogene frequently associated with chronic and acute myeloid leukemia . In hematopoietic cells , EVI1 impairs several pathways including proliferation , differentiation , and apoptosis . Interferon - alpha ( IFN - alpha ) is a powerful cytokine that controls the immune response and limits the expansion of several tissues including bone marrow . These properties contribute to the effectiveness of IFN - alpha in the treatment of many neoplastic disorders especially chronic myeloid leukemia . We report here that in murine hematopoietic progenitors the expression of EVI1 completely abrogates the antiproliferative and apoptotic effects of IFN - alpha . EVI1 does not repress the JAK / P35610 signaling pathway or the activation of many IFN - responsive genes . On the contrary , EVI1 prolongs the phosphorylation of P42224 and the activation of an IFN - dependent reporter gene . However , EVI1 specifically represses the IFN - dependent induction of the tumor suppressor P29590 and blocks the apoptotic pathways activated by P29590 . We show that the position of the ISRE , which is located within the first exon of P29590 , is critical to block P29590 induction by IFN - alpha . The relocation of the ISRE to a position upstream of the transcription start site is sufficient to re - establish the response to IFN in the presence of EVI1 . Our data suggest that stabilized P42224 phosphorylation and prolonged binding of the P42224 complex to the first exon could impair P29590 transcription and inhibit the activation of P29590 - dependent apoptotic pathways resulting in loss of IFN response . These results point to a novel mechanism utilized by an oncogene to escape normal cell response to growth - controlling cytokines .", "Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .", "DB01169 induces cardiac fibroblast apoptosis in vitro and in vivo by up - regulating TGF - β1 expression . DB01169 ( As2O3 ; ATO ) is clinically effective in treating acute promyelocytic leukemia ( APL ) ; however , it frequently causes cardiotoxic effects . This study was designed to investigate whether ATO could induce apoptosis of cardiac fibroblasts ( CFs ) that play very important roles in maintaining the structure integrity and function of the heart . Cardiac fibroblasts from guinea pigs administered with ATO ( 1mg / kgbw ) were used to test the pro - apoptotic role of ATO in vivo . The current study demonstrated that ATO induced morphological characteristics of apoptosis and P42574 activation in CFs of guinea pigs along with a significant up - regulation in TGF - β1 protein expression , Bax / Bcl - 2 ratio and P27361 / 2 phosphorylation . In vitro MTT assay showed that ATO remarkably reduced the viability of cultured cardiac fibroblasts ( NRCFs ) from neonatal rat in a concentration - and time - dependent manner . Consistent with the notions in vivo , ATO significantly induced the apoptosis in NRCFs , dramatically up - regulated TGF - β1 protein level and Bax / Bcl - 2 ratio in a time - dependent fashion and activated P42574 and P27361 / 2 . Finally , pretreatment with LY364947 , an inhibitor of TGF - β signaling could apparently reverse these changes . We therefore conclude that TGF - β is functionally linked to P27361 / 2 and that TGF - β signaling is responsible for ATO - induced CFs apoptosis , which provides a novel mechanism of ATO related cardiac toxicology .", "Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .", "A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK43___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .", "Metallothionein prevention of arsenic trioxide - induced cardiac cell death is associated with its inhibition of mitogen - activated protein kinases activation in vitro and in vivo . Cardiotoxicity induced by arsenic trioxide has become a serious blockade of clinical applications of this effective anticancer agent . The general mechanism responsible for arsenic cardiotoxicity has been attributed to its induction of oxidative stress . Metallothionein ( MT ) has been extensively proven to be a potent endogenous antioxidant that protects heart against oxidative stress - induced cardiac damage . To investigate whether and how MT protects against arsenic cardiotoxicity , MT - overexpressing H9c2 ( MT - H9c2 ) cardiac cells and transgenic ( MT - TG ) mice with their corresponding controls were exposed to the clinical relevant dose of arsenic trioxide . Cardiac cell apoptosis was detected by molecular indices , including the cleavage of caspase 3 and caspase 12 , Bax / Bcl2 expression ratio , P35638 expression and / or confirmed by a terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling assay . DB01169 dose - and time - dependently induced cardiac cell death in H9c2 cells with a significant activation of major MAPK subfamily members such as P27361 / 2 , JNK and p38 , but not in MT - H9c2 cells . Importantly , the protective effect of MT on arsenic trioxide - induced apoptotic cell death was completely recaptured in the heart of MT - TG with a significant prevention of MAPKs activation . These results indicate that arsenic trioxide - upregulated MAPKs might play important role in arsenic trioxide - induced apoptotic cell death in cardiac cells both in vivo and in vitro , and MT ' s suppression of arsenic trioxide apoptotic effect was associated with the inhibition of MAPK activation . Therefore , selective elevation of cardiac MT levels with pharmacological approaches may be a potential strategy for the prevention of arsenic cardiotoxicity .", "___MASK38___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .", "Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK84___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .", "Antitumor activity of arsenic trioxide on retinoblastoma : cell differentiation and apoptosis depending on arsenic trioxide concentration . PURPOSE : DB01169 ( ATO ) targets multiple pathways in malignant cells , resulting in the promotion of differentiation or in the induction of apoptosis . The antitumor activity of ATO on retinoblastoma was investigated . METHODS : Human retinoblastoma cells were incubated with various ATO concentrations . The antiproliferative effect of ATO was evaluated by 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide assay , and the effect of ATO on cell - cycle progression was validated by flow cytometry . At a low concentration , the ATO - induced differentiation of retinoblastoma cells was evaluated by neurofilament expression and extracellular signal - regulated kinase ( P29323 ) 1 / 2 activation , which was confirmed by the inhibition of P27361 / 2 . At a high concentration , ATO - induced H ( 2 ) O ( 2 ) production was investigated with the cell - permeable fluorescent dye 2 ' 7 '- dichlorofluorescein - diacetate , and the relationship of ATO - induced H ( 2 ) O ( 2 ) production with caspase - 3 - dependent apoptosis was validated by Western blot and 4 ' 6 - diamidino - 2 - phenolindole staining , which was confirmed by reactive oxygen species ( ROS ) inhibition . The effect of ATO on tumor formation was assessed with an orthotopic animal model of retinoblastoma . RESULTS : The antitumor activity of ATO in retinoblastoma was related to two main mechanisms , differentiation and apoptosis , which were determined by the level of ATO . At a low dose ( < or = 1 microM ) , ATO induced the differentiation of retinoblastoma cells through P27361 / 2 activation , whereas ROS generation by a high dose ( > or = 2 microM ) of ATO induced apoptosis in retinoblastoma cells . Moreover , ATO at low and high doses effectively inhibited tumor formation . CONCLUSIONS : These results suggest that ATO can be used as an effective alternative therapeutic for the treatment of retinoblastoma .", "Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats . P14324 ( FPPS ) , an essential enzyme in the mevalonate pathway , was reported to be upregulated in young spontaneously hypertensive rats ( SHR ) when compared with Wistar - Kyoto ( WKY ) rats , and this was accompanied by development of left ventricular hypertrophy . Five - week - old rats were daily gavaged with vehicle or an FPPS inhibitor ( alendronate , 1 or 10 mg / kg ) and blood pressures was monitored by the tail - cuff method every other week . Twelve weeks of alendronate treatment attenuated the left ventricular weight to body weight ratio ( LVW / BW ) , hydroxyproline content , collagen deposition in the interstitia , and gene expression of atrial natriuretic peptide , B - type natriuretic peptide , and procollagen type I / III in the SHR left ventricle , all of which were significantly higher in SHRs than in WKY rats . Furthermore , long - term treatment with an FPPS inhibitor significantly reduced RhoA activation , P29323 phosphorylation , and TGF - beta1 expression in the SHR left ventricle , all of which were upregulated more in SHRs than in WKY rats . In conclusion , chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis , and the suppression of P27361 / 2 phosphorylation and TGF - beta1 expression with inhibition of RhoA activation may be an important mechanism .", "Pretreatment of sildenafil attenuates ischemia - reperfusion renal injury in rats . ___MASK100___ was the first selective inhibitor of phosphodiesterase - 5 ( O76074 ) to be widely used for treating erectile dysfunction . Many recent studies have investigated the cardioprotective role of sildenafil in animal models . We evaluated the protective effects of sildenafil in experimental renal ischemia - reperfusion ( IR ) injury in two studies . In study 1 , male Sprague - Dawley rats were divided into four groups : sham , sildenafil - treated sham , vehicle - treated IR , and sildenafil - treated IR groups . In study 2 , we divided the rats into two groups : sildenafil - treated IR rats and PD98059 ( P29323 inhibitor ) + sildenafil - treated IR rats . Functional parameters of the kidney were evaluated at the molecular and structural levels . Blood urea nitrogen ( BUN ) and serum creatinine levels were lower in sildenafil - treated IR rats than in vehicle - treated IR rats . The expression of inducible ( P35228 ) and endothelial nitric oxide synthase ( P29474 ) proteins in sildenafil - treated IR rats was significantly higher than in vehicle - treated IR rats . Pretreatment with sildenafil in IR rats increased P29323 phosphorylation and reduced the renal Bax / Bcl - 2 ratio , renal caspase - 3 activity , and terminal dUTP nick end - labeling - positive apoptotic cells . In contrast , PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil - induced expression of pERK , P35228 , P29474 , and Bcl - 2 . PD98059 also increased caspase - 3 activity but did not decrease the sildenafil - induced accumulation of cGMP . In conclusion , this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via P29323 phosphorylation , induction of P35228 and P29474 production , and a decrease in the Bax / Bcl - 2 ratio .", "Tonic , but not phasic corticosterone , constrains stress activatedextracellular - regulated - kinase 1 / 2 immunoreactivity within the hypothalamic paraventricular nucleus . The negative - feedback actions of corticosterone ( O00230 ) depend on both phasic and tonic O00230 secretion patterns to regulate hypothalamic - pituitary - adrenal ( Q9Y251 ) axis activity . How these two different O00230 secretion pattens influence specific intracellular signal transduction pathway activity within the cellular elements of the Q9Y251 axis has not been determined . For example , it is unknown whether O00230 has suppressive actions over signal transduction events within medial parvocellular paraventricular nucleus ( PVN ) corticotrophin - releasing hormone ( P06850 ) neurones , nor whether these suppressive actions are responsible for alterations in PVN transcriptional processes and neurohormone secretion associated with stress . The extracellular - regulated kinase ( P29323 ) is a stress activated intracellular signalling molecule that is potentially subject to glucocorticoid negative - feedback regulation . We tested the ability of O00230 to modulate levels of the active ( phosphorylated ) form of P29323 ( pERK1 / 2 ) in the PVN of rats . Acute psychological stress ( restraint ) produced a rapid increase in the number of PVN pERK1 / 2 immunopositive cells within P06850 neurones . Absence of tonic O00230 via adrenalectomy ( P10109 ) produced no change in basal pERK1 / 2 cell counts but augmented the increased pERK1 / 2 cell counts elicited by acute restraint . Treatment of P10109 rats with O00230 in the drinking water normalised this enhanced pERK1 / 2 response to stress . By contrast , treatment of P10109 rats with a phasic increase in O00230 1 h before restraint had no effect on pERK1 / 2 cell counts , despite substantially suppressing stress - induced PVN crh gene expression and adrenonocorticotrophic hormone secretion . This tonic O00230 inhibition of stress - induced activation of P27361 / 2 may involve both alteration of the activity of stress - dependent neural inputs to PVN P06850 neurones and alteration within those neurones of stress - dependent intracellular signalling mechanisms associated with P29323 activation .", "Enhancement of the P11362 signaling in the P11362 - P08908 heteroreceptor complex in midbrain raphe 5 - HT neuron systems . Relevance for neuroplasticity and depression . New findings show existence of P11362 - P08908 heteroreceptor complexes in 5 - HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus . Synergistic receptor - receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity . The existence of P11362 - P08908 heteroreceptor complexes also in midbrain raphe 5 - HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5 - HT levels can cause an activation of the P09038 / P11362 mechanism in these nerve cells as well . Therefore , the agonist modulation of the P11362 - P08908 heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5 - HT nerve cells . The combined i . c . v . treatment with P09038 and the P08908 agonist 8 - OHDPAT synergistically increased P11362 and P27361 / 2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells . Cotreatment with P09038 and the P08908 agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5 - HT immunoreactivity . These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the P08908 receptor . Taken together , the P08908 autoreceptors by being part of a P11362 - P08908 heteroreceptor complex in the midbrain raphe 5 - HT nerve cells appears to have also a trophic role in the central 5 - HT neuron systems besides playing a key role in reducing the firing of these neurons .", "TG - interacting factor transcriptionally induced by AKT / O43524 is a negative regulator that antagonizes arsenic trioxide - induced cancer cell apoptosis . DB01169 ( ATO ) is a multi - target drug approved by the Food and Drug Administration as the first - line chemotherapeutic agent for the treatment of acute promyelocytic leukemia . In addition , several clinical trials are being conducted with arsenic - based drugs for the treatment of other hematological malignancies and solid tumors . However , ATO ' s modest clinical efficacy on some cancers , and potential toxic effects on humans have been reported . Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue . Previously , we demonstrated that the JNK - induced complex formation of phosphorylated c - Jun and TG - interacting factor ( Q15583 ) antagonizes P29323 - induced cyclin - dependent kinase inhibitor P38936 ( P38936 ( P38936 / CIP1 ) ) expression and resultant apoptosis in response to ATO in A431 cells . Surprisingly , at low - concentrations ( 0 . 1 - 0 . 2 μM ) , ATO increased cellular proliferation , migration and invasion , involving Q15583 expression , however , at high - concentrations ( 5 - 20 μM ) , ATO induced cell apoptosis . Using a promoter analysis , Q15583 was transcriptionally regulated by ATO at the O43524 binding site ( - 1486 to - 1479bp ) via the c - Src / P00533 / AKT pathway . Stable overexpression of Q15583 promoted advancing the cell cycle into the S phase , and attenuated 20 μM ATO - induced apoptosis . Furthermore , blockage of the AKT pathway enhanced ATO - induced P38936 expression and resultant apoptosis in cancer cells , but overexpression of P31749 inhibited P38936 expression . Therefore , we suggest that Q15583 is transcriptionally regulated by the c - Src / P00533 / AKT pathway , which plays a role as a negative regulator in antagonizing ATO - induced P38936 expression and resultant apoptosis . Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO .", "Activation of the p38 MAPK / Akt / P27361 / 2 signal pathways is required for the protein stabilization of Q99741 and cyclin D1 in low - dose arsenite - induced cell proliferation . DB01169 ( ATO ) is a first - line anti - cancer agent for acute promyelocytic leukemia , and induces apoptosis in other solid cancer cell lines including breast cancer cells . However , as with arsenites found in drinking water and used as raw materials for wood preservatives , insecticides , and herbicides , low doses of ATO can induce carcinogenesis after long - term exposure . At 24 h after exposure , ATO ( 0 . 01 - 1 µM ) significantly increased cell proliferation and promoted cell cycle progression from the P55008 to S / G2 phases in the non - tumorigenic MCF10A breast epithelial cell line . The expression of 14 out of 96 cell - cycle - associated genes significantly increased , and seven of these genes including cell division cycle 6 ( Q99741 ) and cyclin D1 ( P24385 ) were closely related to cell cycle progression from P55008 to S phase . Low - dose ATO steadily increased gene transcript and protein levels of both Q99741 and cyclin D1 in a dose - and time - dependent manner . Low - dose ATO produced reactive oxygen species ( ROS ) , and activated the p38 MAPK , Akt , and P27361 / 2 pathways at different time points within 60 min . Small molecular inhibitors and siRNAs inhibiting the activation of p38 MAPK , Akt , and P27361 / 2 decreased the ATO - increased expression of Q99741 protein . Inhibiting the activation of Akt and P27361 / 2 , but not p38 MAPK , decreased the ATO - induced expression of cyclin D1 protein . This study reports for the first time that p38 MAPK / Akt / P27361 / 2 activation is required for the protein stabilization of Q99741 in addition to cyclin D1 in ATO - induced cell proliferation and cell cycle modulation from P55008 to S phase .", "P98160 - rich epithelial linings as a background of proliferative potentials of keratocystic odontogenic tumor . BACKGROUND : The intraepithelial deposit of perlecan , a basement membrane - type heparan sulfate ( HS ) proteoglycan , has been demonstrated in neoplastic conditions such as salivary gland tumors , odontogenic tumors , and oral carcinoma in situ . Our aim was to determine whether perlecan turnover was enhanced in the lining cells of keratocystic odontogenic tumor ( KCOT ) , which had been recently renamed from odontogenic keratocyst because of its accumulated evidence of neoplasm , as a possible background for neoplastic proliferation . METHODS : Ten surgical specimens from each of KCOT , dentigerous cyst , and radicular cyst were examined for the expressions of perlecan core protein , HS chains , heparanase , and Ki - 67 by immunohistochemistry and in situ hybridization . RESULTS : In KCOT , perlecan core protein and HS chains were localized on the cell border from the parabasal to subkeratinized layers of the lining epithelium . Q9Y251 was localized in a similar fashion to those for perlecan and HS chains but was within the cytoplasm . mRNA signals for perlecan core protein and heparanase were mostly compatible with their protein signals . Ki - 67 - positive cells were localized mainly in the second basal cell layers with definitely higher labeling indices ( approximately 31 . 3 % , second layer ) . In contrast to KCOT , dentigerous cysts and radicular cysts had no perlecan , HS chains , and heparanase deposition in their linings with extremely lower Ki - 67 indices ( 0 . 4 - 0 . 8 % ) . CONCLUSION : The result suggests that the characteristic intra - lining - epithelial deposit of perlecan in KCOT , which has never been seen in other cystic jaw lesions , is a new evidence supporting the neoplastic nature of KCOT .", "Growth inhibition of human glioma cells by transfection - induced P21 and its effects on telomerase activity . The aim of this study is to investigate the effect of the P38936 gene transfection on the growth of cultured human glioma cell lines , and analyze the telomerase activity , and detection of telomerase components in P38936 transfectant . The P38936 gene was transfected into human glioma cell lines , U251MG and T98G with our novel liposome . The cell growth was assessed by counting the number of trypan blue - excluding cells in a hemocytometer and flow cytometry analysis . The expression of P21 protein and its mRNA were examined by Western and Northern blot analysis . The telomerase activity was assayed by TRAP ( telomerase repeat amplification protocol ) / TRAP - Q9Y251 ( hybridization protection assay ) method qualitatively and quantitatively . The length of telomere was measured by Southern blot analysis . The expression of telomerase components ( hTERT , hTERC and TEP1 ) were examined by RT - PCR ( reverse transcriptase - polymerase chain reaction ) . The P38936 transfectant demonstrated the expression of P21 protein and its mRNA . The P38936 transfection of human glioma cells results in growth inhibition and G0 / P55008 arrest . The P38936 transfectant revealed a decrease of telomerase activity and hTERT expression as compared with control cells . These results suggest that P38936 transfection induces G0 / P55008 arrest in human glioma cells which associates with the reduction in the telomerase activity and hTERT expression .", "___MASK73___ attenuates matrix metalloproteinase - 2 and - 9 in monocrotaline - induced right ventricular hypertrophy in rats . Little is known about the influence of angiotensin converting enzyme ( P12821 ) inhibitors on matrix metalloproteinase ( MMP ) in right ventricular remodeling . We investigated the effect of captopril , an P12821 inhibitor , on P08253 and P14780 in monocrotaline - induced right ventricular hypertrophy . Six - week - old male Wistar rats were injected intraperitoneally with monocrotaline ( 60 mg / kg ) or saline . The rats were administrated captopril ( 30 mg / kg per day ) or a vehicle orally for 24 days from the day of monocrotaline injection . At day 25 , echocardiography was performed and hearts were excised . Expressions and activities of P08253 and P14780 were measured by Western blotting and by gelatin zymography , respectively . In monocrotaline - injected rats , right ventricular weight / tail length ratio increased significantly . Histological analysis revealed cardiomyocyte hypertrophy and fibrosis in right ventricular sections . Echocardiography showed right ventricular dysfunction compared with saline - injected rats . The right ventricular hypertrophy , fibrosis , and dysfunction were inhibited by captopril . However , captopril did not attenuate an increase in pulmonary artery pressure . P08253 and P14780 expressions and activities in right ventricles increased significantly in monocrotaline - injected rats and captopril inhibited them . These findings indicate that captopril attenuates the development of monocrotaline - induced right ventricular hypertrophy in association with inhibition of P08253 and P14780 in rats .", "___MASK43___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .", "Inhibition of fatty - acid synthase suppresses P - AKT and induces apoptosis in bladder cancer . OBJECTIVE : To investigate the role of fatty acid synthase ( P49327 ) in bladder transitional cell carcinoma ( BTCC ) . METHODS : P49327 expression was investigated in non - muscle - invasive BTCC tissue specimens by immunohistochemistry and BTCC cell lines by Western blot . After treatment with P49327 - siRNA or P49327 inhibitor cerulenin ( Cer ) , the proliferation and apoptosis of BTCC cell lines 5637 and 253 J were determined by cell counting Kit - 8 ( CCK8 ) assay and flow cytometry respectively . The expression of p - AKT , cyclin D1 ( P24385 ) , and apoptosis - related proteins were detected by Western blot . RESULTS : High levels of P49327 expression were observed in 59 % ( 32 / 54 ) of non - muscle - invasive BTCC tissue specimens , and P49327 expression was associated with histologic grade ( P < . 05 ) and recurrence ( P < . 05 ) . P49327 expression was high in 6 BTCC cell lines . P49327 inhibitor Cer and P49327 - siRNA produced the increased apoptosis and decreased proliferation of bladder cancer cells , and caused inactivity of AKT and downregulation of P24385 . Furthermore , treatment of BTCC cell lines with Cer resulted in apoptosis via the caspase - dependent pathway involving inactivation of antiapoptotic bcl - 2 protein . CONCLUSION : Our data suggest that P49327 plays an important role in BTCC development . Targeting P49327 may be a new therapeutic strategy for BTCC .", "Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .", "Inactivation of CaMIT1 inhibits Candida albicans phospholipomannan beta - mannosylation , reduces virulence , and alters cell wall protein beta - mannosylation . Studies on Candida albicans phospholipomannan have suggested a novel biosynthetic pathway for yeast glycosphingolipids . This pathway is thought to diverge from the usual pathway at the mannose - inositol - phospho - ceramide ( MIPC ) step . To confirm this hypothesis , a C . albicans gene homologue for the Saccharomyces cerevisiae Q09428 gene was identified and named MIT1 as it coded for GDP - mannose : inositol - phospho - ceramide mannose transferase . Two copies of this gene were disrupted . Western blots of cell extracts revealed that strain mit1Delta contained no PLM . Thin layer chromatography and mass spectrometry confirmed that mit1Delta did not synthesize MIPC , demonstrating a role of MIT1 in the mannosylation of C . albicans IPCs . As MIT1 disruption prevented downstream beta - 1 , 2 mannosylation , mit1Delta represents a new C . albicans mutant affected in the expression of these specific virulence attributes , which act as adhesins / immunomodulators . mit1Delta was less virulent during both the acute and chronic phases of systemic infection in mice ( 75 and 50 % reduction in mortality , respectively ) . In vitro , mit1Delta was not able to escape macrophage lysis through down - regulation of the P27361 / 2 phosphorylation pathway previously shown to be triggered by PLM . Phenotypic analysis also revealed pleiotropic effects of MIT1 disruption . The most striking observation was a reduced beta - mannosylation of phosphopeptidomannan . Increased beta - mannosylation of mannoproteins was observed under growth conditions that prevented the association of beta - oligomannosides with phosphopeptidomannan , but not with PLM . This suggests that C . albicans has strong regulatory mechanisms associating beta - oligomannoses with different cell wall carrier molecules . These mechanisms and the impact of the different presentations of beta - oligomannoses on the host response need to be defined .", "Inhibition of matrix metalloproteinase - 9 expression by docosahexaenoic acid mediated by heme oxygenase 1 in 12 - O - tetradecanoylphorbol - 13 - acetate - induced MCF - 7 human breast cancer cells . P14780 ( P14780 ) plays a crucial role in tumor metastasis . Previous studies showed that polyunsaturated fatty acids exhibit an anti - cancer effect in various human carcinoma cells , but the effect of docosahexaenoic acid ( DB01708 ) and linoleic acid ( LA ) on metastasis of breast cancer cells is not fully clarified . We studied the anti - metastasis potential of DB01708 and LA in 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) - induced MCF - 7 cells . We found that TPA ( 100 ng / ml ) induced P14780 enzyme activity both dose - and time - dependently , and 200 μM DB01708 and LA significantly inhibited P14780 mRNA and protein expression , enzyme activity , cell migration , and invasion . Treatment with PD98059 ( 10 μM ) , wortmannin ( 10 μM ) , and GF109203X ( 0 . 5 μM ) decreased TPA - induced P14780 protein expression and enzyme activity . TPA - induced activation of P27361 , Akt , and PKCδ was attenuated by DB01708 , whereas LA attenuated only P27361 activation . GF109203X also suppressed P27361 activation . EMSA showed that DB01708 , LA , PD98059 , and wortmannin decreased TPA - induced NF - κB and AP - 1 DNA - binding activity . Furthermore , DB01708 rather than LA dose - dependently increased P09601 expression . P09601 siRNA alleviated the inhibition by DB01708 of TPA - induced P14780 protein expression and enzyme activity in MCF - 7 cells , and P09601 knockdown reversed the DB01708 inhibition of cell migration . These results suggest that DB01708 and LA have both similar and divergent signaling pathways in the suppression of TPA - induced MCF - 7 metastasis .", "Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK79___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .", "Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines . Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia , and prostate cancer . Although testosterone is the main androgen secreted from the testes , dihydrotestosterone ( DB02901 ) , a more potent androgen converted from testosterone by 5alpha - reductase isozymes , type I and II , is the major androgen in the prostate cells . The aim of this study is to investigate the cellular and molecular effects of dutasteride , a potent inhibitor of 5alpha - reductase type I and type II , in androgen - responsive ( LNCaP ) and androgen - unresponsive ( DU145 ) human prostate cancer ( PCa ) cell lines . The expression pattern of 190 genes , selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling , were analysed using a low density home - made oligoarray ( AndroChip 2 ) . Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested . AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed ( FC > or = +/- 1 . 5 ) . Eight of these genes , were overexpressed and three were underexpressed . Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen ( P14061 ; P37058 ; P19099 ) , androgen receptor and androgen receptor co - regulators ( AR ; P24385 ) , and signal transduction ( P04626 ; V - P62158 ; Q07889 ) whereas , underexpressed genes ( KLK3 ; P20151 ; Q15392 ) were androgen - regulated genes ( ARGs ) . No differentially expressed genes were scored in DU145 . Microarray data were confirmed by quantitative real - time PCR assay ( QRT - PCR ) . These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology ." ]

[ "___MASK100___", "___MASK15___", "___MASK28___", "___MASK31___", "___MASK38___", "___MASK43___", "___MASK73___", "___MASK79___", "___MASK84___" ]

[ "P25116 activation inhibits monocyte spreading by induction of ET ( B ) receptor - coupled nitric oxide release . The effect of thrombin receptor activation on monocyte conformation was evaluated using the human monocyte cell line , THP - 1 , and the thrombin mimetic peptide , Q8NHU6 - 14 . Treatment of THP - 1 cells with Q8NHU6 - 14 induced rapid rounding of ameboid cells adherent to fibronectin - coated slides , whereas cell rounding was abrogated in the presence of the nitric oxide synthase inhibitor , NG - nitro - L - arginine or the endothelin B receptor antagonist , BQ - 788 . P05305 ( ET - 1 ) levels in the culture supernatant increased markedly within minutes of Q8NHU6 - 14 exposure with a concomitant loss in cellular ET - 1 immunoreactivity . Importantly , loss of ET - 1 immunoreactivity was blocked by pretreatment with the vesicle translocation inhibitor , DB08313 . Q8NHU6 - 14 potently induced the release of NO from THP - 1 cells , whereas NO release was ablated by preincubation with BQ - 788 . These data demonstrate that thrombin receptor activation may inhibit cellular spreading as a result of autocrine ET - 1 release and subsequent endothelin B receptor - dependent NO production , and suggest that initial exposure of inflammatory cells to thrombin may limit cellular activation and recruitment .", "Comparison of pharmacological activity of macitentan and DB00559 in preclinical models of systemic and pulmonary hypertension . AIMS : The endothelin ( ET ) system is a tissular system , as the production of ET isoforms is mostly autocrine or paracrine . DB08932 is a novel dual P25101 / ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade . To determine if these features translate into improved efficacy in vivo , a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual P25101 / ETB receptor antagonist , DB00559 , which does not display sustained receptor occupancy and shows less tissue distribution . MAIN METHODS : After establishing dose - response curves of both compounds in conscious , hypertensive Dahl salt - sensitive and pulmonary hypertensive bleomycin - treated rats , macitentan was administered on top of the maximal effective dose of DB00559 . KEY FINDINGS : In hypertensive rats , macitentan 30 mg / kg further decreased mean arterial blood pressure ( Q96HU1 ) by 19 mm Hg when given on top of DB00559 100 mg / kg ( n = 9 , p < 0 . 01 vs . vehicle ) . Conversely , DB00559 given on top of macitentan failed to induce an additional Q96HU1 decrease . In pulmonary hypertensive rats , macitentan 30 mg / kg further decreased mean pulmonary artery pressure ( MPAP ) by 4 mm Hg on top of DB00559 ( n = 8 , p < 0 . 01 vs . vehicle ) , whereas a maximal effective dose of DB00559 given on top of macitentan did not cause any additional MPAP decrease . SIGNIFICANCE : The add - on effect of macitentan on top of DB00559 in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy .", "DB08932 ( Opsumit ) for the treatment of pulmonary arterial hypertension . The endothelin pathway is a key pathway for the pathogenesis of pulmonary arterial hypertension ( PAH ) . Antagonism of this pathway is recommended as initial therapy in low - risk patient with PAH to inhibit fibrosis , cell proliferation , and inflammation caused by endothelin . Prior to October 2013 , ambrisentan , a selective P25101 receptor antagonist and DB00559 , a dual P25101 / ETB antagonist , were the only currently available agents for PAH targeting the endothelin pathway . Based on the results of the SERAPHIN trial , macitentan ( brand name Opsumit ® ) , a new P25101 / ETB antagonist , has been US FDA approved to delay disease progression and reduce hospitalizations for PAH . SERAPHIN is the first ERA trial to use an event - driven strategy with a composite primary end point of morbidity or mortality . Previous trials have focused on short - term outcomes , such as improved 6 - min walk distance and WHO functional class .", "The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK18___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK18___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK18___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK18___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .", "Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens . OBJECTIVE : To investigate whether genetic modifiers of cystic fibrosis ( CF ) lung disease also predispose to congenital bilateral absence of the vas deferens ( CBAVD ) in association with cystic fibrosis transmembrane conductance regulator ( P13569 ) mutations . We tested the hypothesis that polymorphisms of transforming growth factor ( TGF ) - β1 ( rs 1982073 , rs 1800471 ) and endothelin receptor type A ( P25101 ) ( rs 5335 , rs 1801708 ) are associated with the CBAVD phenotype . DESIGN : Genotyping of subjects with clinical CBAVD . SETTING : Outpatient and hospital - based clinical evaluation . PATIENT ( S ) : DNA samples from 80 subjects with CBAVD and 51 healthy male controls from various regions of Europe . This is one of the largest genetic studies of this disease to date . INTERVENTION ( S ) : None . MAIN OUTCOME MEASURE ( S ) : Genotype analysis . RESULT ( S ) : For single nucleotide polymorphism ( SNP ) rs 5335 , we found increased frequency of the CC genotype among subjects with CBAVD . The difference was significant among Turkish patients versus controls ( 45 . 2 % vs . 19 . 4 % ) , and between all cases versus controls ( 36 % vs . 15 . 7 % ) . No associations between CBAVD penetrance and polymorphisms rs 1982073 , rs 1800471 , or rs 1801708 were observed . CONCLUSION ( S ) : Our findings indicate that endothelin receptor type A polymorphism rs 5335 may be associated with CBAVD penetrance . To our knowledge , this is the first study to investigate genetic modifiers relevant to CBAVD .", "DB08932 slows down the dermal fibrotic process in systemic sclerosis : in vitro findings . Systemic sclerosis ( or scleroderma ) is an autoimmune disease characterized by skin and internal organ fibrosis , caused by microvascular dysfunction . The microvascular damage seems to be a consequence of an endothelial autoimmune response , followed by activation of the inflammatory cascade and massive deposition of collagen . P05305 ( ET - 1 ) contributes to the inflammatory and fibrotic processes by increasing the concentration of pro - inflammatory and pro - fibrotic cytokines , and it is considered one of the most relevant mediators of vascular damage in scleroderma . It is indeed found in very high concentration in serum of sclerodermic patients . Moreover , in these pathological conditions there is an increased expression of ET - 1 receptors ( P25101 and ETB ) , which mediate the detrimental action of ET - 1 , and often a change of P25101 / ETB ratio . The aim of the present study is to evaluate the in vitro effect of macitentan , an orally active tissue - targeting dual endothelin receptor antagonist , and its major metabolite ( ACT - 132577 ) on alpha smooth muscle actin ( alphaSMA ) expression , evaluated on dermal fibroblasts from healthy subjects and on dermal fibroblasts from lesional and non - lesional skin from sclerodermic patients . The combination of macitentan and its major metabolite reduced the levels of & # 945 ; SMA after 48 h in sclerodermic fibroblasts from lesional skin . No relevant changes in & # 945 ; SMA levels were found in fibroblasts from non - lesional skin , whose behavior is similar to that of dermal fibroblasts from healthy patients .", "P05305 stimulates glial cell line - derived neurotrophic factor expression in cultured rat astrocytes . Effects of endothelin - 1 ( ET - 1 ) on glial cell line - derived neurotrophic factor ( P39905 ) production in cultured astrocytes were examined . Treatment of cultured astrocytes with ET - 1 ( 100 nM ) increased mRNA levels of P39905 in 1 - 6h . The effect of ET - 1 was inhibited by BQ788 , an ET ( B ) receptor antagonist , but not by FR139317 , an ET ( A ) receptor antagonist . ET - 1 stimulated release of P39905 into culture medium . Dexamethasone ( 1 microM ) and pyrrolidine dithiocarbamate ( PDTC , 100 microM ) , which inhibit activation of NFkappaB , prevented the increases in P39905 mRNA by H ( 2 ) O ( 2 ) . In contrast , the effect of ET - 1 was not affected by dexamethasone and PDTC . The increase of astrocytic P39905 mRNA by ET - 1 was inhibited by BAPTA / AM ( 30 microM ) and PD98059 ( 50 microM ) , but not by calphostin C , staurosporine , and cyclosporine A . These results suggest that ET - 1 stimulated expression of astrocytic P39905 through ET ( B ) receptor - mediated increases in cytosolic Ca ( 2 +) and P29323 activation .", "Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .", "Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK11___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .", "Early increase in pulmonary vascular reactivity with overexpression of endothelin - 1 and vascular endothelial growth factor in canine experimental heart failure . Heart failure is a cause of pulmonary vasoconstriction and remodelling , leading to pulmonary hypertension ( PH ) and decreased survival . The pathobiology of PH in heart failure remains incompletely understood . We investigated pulmonary vascular function and signalling molecules in early stage PH secondary to experimental heart failure . Eight beagle dogs with overpacing - induced heart failure underwent haemodynamic assessment and postmortem pulmonary arterial reactivity , morphometry and quantification of genes encoding for factors involved in vascular reactivity and remodelling : endothelin - 1 ( ET - 1 ) , P25101 and ETB receptors , vascular endothelial growth factor ( P15692 ) , P15692 receptors 1 and 2 ( P17948 and P35968 ) , endothelial nitric oxide synthase , angiopoietin - 1 , bone morphogenetic protein receptors ( P36894 and Q13873 ) , serotonin transporter ( 5 - HTT ) and the 5 - HT ( 2B ) receptor . Overpacing was associated with a decrease in cardiac output and an increase in pulmonary vascular pressures . However , there were no changes in pulmonary vascular resistance or in arteriolar medial thickness . There were increased expressions of genes encoding for ET - 1 , ETB , P15692 and P35968 , while expression of the other genes analysed remained unchanged . In vitro , pulmonary arteries showed decreased relaxation and increased reactivity , while systemic mammary arteries were unaffected . Early PH in heart failure is characterized by altered vasoreactivity and increased ET - 1 / ETB and P15692 / P35968 signalling .", "Endothelin receptor blockade inhibits molecular effectors of Kaposi ' s sarcoma cell invasion and tumor growth in vivo . P05305 ( ET - 1 ) and its receptors are overexpressed in human Kaposi ' s sarcoma lesions . Here we show that in human KS IMM cell line ET - 1 increased secretion and activation of matrix - metalloproteinase - 2 ( P08253 ) , - 3 , - 7 , - 9 and - 13 , as well as of membrane - type 1 - MMP ( P50281 ) . ET - 1 and P14138 also enhanced the expression of tissue inhibitor of P08253 , essential for P50281 - mediated P08253 activation . Combined addition of both ET ( B ) receptor ( ET ( B ) R ) and ET ( A ) R antagonists completely blocked the ET - 1 - induced MMP activity . By immunohistochemistry , we observed that ET - 1 increased P08253 and P50281 expression and their localization at the cell surface . Treatment with both antagonists resulted also in the suppression of ET - 1 - induced phosphorylation of focal adhesion proteins , Q05397 and paxillin , which are essentials for cell motility . ET - 1 induced a dose - dependent enhancement in KS IMM cell migration and MMP - dependent invasiveness that were inhibited by ET - 1 receptor antagonists . The small molecule , A - 182086 , an orally bioavailable ET ( A / B ) R antagonist , completely inhibited cell proliferation and tumor growth in KS IMM xenografts . These findings demonstrate that ET - 1 - driven autocrine loop is crucial for enhanced invasiveness of KS IMM cells and promote tumor growth in vivo . Such activities can be blocked by the ET ( A / B ) R antagonists , which may be effective anti - angiogenic and anti - tumor molecules for the treatment of Kaposi ' s sarcoma .", "Differential involvement of Galpha12 and Galpha13 in receptor - mediated stress fiber formation . The ubiquitously expressed heterotrimeric guanine nucleotide - binding proteins ( G - proteins ) G12 and Q99941 have been shown to activate the small GTPase Rho . Rho stimulation leads to a rapid remodeling of the actin cytoskeleton and subsequent stress fiber formation . We investigated the involvement of G12 or Q99941 in stress fiber formation induced through a variety of Gq / P49842 - coupled receptors . Using fibroblast cell lines derived from wild - type and Galphaq / Galpha11 - deficient mice , we show that agonist - dependent activation of the endogenous receptors for thrombin or lysophosphatidic acid and of the heterologously expressed bradykinin B2 , vasopressin V1A , endothelin P25101 , and serotonin P28335 receptors induced stress fiber formation in either the presence or absence of Galphaq / Galpha11 . Stress fiber assembly induced through the muscarinic M1 and the metabotropic glutamate subtype 1alpha receptors was dependent on Gq / P49842 proteins . The activation of the Gq / P49842 - coupled endothelin ETB and angiotensin AT1A receptors failed to induce stress fiber formation . Lysophosphatidic acid , B2 , and P28335 receptor - mediated stress fiber formation was dependent on Galpha13 and involved epidermal growth factor ( P01133 ) receptors , whereas thrombin , P25101 , and V1A receptors induced stress fiber accumulation via Galpha12 in an P01133 receptor - independent manner . Our data demonstrate that many Gq / P49842 - coupled receptors induce stress fiber assembly in the absence of Galphaq and Galpha11 and that this involves either a Galpha12 or a Galpha13 / P01133 receptor - mediated pathway .", "Purinergic receptors contribute to early mesangial cell transformation and renal vessel hypertrophy during angiotensin II - induced hypertension . Chronic P03950 II infusions lead to increases in intrarenal P03950 II levels , hypertension , and tissue injury . Increased blood pressure also elicits increases in renal interstitial fluid ( Q9HBH0 ) DB00171 concentrations that stimulate cell proliferation . We evaluated the contribution of purinergic receptor activation to P03950 II - induced renal injury in rats by treating with clopidogrel , a Q9H244 receptor blocker , or with PPADS , a nonselective P2 receptor blocker . alpha - Actin expression in mesangial cells , afferent arteriolar wall thickness ( AAWT ) , cortical cell proliferation , and macrophage infiltration were used as early markers of renal injury . ___MASK26___ and PPADS did not alter blood pressure , renin or kidney P03950 II content . alpha - Actin expression increased from control of 0 . 6 +/- 0 . 4 % of mesangial area to 6 . 3 +/- 1 . 9 % in P03950 II - infused rats and this response was prevented by clopidogrel ( 0 . 4 +/- 0 . 2 % ) and PPADS . The increase in AAWT from 4 . 7 +/- 0 . 1 to 6 . 0 +/- 0 . 1 mm in P03950 II rats was also prevented by clopidogrel ( 4 . 8 +/- 0 . 1 mm ) and PPADS . P03950 II infusion led to interstitial macrophage infiltration ( 105 +/- 16 vs . 62 +/- 4 cell / mm ( 2 ) ) and tubular proliferation ( 71 +/- 15 vs . 20 +/- 4 cell / mm ( 2 ) ) and these effects were prevented by clopidogrel ( 52 +/- 4 and 36 +/- 3 cell / mm ( 2 ) ) and PPADS . Q9HBH0 DB00171 levels were higher in P03950 II - infused rats than in control rats ( 11 . 8 +/- 1 . 9 vs . 5 . 6 +/- 0 . 6 nmol / l , P < 0 . 05 ) . The results suggest that activation of vascular and glomerular purinergic P2 receptors may contribute to the mesangial cell transformation , renal inflammation , and vascular hypertrophy observed in P03950 II - dependent hypertension .", "Long - term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6 - chloro - 2 -[ 1 - piperazinyl ]- pyrazine ( MK - 212 ) and (+-)- 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane HCl ( DOI ) . Various endocrine responses to 5 - hydroxytryptamine ( serotonin , 5 - HT ) agonists were used to assess serotonergic receptor function after chronic treatment with the antidepressants fluoxetine ( 10 mg / kg ) , a 5 - HT uptake blocker and the norepinephrine uptake blocker desipramine ( ___MASK6___ , 5 mg / kg ) . Both were injected ( i . p . ) once a day for 21 days . DOI ( P28335 / 2 agonist , 0 - 5 mg / kg i . p . ) and 6 - chloro - 2 -[ 1 - piperazinyl ]- pyrazine ( MK - 212 ) ( less selective , but predominantly a P28335 agonist , 0 - 20 mg / kg i . p . ) were administered 18 hr after the final antidepressant injection and 30 min before decapitation . Chronic treatment with both fluoxetine and ___MASK6___ produced a potentiation in most hormone responses to the 5 - HT agonists (+-)- 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - amino - propane HCl ( DOI ) and MK - 212 , although there were several differences in individual hormone responses to the two 5 - HT agonists . DB00472 and ___MASK6___ potentiated the MK - 212 - and DOI - induced increase of plasma oxytocin levels and potentiated the effect of DOI on plasma adrenocorticotropic hormone ( corticotropin ) and prolactin levels . In contrast , the effect of the high dose of MK - 212 on plasma prolactin concentration was reduced by both antidepressants . Only MK - 212 increased vasopressin levels and this effect was potentiated by fluoxetine , but not by ___MASK6___ . DB00472 also significantly increased the resting level of plasma vasopressin . ___MASK6___ potentiated the effect of MK - 212 on plasma renin concentration . Pretreatment with fluoxetine significantly increased ( 38 % ) the Bmax for the P28335 / 2 agonist sites ( [ 125I ] DOI ) in the hypothalamus . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Regulation and expression of endothelin - 1 ( ET - 1 ) and ET - receptors in rat epithelial cells of renal and intestinal origin . The hormone endothelin - 1 ( ET - 1 ) is involved in many functions of the kidney and intestine . In addition to its vasoactive and proliferative effects , ET - 1 is involved in the maintenance of water and salt balance , and in drug excretion by influencing the activity of different transporters in the epithelial cells of these two organs . To study ET - 1 function and its role in pathophysiological processes in epithelial cells in vitro , we investigated ET - 1 and ET - receptor expression and inducibility of ET - 1 excretion by cytokines in three rat cell lines of intestinal ( IEC - 6 ) and renal ( Q7Z2Y5 - 52E and Q9BZR9 ) origin . Immunocytochemistry showed that all three cell lines express ET - 1 and the P25101 and P24530 receptor . ET - 1 was expressed intracellularly , and also the P25101 receptor showed a punctate intracellular staining pattern . The P24530 receptor was localized in the membrane , which was confirmed by Western blot analysis . Real - time RT - PCR and ELISA showed that exposure of IEC - 6 cells to the cytokines , interleukin - 1beta ( IL - 1beta ) and tumor necrosis factor - alpha ( TNFalpha ) , induced ET - 1 mRNA expression and excretion , while P60568 was ineffective . In Q7Z2Y5 - 52E cells , IL - 1beta and TNFalpha induced ET - 1 excretion as well . In Q9BZR9 cells , adequate measurement of cytokine effects on ET - 1 excretion was not possible , since ET - 1 excretion under non - stimulated conditions was around the lowest level of detection . In conclusion , we showed ET - 1 and ET - receptor expression , and inducibility of ET - 1 by cytokines in IEC - 6 , Q7Z2Y5 - 52E , and Q9BZR9 cells . These rat intestinal and renal cell lines appear to be suitable for further characterisation of ET - 1 function and its role in pathophysiological processes in epithelial cells .", "P24530 antagonists block proliferation and induce apoptosis in glioma cells . The proliferative and antiapoptotic actions of endothelin ( ET ) - 1 in cancer cells have been documented and ET receptor antagonists have been exploited as potential anticancer drugs . Glioblastoma cell lines express both P25101 and ETB receptors and previous works have shown that ETB receptors are involved in the proliferation of different cancer cell types . In this study we have investigated the effects of two structurally unrelated ETB receptor antagonists , BQ788 and A192621 , on cell survival , proliferation and apoptosis in 1321 - N1 , U87 and IPDDCA2 glioma cell lines . BQ788 and A192621 reduced glioma cells viability and proliferation assessed by BrdU incorporation and cell cycle analysis by flow cytometry , while in contrast the P25101 receptor antagonist BQ123 had no effect on cell survival . TUNEL assay and immunocytochemical experiments showed that BQ788 and A192621 trigger apoptotic processes mainly via activation of the intrinsic mitochondrial pathway involving caspase - 9 activation , O95831 release and cytochrome c translocation . Furthermore , treatment with ETB antagonists downregulates P29323 - and p38MAPK - dependent pathways but does not affect P15692 mRNA levels . Our findings support the hypothesis that ETB antagonists represent a new promising therapeutic strategy for the treatment of high grade gliomas .", "In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis . DB01044 ( Q6IB77 ) and moxifloxacin ( MXF ) were evaluated in vitro to determine their activities against Mycobacterium tuberculosis . Q6IB77 was subsequently compared in a dose range study to isoniazid ( DB00951 ) in a murine tuberculosis model . Q6IB77 was somewhat less active than DB00951 . Q6IB77 and MXF were evaluated in mice infected with M . tuberculosis and were found to have similar activities . Q6IB77 was studied alone and in combination with ethambutol , ethionamide ( P25101 ) , and pyrazinamide ( PZA ) and compared to DB00951 and rifampin ( Q9HBH0 ) . Q6IB77 appears to have sufficient activity alone and in combination with P25101 with or without PZA to merit evaluation for treatment of tuberculosis .", "Carotid atherosclerosis in elderly hypertensive patients : potential role of endothelin and plasma antioxidant capacity . P05305 ( ET - 1 ) and oxidative stress are involved in the development of hypertension - induced cardiovascular complications . The aim of this study was to evaluate the relationship between plasma ET - 1 level and plasma antioxidant capacity and carotid atherosclerosis . In 61 treated patients with hypertension ( 44 women , 35 diabetics , mean age 72 . 4 +/- 7 . 2 years ) medical histories , ambulatory blood pressure , blood tests ( glucose , creatinine , cholesterol , haemoglobin A1c ( HbA1c ) , ET - 1 ) and common carotid artery intima - media thickness ( CCA - IMT ) measurement were carried out . Plasma antioxidant capacity was assessed by the ferric - reducing ability of plasma ( P42345 ) . Subjects with diabetes presented with higher concentrations of glucose ( 7 . 01 +/- 2 . 3 vs 5 . 14 +/- 0 . 6 mmol l (- 1 ) , P < 0 . 001 ) , HbA1c ( 7 . 75 +/- 2 . 1 vs 6 . 1 +/- 1 . 2 % , P < 0 . 001 ) and ET - 1 ( 1 . 36 +/- 0 . 53 vs 1 . 01 +/- 0 . 4 pg ml (- 1 ) , P < 0 . 01 ) , and lower cholesterol level ( 5 . 02 +/- 0 . 8 vs 5 . 86 +/- 1 . 3 mmol l (- 1 ) , P < 0 . 01 ) . A significant positive correlation between CCA - IMT and ET - 1 plasma concentration ( r = 0 . 40 , P < 0 . 001 ) and reverse relationship between CCA - IMT and P42345 ( r =- 0 . 36 , P < 0 . 01 ) was observed . In a stepwise regression analysis , after adjustment for all confounders , CCA - IMT was independently influenced by age , systolic blood pressure ( SBP ) , HbA1c and ET - 1 . When P42345 was included in the regression model , CCA - IMT was significantly influenced by age , P42345 , HbA1c and SBP . ET - 1 promotes the increase in CCA - IMT contributing to the development of end - organ damage . Plasma antioxidant capacity may modulate this deleterious effect , but whether better antioxidant defence may prevent against the development of atherosclerosis remains to be elucidated .", "Potentiation by neuropeptide Y of 5HT2A receptor - mediated contraction in porcine coronary artery . Potentiation by neuropeptide Y of serotonin ( 5 - HT ) - induced vasoconstriction was investigated in porcine coronary artery . 5 - HT caused concentration - dependent contraction through 5 - Q13049 receptors . Neuropeptide Y ( 30 nM ) significantly increased the 5HT - induced contraction by 16 +/- 5 % in arteries with intact endothelium . Removal of the endothelium abolished the potentiation . A neuropeptide Q03519 antagonist , BIBP3226 , blocked this neuropeptide Y - induced potentiation . In vessels with intact endothelium , the potentiation by neuropeptide Y was inhibited by in the presence of a cyclo - oxygenase inhibitor , indomethacin ( 30 microM ) , but not by the presence of P25101 or ETB endothelin receptor antagonists or an NO synthase inhibitor , NG - nitro - L - arginine ( DB04223 ) ( 1 mM ) at all . A thromboxane A2 ( TXA2 ) synthase inhibitor , ozagrel , and prostanoid TP receptor antagonists , seratrodast and ONO - 3708 , also inhibited the neuropeptide Y - induced potentiation . In the endothelium - denuded arteries , a prostanoid TP receptor agonist , U - 46619 ( 0 . 01 - 0 . 1 nM ) , potentiated 5 - HT - induced contraction . These results indicate that neuropeptide Y potentiates the 5 - HT - induced contraction , due to release of TXA2 from the endothelium via neuropeptide Q03519 receptors , in porcine coronary artery .", "Characterization of 5 - Q13049 receptor desensitization and the effect of cycloheximide on it in P13671 cells . Effect of prolonged pretreatment with serotonin ( 5 - HT ) on 5 - Q13049 receptor desensitization was examined by the measurement of intracellular calcium ( [ Ca2 +] i ) mobilization in P13671 cells . 5 - HT - induced desensitization of [ Ca2 +] i mobilization was in a time and dose dependent manner and reached a plateau after 3 hr . After 1 and 3 hr 5 - HT pretreatment , 5 - HT concentration in the medium little changed . 5 - HT pretreatment with cycloheximide , a protein synthesis inhibitor , produced an enhancement of the desensitization for 3 and 6 hr pretreatment . However , 5 - HT pretreatment for 3 and 6 hr caused no marked change in the 5 - Q13049 receptor mRNA level or Galphaq / 11 protein in this study , suggesting that 5 - HT may decrease 5 - HT - induced [ Ca2 +] i mobilization independent of 5 - Q13049 receptor mRNA or G - proteins . P05305 - induced [ Ca2 +] i mobilization did not alter after 5 - HT and / or cycloheximide pretreatment . These results showed that activation of the 5 - Q13049 receptor induced homologous desensitization and pretreatment with 5 - HT and / or cycloheximide did not change the efficacy of the second messenger pathway from Gq to a [ Ca2 +] i rise .", "High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK26___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .", "DB08932 : An important addition to the treatment of pulmonary arterial hypertension . DB08932 is an orphan drug for the treatment of pulmonary arterial hypertension ( PAH ) . P05305 ( ET - 1 ) plays a critical role of pathophysiology of PAH . DB08932 , a new dual endothelin receptor antagonist , has reportedly improved prognosis of PAH patients by delaying the progression of disease . It prevents the binding of ET - 1 to both endothelin A ( P25101 ) and endothelin B ( ETB ) receptors . DB08932 displays higher efficacy , lesser adverse effects and drug interactions . It has completed phase III trials in 2012 for treatment of PAH and has been tried for ischemic digital ulcers in systemic sclerosis , recurrent glioblastoma and combination with chemotherapeutic agents against various cancers . Safety data for macitentan were obtained primarily from a placebo - controlled clinical study in 742 patients with PAH . The Food and Drug Administration ( FDA ) approved the drug on 13 October 2013 . It is an important addition to long - term treatment of PAH .", "Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK53___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .", "Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK29___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .", "Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK48___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .", "Endothelin @ 25 - new agonists , antagonists , inhibitors and emerging research frontiers : IUPHAR Review 12 . Since the discovery of endothelin ( ET ) - 1 in 1988 , the main components of the signalling pathway have become established , comprising three structurally similar endogenous 21 - amino acid peptides , ET - 1 , P20800 and P14138 , that activate two GPCRs , P25101 and ETB . Our aim in this review is to highlight the recent progress in ET research . The ET - like domain peptide , corresponding to prepro - ET - 193 - 166 , has been proposed to be co - synthesized and released with ET - 1 , to modulate the actions of the peptide . ET - 1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long - lasting action . To date , the major therapeutic strategy to block the unwanted actions of ET in disease , principally in pulmonary arterial hypertension , has been to use antagonists that are selective for the P25101 receptor ( ambrisentan ) or that block both receptor subtypes ( DB00559 ) . DB08932 represents the next generation of antagonists , being more potent than DB00559 , with longer receptor occupancy and it is converted to an active metabolite ; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy . A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET - converting enzyme and neutral endopeptidase such as SLV306 ( daglutril ) . A third strategy based on activating the ETB receptor , has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti - tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions . Finally , we discuss biased signalling , epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research .", "DB08932 : first global approval . DB08932 ( Opsumit ® ) is a novel dual endothelin receptor antagonist ( ERA ) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd . In October 2013 , oral macitentan 10 mg once daily received its first global approval in the US , followed closely by Canada , for the treatment of pulmonary arterial hypertension ( PAH ) . The drug has also received a positive opinion in the EU from the Committee for Medicinal Products for Human Use for the treatment of PAH , and is under regulatory review in several other countries for the same indication . Endothelin ( ET ) - 1 influences pathological changes via two ET receptor subtypes ( P25101 and ETB ) , to which it binds with high affinity . ET - 1 is implicated in several forms of vascular disease making it a valid target for the treatment of pulmonary vascular diseases such as PAH . Clinical development is underway for other indications , including Eisenmenger syndrome , ischaemic digital ulcers secondary to systemic sclerosis , and glioblastoma . DB08932 was also evaluated in idiopathic pulmonary fibrosis ; however , a phase 2 trial did not meet its primary endpoint and further investigation in this indication was discontinued . DB08932 was developed by modifying the structure of DB00559 in the search for an optimal dual ERA with improved efficacy and tolerability compared with other ERAs . This article summarizes the milestones in the development of macitentan leading to this first approval for PAH .", "DB09280 - ___MASK62___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .", "Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK1___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK1___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK1___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury ." ]

[ "___MASK11___", "___MASK18___", "___MASK1___", "___MASK26___", "___MASK29___", "___MASK48___", "___MASK53___", "___MASK62___", "___MASK6___" ]

[ "DB05812 inhibits 1α , 25 - dihydroxyvitamin D3 metabolism by P08684 in human liver and intestine in vitro . The chemopreventive and therapeutic effects of vitamin D3 are exerted through its dihydroxylated metabolite , 1α , 25 - dihydroxyvitamin D3 [ 1α , 25 ( OH ) 2D3 ] . Inactivation of 1α , 25 ( OH ) 2D3 by cytochrome P450 3A4 ( P08684 ) may be an important determinant of its serum and tissue levels . DB05812 , a steroidogenesis inhibitor used in late stage prostate cancer treatment , is a P05093 inhibitor . The purpose of this study was to assess the potential of abiraterone to block hepatic and intestinal inactivation of biologically active vitamin D3in vitro and to evaluate if abiraterone can alter P08684 marker substrate activities . Biotransformation reactions were initiated with NADPH regenerating solutions following initial preincubation of pooled human hepatic or intestinal microsomal protein or human recombinant P08684 supersomes with 1α , 25 ( OH ) 2D3 , midazolam or triazolam for 10min at 37 ° C . Formation of hydroxylated metabolites of 1α , 25 ( OH ) 2D3 , midazolam or triazolam was analyzed by liquid chromatography - mass spectrometry method . Co - incubation of 1α , 25 ( OH ) 2D3 with abiraterone at varying concentrations ( 0 . 2 - 100μM ) led to up to ∼ 85 % inhibition of formation of hydroxylated metabolites of 1α , 25 ( OH ) 2D3 thus preventing inactivation of active vitamin D3 . The IC50 values for individual metabolites of 1α , 25 ( OH ) 2D3 ranged from 0 . 4 to 2 . 2μM in human liver microsomes or human intestinal microsomes . The mechanism of P08684 - mediated inhibition of 1α , 25 ( OH ) 2D3 by abiraterone was competitive ( apparent Ki 2 . 8 - 4 . 3μM ) . Similar inhibitory effects were also observed upon inclusion of abiraterone into midazolam or triazolam hydroxylation assays . In summary , our results suggest that abiraterone inhibits the P08684 - mediated inactivation of active vitamin D3 in human liver and intestine , potentially providing additional anti - cancer benefits to prostate cancer patients . This article is part of a Special Issue entitled ' 16th Vitamin D Workshop ' .", "[ DB05812 acetate : a novel therapeutic option in hormone - refractory prostate cancer ] . Until recently , only therapy with docetaxel and prednisone has been shown to prolong survival in men with hormonorefractory metastatic prostate cancer . With approvals of sipuleucel - T , cabazitaxel , and abiraterone acetate , all based on improvement in overall survival , the scenary for management of men with metastatic prostate cancer has dramatically changed . DB05812 acetate was developed to specifically inhibit cytochrome P450 ( CYP ) 17A1 , which is an essential enzyme in the biosynthesis of testosterone . In the phase III , the trial treatment with abiraterone acetate plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration - resistant prostate cancer who have disease progression after treatment with docetaxel and associated with an acceptable tolerability profile , which was generally similar to that of the placebo plus prednisone group . However , adverse events resulting from elevated mineralocorticoid levels because of P05093 inhibition , fluid retention and oedema , hypokalaemia , hypertension occurred in significantly more in abiraterone acetate plus prednisone than in placebo plus prednisone .", "DB05812 acetate : targeting persistent androgen dependence in castration - resistant prostate cancer . DB05812 acetate is the first second - line hormonal agent proven to improve survival in metastatic castration - resistant prostate cancer . It selectively inhibits cytochrome P450 17 ( P05093 ) α - hydroxylase and cytochrome17 , 20 ( C17 , 20 ) - lyase , which are enzymes critical for androgen synthesis . DB05812 acetate was initially approved in the United States in 2011 after demonstrating a 4 - month survival benefit in docetaxel - refractory metastatic prostate cancer . The FDA recently expanded its indication for use in the pre - chemotherapy setting after it elicited significant delays in disease progression and a strong trend for increased overall survival in phase III studies . Ongoing investigations of abiraterone are evaluating its efficacy in earlier disease states , exploring its synergy in combination with other therapeutic agents , and assessing the necessity for administration of concurrent steroids and gonadal suppression . The identification and development of predictive biomarkers will optimize the incorporation of abiraterone into the management of advanced prostate cancer .", "DB05812 acetate : oral androgen biosynthesis inhibitor for treatment of castration - resistant prostate cancer . Prostate cancer is the second leading cause of cancer death in men in the US and Europe . The treatment of advanced - stage prostate cancer has been androgen deprivation . Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes , but adrenal glands and even prostate cancer tissue continue to produce androgens , which eventually leads to continued prostate cancer growth despite castrate level of androgens . This stage is known as castrate - resistant prostate cancer ( CRPC ) , which continues to be a challenge to treat . Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate - specific antigen levels further , but has not actually translated into life - prolonging options . The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer . Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting . One such agent is abiraterone acetate , which significantly reduces androgen production by blocking the enzyme , cytochrome P450 17 alpha - hydroxylase ( P05093 ) . This has provided physicians with another treatment option for patients with CRPC . The landscape for prostate cancer treatment has changed with the approval of cabazitaxel , sipuleucel - T and abiraterone . Here we provide an overview of abiraterone acetate , its mechanism of action , and its potential place for therapy in CRPC .", "Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .", "P05093 inhibition as a hormonal strategy for prostate cancer . P10275 ( AR ) signaling has a key role in the pathogenesis of prostate cancer . AR gene amplification , AR overexpression , and activating mutations in the AR occur more frequently as castration - resistant prostate cancer ( CRPC ) evolves , with intratumoral androgen levels remaining sufficient for AR activation despite castration . The source of these androgens might be either adrenal or intratumoral . AR signaling , therefore , remains a valid treatment target for patients with CRPC . P05093 is a key enzyme for androgen biosynthesis . The imidazole antifungal agent ketoconazole weakly and nonspecifically inhibits P05093 , but remains unlicensed for this indication . Chemists at the Cancer Research UK Centre for Cancer Therapeutics have designed a novel , selective , irreversible inhibitor of P05093 called abiraterone , which is more than 20 times more potent than ketoconazole . DB05812 acetate , a prodrug , has undergone phase I assessment , and is rapidly progressing from phase II to phase III trials , in view of its high level of antitumor activity . This agent is safe and well tolerated , and activity profiles suggest that approximately 50 % of CRPC remains AR - ligand driven . Other P05093 inhibitors with alternative mechanisms of action , for example VN / 124 - 1 , are in preclinical development . The rationale for and implications of P05093 inhibition and the P05093 - targeting agents in development are discussed in this Review .", "Limited in vitro efficacy of P05093 inhibition on human castration resistant prostate cancer . Although accumulating evidence indicates high expression of P05093 ( P45017A1 ) allows castration resistant prostate cancer ( CRPC ) to maintain high intratumoral androgen levels , the potential P45017A1 activity has not been characterized yet . The aim of this study was to examine the potential P05093 activity including 17α - hydroxylase and 17 , 20 - lyase activities in human CRPC and the effect of a CYP17A inhibitor . We used three human CRPC cell lines : C4 - 2 and C4 - 2AT6 which was established from C4 - 2 under androgen ablation conditions for 6months , and PC3 . To ascertain the potential P05093 activity , we cultured with the steroid precursors : ( 13 ) C -[ 2 , 3 , 4 ]- progesterone ( 13C - Prog ) , and analyzed the sequential biosynthesis ( 13 ) C -[ 2 , 3 , 4 ]- 17 - hydroxyprogesterone ( 13C - 17OHP ) and ( 13 ) C -[ 2 , 3 , 4 ]- androstenedione ( 13C - Adione ) by liquid chromatography / mass spectrometry ( LC / MS / MS ). The C4 - 2AT6 cells showed significantly higher P05093 expression than C4 - 2 cells ( p < 0 . 001 ) . LC / MS / MS analysis enabled us to detect the 13C - 17 - OHP and 13C - A - dione in these cell lines . The concentration ratio of 13C - Adione / 13C - 17OHP ( Adione - 17OHP ratio ) , which is thought to reflect the differences between 17 - hydroxylase and 17 , 20 - lyase activities , was then determined . The Adione - 17OHP ratio in C4 - 2AT6 cells was significantly higher than that of C4 - 2 cells ( p < 0 . 001 ) . DB05812 were able to inhibit the CYP17A activities , although abiraterone did not have anti - proliferative effects on C4 - 2 and C4 - 2AT6 cells at clinically achievable concentrations of < 1000nM in vitro . The present study clearly demonstrates CRPC have the dual activities of P05093 mediated by 17 - hydroxylase activity and 17 , 20 - lyase activity . DB05812 does n ' t have an in vitro anti - proliferative efficacy in CRPC cells , suggesting limited efficacy in vitro .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK32___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines . Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia , and prostate cancer . Although testosterone is the main androgen secreted from the testes , dihydrotestosterone ( DB02901 ) , a more potent androgen converted from testosterone by 5alpha - reductase isozymes , type I and II , is the major androgen in the prostate cells . The aim of this study is to investigate the cellular and molecular effects of dutasteride , a potent inhibitor of 5alpha - reductase type I and type II , in androgen - responsive ( LNCaP ) and androgen - unresponsive ( DU145 ) human prostate cancer ( PCa ) cell lines . The expression pattern of 190 genes , selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling , were analysed using a low density home - made oligoarray ( AndroChip 2 ) . Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested . AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed ( FC > or = +/- 1 . 5 ) . Eight of these genes , were overexpressed and three were underexpressed . Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen ( P14061 ; P37058 ; P19099 ) , androgen receptor and androgen receptor co - regulators ( AR ; P24385 ) , and signal transduction ( P04626 ; V - P62158 ; Q07889 ) whereas , underexpressed genes ( KLK3 ; P20151 ; Q15392 ) were androgen - regulated genes ( ARGs ) . No differentially expressed genes were scored in DU145 . Microarray data were confirmed by quantitative real - time PCR assay ( QRT - PCR ) . These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK12___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK12___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK12___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK12___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "Novel P05093 inhibitors : synthesis , biological evaluation , structure - activity relationships and modelling of methoxy - and hydroxy - substituted methyleneimidazolyl biphenyls . Recently , the steroidal P05093 inhibitor DB05812 entered phase II clinical trial for the treatment of androgen - dependent prostate cancer . As 17alpha - hydroxylase - 17 , 20 - lyase ( P05093 ) catalyzes the last step in androgen biosynthesis , inhibition of this target should affect not only testicular but also adrenal androgen formation . Therefore P05093 inhibitors should be advantageous over existing therapies , for example with DB00644 analogues . However , steroidal drugs are known for side effects which are due to affinities for steroid receptors . Therefore we decided to synthesize non - steroidal compounds mimicking the natural P05093 substrates pregnenolone and progesterone . The synthesis and biological evaluation of a series of 15 novel and highly active non - steroidal P05093 inhibitors are reported . The compounds were prepared via Suzuki - cross - coupling , Grignard reaction and CDI - assisted S ( N ) t - reaction with imidazole and their inhibitory activity was examined with recombinant human P05093 expressed in Escherichia coli . Promising compounds were further tested for their selectivity against the hepatic enzyme P08684 and the glucocorticoid - forming enzyme P15538 . All compounds turned out to be potent P05093 inhibitors . The most active compounds 7 and 8 were much more active than Ketoconazole showing activity comparable to DB05812 ( IC ( 50 ) values of 90 and 52nM vs . 72nM ) . Most compounds also showed higher selectivities than Ketoconazole , but turned out to be less selective than DB05812 . Docking studies using our P05093 protein model were performed with selected compounds to study the interactions between the inhibitors and the amino acid residues of the active site .", "Resistance to abiraterone in castration - resistant prostate cancer : a review of the literature . Persistent androgen signaling is functionally significant in castration - resistant prostate cancer ( CRPC ) and it is actually considered a validated therapeutic target . Residual intra - tumoral androgens compensate for the effects of androgen ablation , activating the androgen receptor ( AR ) , AR - mediated gene expression and driving CRPC . The intra - tumoral biosynthesis of androgens takes place in different ways and cytochrome P450 17A1 ( P05093 ) has a crucial role in this context . DB05812 , a P05093 inhibitor , has shown impressive results in pre - and post - chemotherapy settings , prolonging the survival of patients with CRPC . However , not all patients respond to the treatment and most responders develop resistance , with a widely variable duration of response . Although many hypotheses are emerging , the mechanisms of resistance to abiraterone treatment have not yet been elucidated . The aim of the present review is to describe the main data currently available on resistance to abiraterone .", "Antitumor activity with P05093 blockade indicates that castration - resistant prostate cancer frequently remains hormone driven . DB05812 acetate is a potent , selective , and orally bioavailable small molecule inhibitor of P05093 , an enzyme that catalyzes two key serial reactions ( 17 alpha hydroxylase and 17 , 20 lyase ) in androgen and estrogen biosynthesis . Clinical trials have confirmed that specific inhibition of P05093 is safe and results in clinically important antitumor activity in up to 70 % of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies . These clinical data indicate that castration - resistant prostate cancer frequently remains hormone dependent and has confirmed that this disease should no longer be described as \" hormone resistant or refractory \" . Biomarker studies , including the analysis of ETS gene fusion status , on patients treated with abiraterone acetate may allow enrichment of patients with a sensitive phenotype in future studies of therapeutics targeting P05093 .", "[ DB05812 acetate ( ZYTIGA ®)- development and literature review ] . DB05812 acetate ( AA ) has been approved in more than 80 countries for the treatment of patients with metastatic castration - resistant prostate cancer ( mCRPC ) . In July 2013 , a marketing approval application for AA was submitted to the Japanese Ministry of Health , Labour , and Welfare . AA is a selective inhibitor of P05093 , a crucial enzyme for androgen biosynthesis . AA exerts its anti - tumor activity by directly inhibiting androgen production at all three sources , i . e . , the testes , adrenal glands , and tumor itself . Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life ( QoL ) of patients with mCRPC . Herein , we have summarized the development of AA and the results of important international and local clinical trials in Japan . In addition , the effect of food on AA bioavailability , concomitant steroid use , and liver function test abnormalities have been discussed regarding the appropriate use of AA .", "Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK68___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .", "Highly - selective 4 -( 1 , 2 , 3 - triazole )- based P450c17a 17 , 20 - lyase inhibitors . The orally - active P05093 inhibitor abiraterone acetate ( AA ) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer . DB05812 potently inhibits both reactions catalyzed by P05093 , the 17α - hydroxylase ( hydroxylase ) reaction as well as the 17 , 20 - lyase ( lyase ) transformation . P05093 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids . As a consequence of potent P05093 hydroxylase inhibition ( i . e . , lack of lyase selectivity ) , AA must be co - administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome ( MES ) . Herein , we describe rationally - designed , P05093 lyase - selective inhibitors that could prove safer and more effective than abiraterone . Using proprietary methodology , the high - affinity pyridine or imidazole metal - binding group found in current clinical P05093 inhibitors was replaced with novel , less avid , metal - binding groups in concert with potency - enhancing molecular scaffold modifications . This process produced a unique series of P05093 lyase - selective inhibitors that included the oral agent 6 ( VT - 464 ) , now in Phase 2 prostate cancer clinical trials . The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases .", "[ DB01373 signaling mediated by nicotine receptors in neurons ] . DB00184 has many acute and chronic pharmacological effects . DB00184 treatment activates neuronal nicotinic acetylcholine receptors ( nAChR ) in peripheral and central nervous systems leading to depolarization and elevation of intracellular calcium levels , which are considered to cause stimulation of neurotransmitter release , synaptic transmission , intracellular signal transduction and gene expression . Multiple subtypes of nAChRs display different sensitivity to nicotinic agonists and antagonists . Each of these subtypes has a unique distribution in peripheral and central nervous systems . Although presynaptic nAChRs have been extensively studied to modulate the release of neurotransmitters , the functional importance of nAChRs in somata is not sufficiently characterized . To clarify the mechanisms of calcium signaling and its stimulation of gene expression via nAChRs in somata , we have investigated nAChR - mediating calcium signaling mechanisms including phosphorylation of Q8NFH3 / 44 Q96HU1 kinase ( P29323 ) , CREB and Akt in PC12h cells . DB00184 transiently activates phosphorylation of P29323 - , CREB and Akt . DB00184 induces the activation of both P19957 kinase / Act and P29323 / CREB pathways via common pathways including non - alpha 7 - nAChRs , L - type VSCC , P62158 kinase and P00533 in PC12h cells , but Src family tyrosine kinases only participate in the pathway to activate Akt . Based on these results , we discuss nAChR signaling mechanisms in neurons .", "Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK59___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .", "Androgen synthesis inhibitors in the treatment of castration - resistant prostate cancer . Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer . However , in the majority of patients who develop castration - resistant prostate cancer ( CRPC ) , it is possible to detect persistent activation of the androgen receptor ( AR ) through androgens produced in the adrenal gland or within the tumor itself . DB05812 acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme P05093 with activity as a 17α - hydroxylase and 17 , 20 - lyase . P05093 is necessary for production of nongonadal androgens from cholesterol . Regulatory approval of abiraterone in 2011 , based on a phase III trial showing a significant improvement in overall survival ( OS ) with abiraterone and prednisone versus prednisone , represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC . Inhibition of 17α - hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol - mediated suppression of pituitary adrenocorticotropic hormone ( DB01285 ) , providing a rationale for development of P05093 inhibitors with increased specificity for 17 , 20 - lyase ( orteronel , galeterone and VT - 464 ) that can potentially be administered without exogenous corticosteroids . In this article , we review the development of abiraterone and other P05093 inhibitors ; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality - of - life , potential early predictors of response , and optimal sequencing of abiraterone with respect to other agents ; and results of translational studies providing insights into resistance mechanisms to P05093 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity .", "DB05812 in heavily pretreated patients with metastatic castrate - resistant prostate cancer . The aim of this study was to evaluate the activity and tolerability of abiraterone acetate in patients with metastatic castrate - resistant prostate cancer treated previously with more than three lines of chemotherapy . Patients received 1 g of abiraterone acetate ( administered as four 250 mg tablets ) orally once daily with prednisone at a dose of 5 mg orally twice daily . The primary endpoint was prostate - specific antigen ( PSA ) response . From August 2011 to January 2013 , 36 patients were enrolled . PSA response was observed in 22 patients ( 61 . 1 % , 95 % confidence interval : 0 . 41 - 0 . 81 ) . The median time to PSA progression was 7 . 3 months and after a median follow - up of 10 . 1 months , all patients were alive . The treatment was generally well tolerated ; side effects secondary to mineralocorticoid excess resulting from blockade of P05093 were largely controlled with prednisone . DB05812 acetate seems to be an effective and well - tolerated treatment option for patients with metastatic castrate - resistant prostate cancer irrespective of the number of chemotherapy lines administered previously .", "Long - term hypoxia increases endothelial nitric oxide synthase expression in the ovine fetal adrenal . This study was designed to test the hypothesis that fetal adrenal nitric oxide synthase ( NOS ) is elevated in response to long - term hypoxia ( LTH ) . Pregnant ewes were maintained at high altitude ( 3820 m ) for approximately the last 100 days of gestation . Between days 138 and 141 of gestation , adrenal glands were collected from LTH fetuses and age - matched normoxic controls . Quantitative real - time polymerase chain reaction ( qRT - PCR ) and Western analysis were used to quantify NOS expression , and NOS distribution was examined by immunohistochemistry and double - staining immunofluorescence for endothelial NOS ( P29474 ) and 17alpha - hydroxylase ( P05093 ) . P29475 ( P29475 ) was expressed at very low levels and with no differences between groups . Expression of P29474 was significantly greater in the LTH group compared with control . P29475 was distributed throughout the cortex while the greatest density of P29474 was observed in the zona fasciculata / reticularis area and P29474 co - localized with P05093 . We conclude that LTH enhances P29474 expression in the inner adrenal cortex which may play a role in regulation of cortisol biosynthesis in the LTH fetus .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .", "Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( DB02901 ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .", "Retreatment of men with metastatic castrate - resistant prostate cancer with abiraterone . BACKGROUND : DB05812 acetate ( AA ) , oral P05093 inhibitor , is an active agent in the treatment of metastatic castrate - resistant prostate cancer ( mCRPC ) . METHODS : We ( R . L . A and N . A ) retrospectively evaluated outcome in 12 men who were re - treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre . RESULTS : All men were heavily pre - treated for mCRPC with a median of four prior lines of therapy , one of which was AA ( given either pre - or post - chemotherapy ) . Eleven out of 12 ( 92 % ) men stopped their first treatment course of AA due to progression and one stopped for financial reasons . Seven men had a PSA decrease ≥ 50 % following their first AA treatment , of which three ( 46 % ) had a PSA decrease ≥ 50 % to AA re - treatment . The responses to AA re - treatment were generally short - lived with a median biochemical progression - free survival of 2 . 3 months and median treatment duration of 3 . 2 months . No PSA responses to AA re - treatment were seen in five men who did not have an initial PSA response to AA . CONCLUSIONS : Our data suggest that AA re - challenge may have limited benefit in select men with mCRPC , and warrants further formal research .", "Androgen metabolism and JAK / P35610 pathway genes and prostate cancer risk . BACKGROUND : Prostate cancer ( PC ) is the most frequently diagnosed solid tumor in U . S . men . Genome - wide association studies ( GWAS ) have identified over 40 risk - associated single nucleotide polymorphisms ( SNPs ) , including variants in androgen pathway genes ( e . g . , KLK3 and AR ) . Androgens are important in PC and genes involved in this pathway are therefore candidates for conferring susceptibility to PC . METHODS : In this hypothesis - testing study , we evaluated PC risk in association with SNPs in 22 candidate genes involved in androgen metabolism or interactions with the androgen receptor ( AR ) . A total of 187 SNPs were genotyped in 1458 cases and 1351 age - matched controls from a population - based study . PC risk was estimated using adjusted unconditional logistic regression and multinomial regression models . RESULTS : Single SNP analyses showed evidence ( p < 0 . 05 ) for associations with 14 SNPs in 9 genes : Q99801 , P37058 , P42330 , Q06520 , P05093 , KLK3 , O60674 , Q13772 and P40763 . The most significant result was observed for rs2253502 in P37058 ( odds ratio , OR = 0 . 57 , 95 % CI : 0 . 39 - 0 . 84 ) . In addition , five SNPs in four genes ( P05093 , P51659 , Q13772 , and Q06520 ) were associated with more aggressive disease ( p < 0 . 01 ) . CONCLUSIONS : Our results replicate previously reported associations for SNPs in P05093 , P37058 , ARK1C3 , Q99801 , Q13772 and KLK3 . In addition , novel associations were observed for SNPs in O60674 , P51659 , and Q06520 . These results will require replication in larger studies .", "Use of prednisone with abiraterone acetate in metastatic castration - resistant prostate cancer . DB05812 acetate , a prodrug of the P05093 inhibitor abiraterone that blocks androgen biosynthesis , is approved for treatment of patients with metastatic castration - resistant prostate cancer ( mCRPC ) in combination with prednisone or prednisolone 5 mg twice daily . This review evaluates the basis for the effects of prednisone on mineralocorticoid - related adverse events that arise because of P05093 inhibition with abiraterone . Coadministration with the recommended dose of glucocorticoid compensates for abiraterone - induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone . Consequently , 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate , analogous to use of glucocorticoid replacement therapy for certain endocrine disorders . We searched PubMed to identify safety concerns regarding glucocorticoid use , placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer . In general , glucocorticoid - related adverse events , including bone loss , immunosuppression , hyperglycemia , mood and cognitive alterations , and myopathy , appear dose related and tend to occur at doses and / or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC . Although glucocorticoids are often used to manage tumor - related symptoms or to prevent treatment - related toxicity , available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC . Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone , the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens .", "Antitumour activity of docetaxel following treatment with the P05093 inhibitor abiraterone : clinical evidence for cross - resistance ? BACKGROUND : DB05812 and docetaxel are both approved treatments for men with metastatic castration - resistant prostate cancer ( mCRPC ) . DB05812 pre - docetaxel is currently undergoing evaluation in a phase III study . In vitro studies indicate that taxanes may act by disrupting androgen receptor signalling . We hypothesised that prior abiraterone exposure would adversely impact docetaxel efficacy . PATIENTS AND METHODS : We retrospectively evaluated activity of docetaxel in mCRPC patients previously treated with abiraterone , using Prostate Cancer Working Group and radiological criteria . RESULTS : Of the 54 patients treated with abiraterone , 35 subsequently received docetaxel . DB01248 resulted in a prostate - specific antigen ( PSA ) decline of ≥ 50 % in nine patients [ 26 % , 95 % confidence interval ( CI ) 13 % to 43 % ] , with a median time to PSA progression of 4 . 6 months ( 95 % CI 4 . 2 % to 5 . 9 % ) . PSA declines ≥ 30 % were achieved by 13 patients ( 37 % , 95 % CI 22 % to 55 % ) . The median overall survival was 12 . 5 months ( 95 % CI 10 . 6 - 19 . 4 ) . All patients who failed to achieve a PSA fall on abiraterone and were deemed abiraterone - refractory were also docetaxel - refractory ( N = 8 ) . In the 24 patients with radiologically evaluable disease , partial responses were reported in four patients ( 11 % ) , none of whom were abiraterone - refractory . CONCLUSION : The activity of docetaxel post - abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone - refractory patients .", "P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK76___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Role of adiponectin in regulating ovarian theca and granulosa cell function . Q15848 is an adipokine that has been implicated in insulin resistance , a condition associated with polycystic ovarian syndrome in humans , but whether adiponectin can directly affect ovarian theca or granulosa cell function is unknown . Therefore , to determine the effects of adiponectin on proliferation , steroidogenesis and gene expression of large - follicle theca and granulosa cells , experiments were conducted using bovine ovarian cell cultures . RT - PCR was used to elucidate the effects of adiponectin on gene expression of P05108 and LH receptor ( LHR ) in large - follicle theca and granulosa cells , as well as expression of P05093 in theca cells and P11511 in granulosa cells . Q15848 decreased ( P < 0 . 05 ) insulin - induced progesterone and androstenedione production as well as attenuated P05019 - induced LHR , P05108 , and P05093 gene expression in theca cells . In contrast , adiponectin decreased ( P < 0 . 05 ) LHR mRNA abundance in granulosa cells but did not affect steroidogenic enzyme gene expression in granulosa cells . Q15848 had no effect ( P > 0 . 10 ) on proliferation of large - follicle theca cells . RT - PCR also revealed that abundance of mRNA for the adiponectin receptor ( Q86V24 ) was greater ( P < 0 . 05 ) in large - follicle than in small - follicle theca cells and did not significantly differ between small - and large - follicle granulosa cells . In cultured theca cells , LH increased ( P < 0 . 05 ) and P05019 decreased ( P < 0 . 05 ) Q86V24 mRNA abundance . These results indicate that the inhibitory effects of adiponectin on steroidogenesis are primarily localized to theca cells and that the response of theca cells to adiponectin ( i . e . , Q86V24 ) may be regulated by LH and P05019 .", "Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium . NO , produced by endothelial NO synthase ( P29474 ) , is a key mediator of pulmonary vasodilation during cardiopulmonary transition at birth . The capacity for NO production is maximal at term because pulmonary P29474 expression increases during late gestation . Since fetal estrogen levels rise markedly during late gestation and there is indirect evidence that the hormone enhances nonpulmonary NO production in adults , estrogen may upregulate P29474 in fetal pulmonary artery endothelium . Therefore , we studied the direct effects of estrogen on P29474 expression in ovine fetal pulmonary artery endothelial cells ( PAECs ) . ___MASK47___ caused a 2 . 5 - fold increase in NOS enzymatic activity in PAEC lysates . This effect was evident after 48 hours , and it occurred in response to physiological concentrations of the hormone ( 10 (- 10 ) to 10 (- 6 ) mol / L ) . The increase in NOS activity was related to an upregulation in P29474 protein expression , and P29474 mRNA abundance was also enhanced . P03372 antagonism with DB00947 completely inhibited estrogen - mediated P29474 upregulation , indicating that estrogen receptor activation is necessary for this response . In addition , immunocytochemistry revealed that fetal PAECs express estrogen receptor protein . Furthermore , transient transfection assays with a specific estrogen - responsive reporter system have demonstrated that the endothelial estrogen receptor is capable of estrogen - induced transcriptional transactivation . Thus , estrogen upregulates P29474 gene expression in fetal PAECs through the activation of PAEC estrogen receptors . This mechanism may be responsible for pulmonary P29474 upregulation during late gestation , thereby optimizing the capacity for NO - mediated pulmonary vasodilation at birth .", "[ Roles of medical oncologists in the new era of CRPC therapy in Japan ] . Currently , the standard therapy for advanced prostate cancer is endocrine therapy ( luteinizing hormone - releasing hormone [ LH - RH ] agonists alone or LH - RHagonists plus antiandrogens ) . However , most patients eventually become resistant to these therapies as well as castration therapy . New endocrine therapies for castration - resistant prostate cancer ( CRPC ) have been developed . DB05812 , a P05093 inhibitor , and enzalutamide , a novel androgen receptor antagonist , have been shown to improve the overall survival , and they are set to be approved in Japan soon . Moreover , docetaxel and cabazitaxel have been established as first - and second - line chemotherapeutic drugs , respectively . Although there is currently no established molecular target drug for CRPC , some drugs such as cabozantinib seem to be effective , and they may be used in the future . In these situations of new drug development , the contribution of medical oncologists is predictable . While medical oncologists can not play central roles in all aspects of drug therapy for urological malignancies in Japan , they must play roles in certain aspects such as new drug development starting from phase I trials , improving multidisciplinary care for adverse events , and promoting translational research .", "17 ___MASK47___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .", "Recent progress in pharmaceutical therapies for castration - resistant prostate cancer . Since 2010 , six drugs have been approved for the treatment of castration - resistant prostate cancer , i . e . , P05093 inhibitor DB05812 , androgen receptor antagonist DB08899 , cytotoxic agent DB06772 , vaccine Sipuleucel - T , antibody DB06643 against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin . All these drugs demonstrate improvement on overall survival , expect for DB06643 , which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone - metastasis - free survival . Besides further P05093 inhibitors ( Orteronel , Galeterone , VT - 464 and CFG920 ) , androgen receptor antagonists ( ARN - 509 , ODM - 201 , AZD - 3514 and EZN - 4176 ) and vaccine Prostvac , more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials , including various kinase inhibitors and platinum complexes . Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments . Under these flourishing circumstances , more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients .", "P05093 inhibitors in castration - resistant prostate cancer . The majority of prostate cancer ( PCa ) cases are diagnosed as a localized disease . Definitive treatment , active surveillance or watchful waiting are employed as therapeutic paradigms . The current standard of care for the treatment of metastatic PCa is either medical or surgical castration . Once PCa progresses in spite of castrate androgen levels it is termed ' castration - resistant prostate cancer ' ( CRPC ) . Patients may even exhibit rising PSA levels with possible bone , lymph node or solid organ metastases . In 2010 , the only agent approved for the treatment of CRPC was docetaxel , a chemotherapeutic agent . It is now known that cells from patients with CRPC express androgen receptors ( AR ) and remain continuously influenced by androgens . As such , treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront . The use of cytochrome P450c17 ( P05093 ) inhibitor underlies one of the most recent advances in the treatment of CRPC . DB05812 acetate ( AA ) was the first P05093 inhibitor approved in the United States . This review will discuss CRPC in general with a specific focus on AA and novel P05093 inhibitors . AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy . Furthermore , the most recently identified P05093 inhibitors Orteronel , Galeterone , VT - 464 , and CFG920 will also be explored .", "Battle of the kinases : integration of adrenal responses to DB02527 , DG and Ca2 + at the level of steroidogenic cytochromes P450 and 3betaHSD expression in H295R cells . While DB01285 receptors ( activating the protein kinase A pathway ) are expressed throughout the human / bovine / ovine zona glomerulosa ( zg ) and zona fasciculata ( zf ) , there are clear zonal differences in AII Type - 1 receptor levels ( activating protein kinase C / Ca2 + ) , as well as resting membrane potential . Thus zg is most responsive to AII and K + ( Ca2 + signalling ) , while zf is less responsive to AII with no K + response . Zonal function in turn requires differential expression of P05093 / 3betaHSD and P19099 / P15538 . We have used the H295R cell to study how differential activation of kinase A , kinase C and Ca2 +/ calmodulin ( P62158 ) kinases may alter the relative expression of the steroidogenic P450s and 3betaHSDII . While P05108 , P05093 , 3betaHSDII , P08686 , and P15538 are all induced by increases in DB02527 , studies with TPA alone or in combination with forskolin reveal subsets of steroidogenic enzymes regulated either positively ( P08686 , 3betaHSDII ) or negatively ( P05093 , P05108 ) by protein kinase C . Thus adrenal 3betaHSDII and P08686 expression is high in zg and zf , but P05093 is not expressed in the zg where AII activation of kinase C is highest . In turn both K + and AII - induced elevation of Ca2 + strongly induces P19099 but not P15538 , consistent with preferential expression of P19099 in the zg . We conclude that differential signaling through kinase C and P62158 kinases in addition to kinase A underlies zonal differences in both the early and late pathways involved in steroid hormone production within the adrenocortical zones .", "A - ring modified steroidal azoles retaining similar potent and slowly reversible P05093 inhibition as abiraterone . DB05812 acetate is a potent inhibitor of human cytochrome P450c17 ( P05093 , 17α - hydroxylase / 17 , 20 - lyase ) and is clinically used in combination with prednisone for the treatment of castration - resistant prostate cancer . Although many studies have documented the potency of abiraterone ( Abi ) in a variety of in vitro and in vivo systems for several species , the exact potency of Abi for human P05093 enzyme has not yet been determined , and the structural requirements for high - potency steroidal azole inhibitors are not established . We synthesized 4 Abi analogs differing in the A - B ring substitution patterns : 3α - hydroxy - Δ ( 4 )- Abi ( 13 ) , 3 - keto - Δ ( 4 )- Abi ( 11 ) , 3 - keto - 5α - Abi ( 6 ) , and 3α - hydroxy - 5α - Abi ( 5 ) . We measured the spectral binding constants ( Ks ) using purified and modified human P05093 along with the determination constants ( Ki ) applying a native human P05093 enzyme in yeast microsomes for these compounds as well as for ketoconazole . For Abi , 3 - keto - Δ ( 4 )- Abi , 3 - keto - 5α - Abi , and 3α - hydroxy - 5α - Abi , the type 2 spectral changes gave the best fit for a quadratic equation , since in these experiments Ks values were 0 . 1 - 2 . 6nM , much lower than that for ketoconazole and 3α - hydroxy - Δ ( 4 )- Abi ( Ks values were 140 and 1660nM , respectively ) . Inhibition experiments showed mixed inhibition patterns with Ki values of 7 - 80nM . Abi dissociation from the P05093 - Abi complex was incomplete and slow ; the t1 / 2 for dissociation was 1 . 8h , with 55 % of complex remaining after 5h . We conclude that Abi and the 3 related steroidal azoles ( 3 - keto - Δ ( 4 )- Abi , 3 - keto - 5α - Abi , and 3α - hydroxy - 5α - Abi ) , which also mimic natural substrates , are extraordinarily potent inhibitors of human P05093 , whereas the 3α - hydroxy - Δ ( 4 )- Abi is moderately potent and comparable to ketoconazole .", "DB05812 acetate : redefining hormone treatment for advanced prostate cancer . Prostate cancer has long since been recognised as being hormonally driven via androgen receptor signalling . DB05812 acetate ( AA ) is a rationally designed P05093 inhibitor that blocks the conversion of androgens from non - gonadal precursors effectively , thus reducing testosterone to undetectable levels . AA has recently been proved to extend survival for men with metastatic castration - resistant prostate cancer who have progressive disease after first - line chemotherapy treatment . In addition , it is currently being tested in a Phase III trial in the pre - chemotherapy setting . This paper will review the preclinical discovery and clinical development of AA and will outline the strategy of parallel translational research .", "The 5α - androstanedione pathway to dihydrotestosterone in castration - resistant prostate cancer . The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor ( AR ) , as well as the availability of endogenous AR agonists . Originating from the gonads , testosterone is released into circulation and is converted by steroid - 5α - reductase in prostate cancer to 5α - dihydrotestosterone ( DB02901 ) , potently activating AR and driving tumor progression . Advanced prostate cancer is initially treated with gonadal testosterone depletion , which suppresses this cascade of events and typically leads to a treatment response . Eventually , resistance to testosterone deprivation occurs with \" castration - resistant \" prostate cancer ( CRPC ) and is driven by the intratumoral synthesis of DB02901 . The generation of DB02901 occurs in large part from adrenal 19 - carbon precursor steroids , which are dependent on expression of P05093 . Although the path from adrenal precursor steroids to DB02901 was generally thought to require 5α - reduction of testosterone , recent data suggest that it instead involves conversion from Δ - androstenedione by steroid - 5α - reductase isoenzyme - 1 to 5α - androstanedione , followed by subsequent conversion to DB02901 . The 5α - androstanedione pathway to DB02901 therefore bypasses testosterone entirely . DB05812 acetate effectively inhibits P05093 , blocks the synthesis of androgens , and extends the survival of men with CRPC . Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate .", "Hormonal therapy for prostate cancer : toward further unraveling of androgen receptor function . Prostate cancer is a major cause of cancer - related death in men . Prostate cancer is an androgen - responsive tumor and the treatment of advanced prostate cancer involves hormonal therapy . First - line treatment for advanced prostate cancer is androgen deprivation therapy ( ADT ) , usually with agents that suppress gonadotropins through a pituitary mechanism . DB00644 agonists and antagonists both suppress gonadal release of testosterone , although their activity profiles vary . ADT down - regulates androgen receptor ( AR ) transcriptional activity in the tumor but the response in metastatic disease is transient and tumors progress as castration - resistant prostate cancer ( CRPC ) . Although serum testosterone concentrations decline dramatically with ADT , CRPC growth remains largely dependent on AR activity . Secondary hormonal therapies are then often employed to further dampen AR - driven transcription . These secondary hormonal therapies either further deplete adrenal or intratumoral androgen synthesis , or directly and competitively antagonize AR . New hormonal agents with both of these mechanisms are in clinical trials and show promising activity in patients with CRPC . DB05812 acetate is an inhibitor of P05093 , which is an enzyme required for the synthesis of all androgens and estrogens . MDV3100 is an AR antagonist that has a higher affinity for AR than any other AR antagonist in clinic use . In phase I and phase II clinical trials , both agents have significant activity . These agents and the promise of the development of others provide hope that more effective hormonal therapies may soon be offered to patients , which will improve clinical outcomes .", "DB05812 acetate , a novel adrenal inhibitor in metastatic castration - resistant prostate cancer . The androgen receptor remains the key player in patients with castration - resistant prostate cancer ( CRPC ) . Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities . DB05812 acetate , a pregnenolone analog , is a small molecule that irreversibly inhibits P05093 , a rate - limiting enzyme in androgen biosynthesis . Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC . Recently , a randomized phase 3 trial evaluating abiraterone acetate in docetaxel - refractory CRPC patients demonstrated a survival improvement over placebo - treated patients ( 14 . 8 vs 10 . 9 months ; HR 0 . 646 ; P < 0 . 0001 ) . A similar trial in the pre - chemotherapy setting has completed accrual and is undergoing analysis . Here we review the rationale and clinical development of abiraterone acetate in men with CRPC .", "New agents and strategies for the hormonal treatment of castration - resistant prostate cancer . IMPORTANCE OF THE FIELD : Hormonal therapy with medical or surgical castration is the mainstay of systemic therapy for advanced prostate cancer . Depletion of gonadal testosterone in circulation is typically initially effective , although responses are transient and metastatic disease progresses as castration - resistant prostate cancer ( CRPC ) . AREAS COVERED IN THIS REVIEW : CRPC is accompanied by a gain of function in the androgen receptor ( AR ) , which may occur at the level of AR itself or through intratumoral repletion of androgens that in turn stimulate AR . Investigational drugs in clinical trials have promising activity in CRPC . DB05812 acetate is a P05093 inhibitor that blocks the synthesis of adrenal androgens . MDV3100 is a nonsteroidal AR antagonist with a greater binding affinity than other AR antagonists currently in clinical use . Insights into the mechanisms of intratumoral steroidogenesis in CRPC have defined other potential targets . Metabolism from DB01708 to testosterone and dihydrotestosterone requires 3 - hydroxyl oxidation and Delta ( 5 ) isomerization to Delta ( 4 ) by 3beta - hydroxysteroid dehydrogenase ( 3betaHSD ) and 17 - keto reduction by 17beta - hydroxysteroid dehydrogenase ( 17betaHSD ) - 3 or - 5 . AR activation in CRPC by intratumoral steroids requires these enzymatic steps . Investigation into specific inhibitors of 3betaHSD and 17betaHSD are required to determine their efficacy and potential roles in the treatment of CPRC . WHAT THE READER WILL GAIN : Readers will gain an understanding of the biology of CRPC , new investigational hormonal agents and novel approaches to the treatment of CRPC . TAKE HOME MESSAGE : Intratumoral androgens drive CRPC progression . New investigational hormonal agents that inhibit intratumoral androgens are highly active in the treatment of CRPC . Alternative strategies hold the promise for the development of other agents with novel mechanisms of action .", "DB05812 acetate : a review of its use in patients with metastatic castration - resistant prostate cancer . DB05812 acetate ( Zytiga (®) ) is an orally administered , selective inhibitor of the 17α - hydroxylase and C17 , 20 - lyase enzymatic activities of cytochrome P450 ( CYP ) 17 . P05093 is required for androgen biosynthesis , with androgen receptor signalling crucial in the progression from primary to metastatic prostate cancer . DB05812 acetate is approved in the European Union and the US , in combination with prednisone or prednisolone , for the treatment of men with metastatic castration - resistant prostate cancer ( CRPC ) . When administered in combination with prednisone in a placebo - controlled , multinational phase III study , abiraterone acetate significantly prolonged overall survival and radiographic progression - free survival ( rPFS ) in men with metastatic CRPC who had previously received docetaxel . In men with metastatic CRPC who had not previously received chemotherapy participating in a placebo - controlled , multinational phase III study , there was a strong trend towards an overall survival benefit , a significant prolongation in rPFS and significant delays in clinical decline , the need for chemotherapy and the onset of pain observed . Given the nature of the therapy , the overall tolerability profile of abiraterone acetate , in combination with prednisone , was acceptable in men with metastatic CRPC . DB05812 acetate is associated with hypokalaemia , hypertension , and fluid retention or oedema , secondary to its mechanism of action , and with cardiac adverse events and hepatotoxicity ; however , in the phase III studies the incidences of the most frequently reported grade 3 or 4 adverse events of special interest were relatively low . Although the final overall survival data in men with metastatic CRPC who have not previously received chemotherapy are awaited , current evidence indicates that abiraterone acetate is a useful option for the treatment of metastatic CRPC .", "17 ( E )- picolinylidene androstane derivatives as potential inhibitors of prostate cancer cell growth : antiproliferative activity and molecular docking studies . We report a rapid and efficient synthesis of A - ring modified 17α - picolyl and 17 ( E )- picolinylidene androstane derivatives from dehydroepiandrosterone . Compounds were validated spectroscopically and structurally characterized by X - ray crystallography . Virtual screening by molecular docking against clinical targets of steroidal anticancer drugs ( ERα , AR , P11511 and P05093 ) suggests that 17 ( E )- picolinylidene , but not 17α - picolyl androstanes could specifically interact with P05093 ( 17α - hydroxylase ) with similar geometry and affinity as DB05812 , a 17 - pyridinyl androstane drug clinically used in the treatment of prostate cancer . In addition , several 17 ( E )- picolinylidene androstanes demonstrated selective antiproliferative activity against PC3 prostate cancer cells , which correlates with DB05812 antiproliferative activity and predicted P05093 binding affinities . Based on these preliminary results , 17 ( E )- picolinylidene androstane derivatives could be a promising starting point for the development of new compounds for the treatment of prostate cancer .", "Recent findings in the genetics of blood pressure and hypertension traits . We provide an overview of ongoing discovery efforts in the genetics of blood pressure ( BP ) and hypertension ( HTN ) traits . Two large genome - wide association meta - analyses of individuals of European descent were recently published , revealing ~ 13 new loci for BP traits . Only two of these loci harbor genes in a pathway known to affect BP ( P05093 and P01160 / P16860 ) . Functional variants in these loci are still unknown . Few genome - wide association studies ( GWAS ) of complex diseases have been published from non - European populations . The study of populations with different evolutionary history and linkage disequilibrium ( LD ) structure , such as individuals of African ancestry , may provide an opportunity to further narrow these regions to identify the causal gene ( s ) . Several collaborative efforts toward discovery of low - frequency variants and copy number variation for BP traits are currently underway . As evidence for new loci for complex diseases accumulates the assessment of the epidemiologic architecture of these variants in populations assumes higher priority . The impact of public health - relevant contexts such as diet , physical activity , psychosocial factors , and aging has not been examined for most common variants associated with BP .", "Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK94___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .", "DB05812 acetate : a promising drug for the treatment of castration - resistant prostate cancer . DB05812 acetate ( CB7630 ) , a pregnenolone analog , is an orally administered small molecule that irreversibly inhibits a rate - limiting enzyme in androgen biosynthesis , P05093 , and blocks the synthesis of androgens in the testes , adrenal glands and prostate without causing adrenal insufficiency . In clinical studies , abiraterone acetate is well tolerated and shows promising clinical activity in castration - resistant prostate cancer . The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily . Side effects are minimal and mostly associated with secondary mineralocorticoid excess , owing to a compensatory increase in upstream steroids , such as deoxycorticosterone and corticosterone . These include hypertension , hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist , such as eplerenone , or low - dose corticosteroids . Currently , abiraterone acetate is being tested in a Phase III trial for men with progressive castration - resistant prostate cancer who are chemotherapy naive . A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis .", "Clinical and biochemical consequences of P05093 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer . CONTEXT : DB05812 acetate is a small - molecule cytochrome P450 17A1 ( P05093 ) inhibitor that is active in castration - resistant prostate cancer . OBJECTIVE : Our objective was to determine the impact of abiraterone with and without dexamethasone treatment on in vivo steroidogenesis . DESIGN AND METHODS : We treated 42 castrate , castration - resistant prostate cancer patients with continuous , daily abiraterone acetate and prospectively collected blood and urine before and during abiraterone treatment and after addition of dexamethasone 0 . 5 mg daily . RESULTS : Treatment with single - agent abiraterone acetate was associated with accumulation of steroids with mineralocorticoid properties upstream of P05093 . This resulted in side effects , including hypertension , hypokalemia , and fluid overload , in 38 of 42 patients that were generally treated effectively with eplerenone . Importantly , serum and urinary androgens were suppressed by more than 90 % from baseline . Urinary metabolites of 17 - hydroxypregnenolone and 17 - hydroxyprogesterone downstream of 17α - hydroxylase remained unchanged . However , 3α5α - 17 - hydroxypregnanolone , which can be converted via the backdoor pathway toward 5α - dihydrotestosterone , increased significantly and correlated with levels of the major 5α - dihydrotestosterone metabolite androsterone . In contrast , urinary metabolites of 11 - deoxycortisol and active glucocorticoids declined significantly . Addition of dexamethasone to abiraterone acetate significantly suppressed DB01285 and endogenous steroids , including 3α5α - 17 - hydroxypregnanolone . CONCLUSION : P05093 inhibition with abiraterone acetate is characterized by significant suppression of androgen and cortisol synthesis . The latter is associated with a rise in DB01285 that causes raised mineralocorticoids , leading to side effects and incomplete 17α - hydroxylase inhibition . Concomitant inhibition of 17 , 20 - lyase results in diversion of 17 - hydroxyprogesterone metabolites toward androgen synthesis via the backdoor pathway . Addition of dexamethasone reverses toxicity and could further suppress androgens by preventing a rise in substrates of backdoor androgen synthesis .", "P12004 T1 overexpression induces malignant transformation and tumor growth . Human DB04428 Fb is a protein kinase composed by P50750 and P12004 T that controls the elongation phase of RNA Pol II . This complex also affects the activation and differentiation program of lymphoid cells . In this study we found that several head and neck tumor cell lines overexpress DB04428 Fb . We also established that P12004 T1 is able to induce transformation in vitro , as we determined by foci and colony formation assays . Nu / nu mice s . c . injected with stable transfected P12004 T1 cells ( NIH 3T3 P12004 T1 ) developed tumors faster than animals injected with control cells ( NIH 3T3 beta - gal ) . In vitro , NIH 3T3 P12004 T1 cells show increased proliferation and P11802 - Rb phosphorylation . Even more , silencing Q01094 expression ( shRNA Q01094 ) in NIH 3T3 cells resulted in a dramatic inhibition of P12004 T1 - induced foci . All these data demonstrate for the first time the P12004 T1 oncogenic function and suggest a role for this protein in controlling cell cycle probably via Rb / Q01094 pathway .", "DB05812 in prostate cancer : a new angle to an old problem . DB05812 acetate is an orally administered potent inhibitor of cytochrome P450 , family 17 , subfamily A , polypeptide 1 ( P05093 ) , which is essential for synthesis of testosterone from cholesterol . Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer , residual androgens may still be detected in patients treated with luteinizing hormone - releasing hormone agonists or antagonists . Treatment with abiraterone results in rapid , and complete , inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself . An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo - controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate - resistant prostate cancer previously treated with docetaxel chemotherapy . DB05812 ' s efficacy shows the importance of androgen signaling in patients with castrate - resistant metastatic disease , with additional confirmation from recent studies of other novel agents such as MDV3100 , an androgen receptor signaling inhibitor . These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops , how to best sequence therapy , and how to optimize combinations with other emerging novel agents .", "[ Mechanisms of resistance to P05093 inhibitors in castrate resistant prostate cancer ] . INTRODUCTION : DB05812 acetate has increased the overall survival of patients with metastatic castration - resistant prostate cancer . However , despite an initial response to treatment , many patients develop resistance to the drug . In this paper we present different hypotheses that may explain the emergence of resistance . METHOD : This review was conducted from the PubMed database . The most relevant articles were selected and analyzed . RESULTS : The molecular mechanisms of resistance to abiraterone acetate remain largely elusive . We detailed some of them including the reactivation of the androgen receptor through alternative biosynthesis of androgens , over expression or mutation of the androgen receptor gene , or the action of co - activators . The over expression of P05093 or the alteration of other genes ' expression involved in steroidogenesis could also contribute to the resistance . CONCLUSION : Some of the molecular mechanisms involved in the resistance to abiraterone acetate were detailed . Better understanding of these mechanisms is a key step to allow the emergence of new therapeutic options and personalized treatments of castration resistant prostate cancer .", "Synthesis , biological evaluation , and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17alpha - hydroxylase - 17 , 20 - lyase ( P05093 ) -- part II : Core rigidification and influence of substituents at the methylene bridge . Thirty - five novel substituted imidazolyl methylene biphenyls have been synthesized as P05093 inhibitors for the potential treatment of prostate cancer . Their activities have been tested with recombinant human P05093 expressed in Escherichia coli . Promising compounds were tested for selectivity against P15538 , P19099 , and hepatic CYP enzymes 3A4 , 1A2 , 2B6 and 2D6 . The core rigidified compounds ( 30 - 35 ) were the most active ones , being much more potent than Ketoconazole and reaching the activity of DB05812 . However , they were not very selective . Another rather potent and more selective inhibitor ( compound 23 , IC ( 50 )= 345 nM ) was further examined in rats regarding plasma testosterone levels and pharmacokinetic properties . Compared to the reference DB05812 , 23 was more active in vivo , showed a longer plasma half - life ( 10h ) and a higher bioavailability . Using our P05093 homology protein model , docking studies with selected compounds were performed to study possible interactions between inhibitors and amino acid residues of the active site .", "Synthesis , biological evaluation , and molecular modeling of abiraterone analogues : novel P05093 inhibitors for the treatment of prostate cancer . DB05812 , a steroidal cytochrome P450 17alpha - hydroxylase - 17 , 20 - lyase inhibitor ( P05093 ) , is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen - dependent prostate cancer . Since steroidal compounds often show side effects attributable to their structure , we have tried to replace the sterane scaffold by nonsteroidal core structures . The design and synthesis of 20 new abiraterone mimetics are described . Their activities have been tested with recombinant human P05093 expressed in E . coli . Promising compounds were further evaluated for selectivity against P15538 , P19099 , and the hepatic P08684 . Compounds 19 and 20 showed comparable activity to abiraterone ( IC50 values of 144 and 64 nM vs 72 nM ) and similar or even better selectivity against the other CYP enzymes . Selected compounds were also docked into our homology model , and the same binding modes as for abiraterone were found .", "Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration - resistant prostate cancer . PURPOSE : DB05812 is the active metabolite of the pro - drug abiraterone acetate ( AA ) and a selective inhibitor of P05093 , a key enzyme in testosterone synthesis , and improves overall survival in postdocetaxel metastatic castration - resistant prostate cancer ( mCRPC ) . This open - label , single - arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval . METHODS : The study was conducted in 33 patients with mCRPC . Patients received AA 1 , 000 mg orally once daily + prednisone 5 mg orally twice daily . Electrocardiograms ( ECGs ) were collected in triplicate using 12 - lead Holter monitoring . Baseline ECGs were obtained on Cycle 1 Day - 1 . Serial ECG recordings and time - matched pharmacokinetic ( PK ) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1 . Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8 . RESULTS : After AA administration , the upper bound of the 2 - sided 90 % confidence interval ( CI ) for the mean baseline - adjusted QTcF change was < 10 ms ; no patients discontinued due to QTc prolongation or adverse events . No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [ estimated slope ( 90 % CI ) : 0 . 0031 ( - 0 . 0040 , 0 . 0102 ) ] . CONCLUSIONS : There is no significant effect of AA plus prednisone on the QT / QTc interval in patients with mCRPC .", "P19957 kinase p110β : a therapeutic target in advanced prostate cancers . Prostate cancers in the castration - resistant stage are life - threatening because they are not curable in clinic . The novel androgen receptor inhibitor Xandi ( DB08899 ) and the new P05093 inhibitor Zytiga ( DB05812 ) prolonged patient survival only a few months in advanced prostate cancers . Therefore , novel therapeutic agents for advanced prostate cancers are urgently needed . P19957 kinases are major intracellular signaling molecules that regulate multiple signal pathways related to cellular metabolism , cytokinesis , growth and survival . Accumulating evidence in the literature indicates that some isoforms of this kinase family are oncogenic and abnormally expressed in various human cancers , including prostate cancers . Recent extensive studies from our group and others showed that P19957 kinase p110β is aberrantly overexpressed in advanced prostate cancers and is critical for prostate cancer development and progression as demonstrated in cell - based and animal models . Importantly , novel p110β - specific inhibitors have been developed and are currently been testing in clinical trials . In this article , we will briefly summarize recent developments in this regard .", "Genetic polymorphisms of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes in adolescent girls with polycystic ovary syndrome . BACKGROUND : Polycystic ovary syndrome ( PCOS ) , whose genetic basis is not completely well understood , is the most common endocrine disorder in women and it typically develops during adolescence . The aim of this study is to investigate the possible association between single nucleotide polymorphisms ( SNPs ) of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes and PCOS in adolescent girls . METHODS : DNA samples from forty - four adolescent girls with PCOS and 50 healthy controls were analyzed by PCR - RFLP and direct DNA sequencing to determine the genotypic frequency of 17 different polymorphic loci on the P23945 ( A307T , N680S ) , P05093 ( - 34 T / C ) , P04798 ( T6235C ) , Q9HC96 ( 44 , 43 , 19 , 63 ) , P06213 ( exon 17 C / T ) , P05121 ( 4G / 5G ) genes . Genotyping of exon 12 ( six polymorphisms ) and intron 12 ( one polymorphism ) of P06213 gene by direct DNA sequencing was performed for the first time in this study . RESULTS : No significant differences were observed in the genotype and allele distributions of above mentioned polymorphisms between cases and control groups . CONCLUSION : Our data does not support an association between SNPs of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes and susceptibility to PCOS or related traits in Turkish adolescent girls .", "DB05812 acetate , a first - in - class P05093 inhibitor , establishes a new treatment paradigm in castration - resistant prostate cancer .", "[ ___MASK37___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK37___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .", "P05093 inhibitors -- abiraterone , C17 , 20 - lyase inhibitors and multi - targeting agents . As the first in class steroid 17α - hydroxylase / C17 , 20 - lyase ( P05093 ) inhibitor , abiraterone acetate ( of which the active metabolite is abiraterone ) has been shown to improve overall survival in patients with castration - resistant prostate cancer ( CRPC ) -- in those who are chemotherapy - naive and those previously treated with docetaxel . Furthermore , the clinical success of abiraterone demonstrated that CRPC , which has previously been regarded as an androgen - independent disease , is still driven , at least in part , by androgens . More importantly , abiraterone is a ' promiscuous ' drug that interacts with a number of targets , which dictate its clinical benefits and adverse effects profile . Besides P05093 inhibition , abiraterone acts as an antagonist to the androgen receptor and inhibits 3β - hydroxysteroid dehydrogenase -- two effects that potentially contribute to its antitumour effects . However , the inhibition of the 17α - hydroxylase activity of P05093 , P15538 and a panel of hepatic CYP enzymes leads to adverse effects and toxicities that include secondary mineralocorticoid excess . DB05812 is also associated with increased incidence of cardiac disorders . Under such circumstances , development of new P05093 inhibitors as an additional line of defence is urgently needed . To achieve enhanced clinical benefits , new strategies are being explored that include selective inhibition of the C17 , 20 - lyase activity of P05093 and multi - targeting strategies that affect androgen synthesis and signalling at different points . Some of these strategies - including the drugs orteronel , VT - 464 and galeterone -- are supported by preclinical data and are being explored in the clinic .", "___MASK29___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK29___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK29___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK29___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .", "Prostate cancer - from steroid transformations to clinical translation . The survival benefit conferred by two hormonal agents in phase III trials has clinically validated the long suspected and now widely recognized phenomenon of castration - resistant prostate cancer ( CRPC ) hormone dependence . DB05812 inhibits steroid 17α - hydroxylase / 17 , 20 - lyase ( P05093 ) and blocks androgen synthesis , whereas enzalutamide directly binds and antagonizes the androgen receptor . Both agents are highly effective against CRPC and significantly prolong survival following docetaxel treatment . However , this clinical validation of the androgen pathway has led to questions regarding the fundamental mechanisms of CRPC , as well as resistance to abiraterone and enzalutamide . Our understanding of the predominant steroid transformation pathways that lead to dihydrotestosterone synthesis in CRPC is evolving . The role of steroidogenesis in the development of resistance to abiraterone and enzalutamide remains uncertain . The specific roles of candidate enzyme targets in the development of resistance to these agents must be defined if we are to identify novel targets for improved pharmacologic therapies .", "Medical strategies for treatment of castration resistant prostate cancer ( CRPC ) docetaxel resistant . Current landscape of treatment of castration - resistant prostate cancer ( CRPC ) has recently changed . DB06772 , a new taxane with potential antineoplastic activity , has been approved by Food and Drug Administration ( FDA ) after docetaxel failure . In a phase III trial , cabazitaxel showed increased overall survival ( OS ) compared with mitoxantrone ( 15 . 1 vs . 12 . 7 mo , HR 0 . 70 , 95 % CI 0 . 59 - 0 . 83 , p < 0 . 0001 ) . Furthermore , chemotherapy is not the only strategy available : several studies have shown as CRPC remains dependent on androgen receptor function for growth . DB05812 acetate , an irreversible inhibitor of P05093 , has also been approved by FDA after docetaxel failure . In a phase III trial comparing abiraterone acetate to placebo , abiraterone showed improvement in OS ( 14 . 8 vs . 10 . 4 mo , HR 0 . 65 , 95 % CI 0 . 54 - 0 . 77 ; p < 0 . 0001 ) . This review will discuss current options and the ongoing trials for second - line treatment of CRPC including chemotherapy , hormonal therapies , antiangiogenetic and immune strategies .", "Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate . BACKGROUND : DB05812 acetate ( AA ) , a highly potent P05093 inhibitor , has demonstrated marked clinical benefit in patients with metastatic castration - resistant prostate cancer ( CRPC ) . Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations . The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor ( AR ) activity in prostate cancer ( PC ) cells . METHODS : Fluorescence resonance energy transfer ( FRET ) assay was used to assess the effect of mineralocorticoids on androgen - induced conformational change of the AR . LAPC4 , LNCaP and LN - AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations , including levels measured in the serum of AA - treated patients in a phase I trial . AR - dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells . RESULTS : Corticosterone ( CS ) and deoxycorticosterone ( DOC ) inhibited androgen - induced conformational change of the AR in the FRET assay . CS inhibited AR - dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA - treated patients . DOC inhibited AR transcriptional activity and cell growth at 10 - fold greater concentrations than measured in the serum of AA - treated patients . CONCLUSIONS : Mineralocorticoids directly inhibit androgen - induced conformational change of the AR . CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA . Further investigation of the potential therapeutic implications of mineralocorticoids in AA - treated CRPC patients is warranted .", "Is abiraterone acetate well tolerated and effective in the treatment of castration - resistant prostate cancer ? This Practice Point commentary discusses the findings of the first phase I trial to evaluate abiraterone acetate ( an inhibitor of the androgen - regulating enzyme P05093 ) in the treatment of castration - resistant prostate cancer . This open - label , dose - escalation study by Attard et al . showed that abiraterone was well tolerated but often induced a syndrome of secondary mineralocorticoid excess that improved with eplerenone ( a mineralocorticoid receptor antagonist ) . DB05812 is a potent suppressor of adrenal androgen synthesis , and produced lasting prostate - specific antigen responses in approximately half of the patients . A few patients had partial regression of distant metastases . Although promising , these results should be interpreted with caution owing to the small sample size and because the study was not primarily designed to examine drug efficacy . Multi - institutional , prospective trials should provide additional information on the tolerability and activity of this compound and further define the population most likely to benefit from this endocrine approach .", "Beyond castration and chemotherapy : novel approaches to targeting androgen - driven pathways . In castrate - resistant prostate cancer , beyond chemotherapy , existing guidelines suggest only supportive care . However , recent evidence suggests that continued targeting of androgen - dependent pathways may be an efficacious approach . Clinical data is now available for two mechanistically distinct agents ( abiraterone and MDV3100 ) that both ultimately target these pathways . DB05812 is a potent and irreversible inhibitor of P05093 , a critical enzyme in androgen biosynthesis . Phase II studies indicate substantial declines in PSA amongst castrate - resistant patients treated with abiraterone , both prior to and following cytotoxic chemotherapy . In contrast to abiraterone , MDV3100 is a direct inhibitor of the androgen receptor , binding the receptor irreversibly with substantially higher affinity as compared to bicalutamide . A recent phase I / II trial of MDV3100 in castrate - resistant prostate cancer demonstrated tolerability of the agent with activity at the lowest dose level . On the basis of these compelling data , both abiraterone and MDV3100 will be examined in the phase III setting ." ]

[ "___MASK12___", "___MASK29___", "___MASK32___", "___MASK37___", "___MASK47___", "___MASK59___", "___MASK68___", "___MASK76___", "___MASK94___" ]

[ "Molecular systematics of armadillos ( Xenarthra , Dasypodidae ) : contribution of maximum likelihood and Bayesian analyses of mitochondrial and nuclear genes . The 30 living species of armadillos , anteaters , and sloths ( Mammalia : Xenarthra ) represent one of the three major clades of placentals . Armadillos ( Cingulata : Dasypodidae ) are the earliest and most speciose xenarthran lineage with 21 described species . The question of their tricky phylogeny was here studied by adding two mitochondrial genes ( P03886 [ P03886 ] and 12S ribosomal RNA [ 12S rRNA ] ) to the three protein - coding nuclear genes ( alpha2B adrenergic receptor [ P18089 ] , breast cancer susceptibility exon 11 [ P38398 ] , and P04275 exon 28 [ P04275 ] ) yielding a total of 6869 aligned nucleotide sites for thirteen xenarthran species . The two mitochondrial genes were characterized by marked excesses of transitions over transversions - with a strong bias toward CT transitions for the 12S rRNA - and exhibited two - to fivefold faster evolutionary rates than the fastest nuclear gene ( P18089 ) . Maximum likelihood and Bayesian phylogenetic analyses supported the monophyly of Dasypodinae , Tolypeutinae , and Euphractinae , with the latter two armadillo subfamilies strongly clustering together . Conflicting branching points between individual genes involved relationships within the subfamilies Tolypeutinae and Euphractinae . Owing to a greater number of informative sites , the overall concatenation favored the mitochondrial topology with the classical grouping of Cabassous and Priodontes within Tolypeutinae , and a close relationship between Euphractus and Chaetophractus within Euphractinae . However , low statistical support values associated with almost equal distributions of apomorphies among alternatives suggested that two parallel events of rapid speciation occurred within these two armadillo subfamilies .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK24___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK5___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK5___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .", "Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK38___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK38___ .", "___MASK18___ binding to human and rat dopamine and 5 - HT receptors . ___MASK18___ ( ___MASK18___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK18___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK18___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK18___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .", "Q14954 - positive NK cells mediate alloresponse against the P06681 HLA - P55040 ligand group in vitro . The inhibitory 2DL1 and activating 2DS1 killer Ig - like receptors ( P55040 ) both have shared ligand specificity for codon sequences in the P06681 group HLA - Cw Ags . In this study , we have investigated NK cell activation by allogeneic target cells expressing different combinations of the HLA - P55040 ligand groups C1 , P06681 , and Bw4 . We demonstrate that fresh NK cells as well as P60568 - propagated NK cells from 2DS1 - positive donors that are homozygous for the C1 ligand group are activated in vitro by B lymphoblastoid cell lines expressing the P06681 group . This response is , in part , due to the absence of C1 group recognition mediated by the inhibitory receptor 2DL2 / 3 . This \" missing self \" alloresponse to P06681 , however , is rarely observed in NK cells from donors lacking 2DS1 . Even in presence of 2DS1 , the NK alloresponse is dramatically reduced in donors that have P06681 group as \" self . \" Analysis of selected NK clones that express 2DS1 mRNA and lack mRNA for 2DL1 demonstrates that activation by the P06681 ligand and mAb cross - linking of 2DS1 in these clones induces P01579 . Furthermore , this P06681 group - induced activation is inhibited by Abs to both HLA class I and the receptor . Collectively , these studies demonstrate that NK cells from 2DS1 - positive donors are activated by target cells that express the P06681 group as an alloantigen . This leads to increased P01579 - positive fresh NK cells and induces NK allocytotoxicity in P60568 - propagated polyclonal NK cells and NK clones . This study also provides support for the concept that incompatibility for the HLA - P55040 ligand groups C1 , P06681 , and Bw4 dominates NK alloactivation in vitro .", "Association analysis of P50406 and P28223 polymorphisms in sporadic Alzheimer ' s disease . In order to identify gene variants related to the serotonergic neurotransmitter system that possibly represent a hereditary risk factor for sporadic Alzheimer ' s disease ( AD ) , patients suffering from AD and non - demented psychiatric inpatients without symptoms of dementia were genotyped for polymorphisms of P50406 ( 267C / T ) and P28223 ( - 1438G / A ) . Although there was a tendency toward an increased number of the genotype TT of the P50406 receptor polymorphism in AD patients when compared to controls ( 2 . 8 % vs . 1 . 3 % ) , neither this nor the 5 - Q13049 promoter polymorphism showed significant differences in their genotypic or allelic distribution among patients and controls . These polymorphisms probably do not represent major genetic risk factors of AD . However , further studies including other genetic variants of the serotonergic neurotransmitter system are needed in order to elucidate their role in AD .", "[ Polymorphisms of 2B - adrenergic receptor and endothelial NO - Synthase genes in genesis of the hereditary sick sinus node syndrome ] . In this work we have demonstrated for the first time on the clinico - genetic material association between hereditary sick sinus node syndrome ( SSNS ) P18089 and P29474 genes polymorphisms . We have established predominance of homozygote genotype of more rare DD allele in patients with SSNS ( 28 % ) compared with subjects of control group ( 8 . 99 % ) . We have found predominance of heterozygote genotype 4a / 4b in patients with SSNS compared with subjects of control group ( 41 . 8 and 25 . 39 % , respectively ) . The data obtained allow to suggest that P29474 gene polymorphism might be associated with SSNS .", "Frequent promoter methylation of CDH1 , P53355 , P10826 , and Q14526 genes in carcinoma of cervix uteri : its relationship to clinical outcome . BACKGROUND : Cervical cancer ( CC ) , a leading cause of cancer - related deaths in women worldwide , has been causally linked to genital human papillomavirus ( HPV ) infection . Although a host of genetic alterations have been identified , molecular basis of CC development is still poorly understood . RESULTS : We examined the role of promoter hypermethylation , an epigenetic alteration that is associated with the silencing tumor suppressor genes in human cancer , by studying 16 gene promoters in 90 CC cases . We found a high frequency of promoter methylation in CDH1 , P53355 , P10826 , and Q14526 genes . Correlation of promoter methylation with clinical characteristics and other genetic changes revealed the following : a ) overall promoter methylation was higher in more advanced stage of the disease , b ) promoter methylation of P10826 and P38398 predicted worse prognosis , and c ) the Q14526 promoter methylation was frequently seen in association with microsatellite instability . Promoter methylation was associated with gene silencing in CC cell lines . Treatment with methylation or histone deacetylation - inhibiting agents resulted in profound reactivation of gene expression . CONCLUSIONS : These results may have implications in understanding the underlying epigenetic mechanisms in CC development , provide prognostic indicators , and identify important gene targets for treatment .", "Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK7___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .", "Modulation of a number of genes on personality traits in a sample of healthy subjects . A large number of studies investigated the genetic modulation of personality with mixed results . As a confirmatory analysis of previous findings , we firstly examined the association between several previously examined single nucleotide polymorphisms ( SNPs ) and personality traits in a sample of 158 healthy subjects . As a secondary aim , we tested the potential modulation of additional never previously investigated genes on personality . A blood sample was collected and the Temperament and Character Inventory ( TCI ) has been administered to all participants . Multivariate analysis of covariance , controlling for sex and age , was used to test SNP influence on TCI scores . Examination of previously studied gene variants showed an effect of adrenergic alpha 2B receptor ( P18089 ) on Cooperativeness and of serotonin receptor P28223 on Self Directedness . Examination of new variants revealed that sex hormone binding protein ( P04278 ) was associated with reward dependence . Moreover , several additional variants showed a tendency towards association with some TCI traits , confirming previous results . This study suggests that P18089 , P28223 and P04278 genes may be involved in the modulation of personality in healthy subjects . The major limitation of this study was the small sample size .", "Pivotal role of the P06681 domain of the Smurf1 ubiquitin ligase in substrate selection . The P06681 - WW - HECT - type ubiquitin ligases Smurf1 and Smurf2 play a critical role in embryogenesis and adult bone homeostasis via regulation of bone morphogenetic protein , Wnt , and RhoA signaling pathways . The intramolecular interaction between P06681 and HECT domains autoinhibits the ligase activity of Smurf2 . However , the role of the Smurf1 P06681 domain remains elusive . Here , we show that the P06681 - HECT autoinhibition mechanism is not observed in Smurf1 , and instead its P06681 domain functions in substrate selection . The Smurf1 P06681 domain exerts a key role in localization to the plasma membrane and endows Smurf1 with differential activity toward RhoA versus Q99717 and Runx2 . Crystal structure analysis reveals that the Smurf1 P06681 domain possesses a typical anti - parallel β - sandwich fold . Examination of the sulfate - binding site analysis reveals two key lysine residues , Lys - 28 and Lys - 85 , within the P06681 domain that are important for Smurf1 localization at the plasma membrane , regulation on cell migration , and robust ligase activity toward RhoA , which further supports a Ca ( 2 +)- independent localization mechanism for Smurf1 . These findings demonstrate a previously unidentified role of the Smurf1 P06681 domain in substrate selection and cellular localization .", "Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK45___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .", "Comparative study on gene tags of the neurotransmission system in schizophrenic and suicidal subjects . Schizophrenia and suicidal behaviour are sever and complex mental disorders , largely determined by factors of inheritance . Both disorders present pathological changes in the catecholamine neurotransmitter system . The study was conducted on three groups ; a group of subjects suffering from schizophrenia , a second compounded by individuals who attempted suicide and a third group of phenotypically healthy examinees . The blood samples of schizophrenic patients as of those who attempted suicide were obtained at the Psychiatric Hospital \" Sveti Ivan \" in Zagreb in the year 2004 . Tests were conducted on the statistic relation between a total of 18 SNPs within three candidate - genes of the dopamine and adrenergic system ( P21917 , Q01959 and P18089 ) and the manifestation of schzophrenia and suicidal behaviour . Cases were genotyped by use of SNPlex system . Statistically significant differences were determined in the allelic frequency between the mentioned groups . Findings show a significant connection between 4 SNPs ( P18089 rs749457 , Q01959 rs464094 , P21917 rs11246226 and rs4331145 ) and schizophrenia , and 2 SNPs with suicidal attempt ( P18089 rs1018351 i Q01959 rs403636 ) . In addition , this is the first study that highlights the potential role / effect of polymorphisms in P18089 on the manifestation of schizophrenia , as on suicidal behaviour .", "[ New immunological weapons for medicine in the 21st Century : biological therapy based on the use of the latest generation monoclonal antibodies ] . The fusion of a murine B cell and a myeloma cell generates a hybridoma that produces monoclonal antibody ( mAb ) . These murine mAb induce the HAMA ( human anti - mouse antibodies ) response . Murine mAb have been modified by genetic engineering , producing molecules with a higher proportion of human protein . At present , chimeric , humanized and fully human mAb are available . mAb block interactions between target molecules and their ligands or trigger the lyses of mAb - coated tumor cells . Numerous mAb have been developed using the recombinant DNA technology and several are available in the market . ___MASK23___ , against P04626 / neu , is useful in breast cancer ; rituximab , against P11836 in B lymphocytes is useful in lymphoma ; alemtuzumah , against P31358 is used in lymphoma and leukemia ; daclizumab and basiliximab block the P60568 receptor interaction and reduce acute rejection in kidney transplantation ; abciximab , an antagonist of P08514 / IIIa platelet receptor , is used in patients undergoing acute coronary syndromes . In autoimmunity diseases , blocking tumor necrosis factor by infliximab and adalimumab has demonstrated excellent results . Thus , infliximab is useful in the treatment of rheumatoid arthritis ( RA ) , Crohn ' s disease and ulcerative colitis while adalimumab is the first fully human mAb available for RA . DB00065 and adalimumab reduce signs and symptoms in RA and they also interfere with progression of joint damage . Finally , the direct benefits of antagonist treatment can occur at the expense of a major adverse effect in some other biological function .", "P18089 genotype differentially modulates stress - induced neural activity in the amygdala and hippocampus during emotional memory retrieval . RATIONALE : DB00368 interacts with stress hormones in the amygdala and hippocampus to enhance emotional memory consolidation , but the noradrenergic - glucocorticoid interaction at retrieval , where stress impairs memory , is less understood . OBJECTIVES : We used a genetic neuroimaging approach to investigate whether a genetic variation of the noradrenergic system impacts stress - induced neural activity in amygdala and hippocampus during recognition of emotional memory . METHODS : This study is based on genotype - dependent reanalysis of data from our previous publication ( Li et al . Brain Imaging Behav 2014 ) . Twenty - two healthy male volunteers were genotyped for the P18089 gene encoding the α2B - adrenergic receptor . Ten deletion carriers and 12 noncarriers performed an emotional face recognition task , while their brain activity was measured with fMRI . During encoding , 50 fearful and 50 neutral faces were presented . One hour later , they underwent either an acute stress ( Trier Social Stress Test ) or a control procedure which was followed immediately by the retrieval session , where participants had to discriminate between 100 old and 50 new faces . RESULTS : A genotype - dependent modulation of neural activity at retrieval was found in the bilateral amygdala and right hippocampus . Deletion carriers showed decreased neural activity in the amygdala when recognizing emotional faces in control condition and increased amygdala activity under stress . Noncarriers showed no differences in emotional modulated amygdala activation under stress or control . Instead , stress - induced increases during recognition of emotional faces were present in the right hippocampus . CONCLUSION : The genotype - dependent effects of acute stress on neural activity in amygdala and hippocampus provide evidence for noradrenergic - glucocorticoid interaction in emotional memory retrieval .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .", "P04035 inhibitor , atorvastatin , promotes sensorimotor recovery , suppressing acute inflammatory reaction after experimental intracerebral hemorrhage . BACKGROUND AND PURPOSE : Statins have neuroprotective effects on ischemic stroke . They modify the endothelial function , increase blood flow , and inhibit thrombus formation , which are independent of lipid - lowering effects . However , whether statins have a protective effect toward hemorrhagic stroke is yet unknown . To test this possibility , we attempted to determine the effect of atorvastatin on experimental intracerebral hemorrhage ( ICH ) . METHODS : ICH was induced using stereotaxic infusion of collagenase into the left basal ganglia in adult rats . ___MASK17___ ( 1 mg / kg or 10 mg / kg ) or phosphate - buffered saline was administered for 2 weeks . To monitor the sensorimotor deficits , limb placing and Rotorod tests were performed . Hematoma volume , brain water content , and hemispheric atrophy were analyzed . Immunohistochemical staining for myeloperoxidase ( P05164 ) , microglia ( OX42 ) , inducible nitric oxide synthase ( P35228 ) , or endothelial nitric oxide synthase ( P29474 ) was performed . Perihematomal cell death was determined by TUNEL staining . RESULTS : The atorvastatin - treated ICH group showed better performance on Rotorod and limb placing tests when compared with the vehicle - treated group ( P < 0 . 01 ) . The hematoma volumes between groups were not different , but the brain water content and hemispheric atrophy were reduced in the atorvastatin - treated ICH group . ___MASK17___ reduced TUNEL - positive cells , P35228 expression , and P05164 - positive or OX42 - positive cells in the perihematomal regions in a dose - dependent manner , whereas it increased P29474 expression . CONCLUSIONS : The present study shows that atorvastatin reduces the perihematomal cell death via antiinflammation , which is associated with sensorimotor recovery after experimental ICH .", "P18089 gene insertion / deletion polymorphism and artery compliance . BACKGROUND : The P18089 gene insertion / deletion ( I / D ) polymorphism is associated with various cardiovascular and metabolic phenotypes . Large ( C1 ) and small ( P06681 ) artery compliance , assessed by pulse wave analysis , is considered as sensitive markers or risk factors for cardiovascular disease . Therefore whether the P18089 I / D polymorphism is associated with C1 and P06681 need to be investigated . METHODS : A total of 227 men and 243 women were enrolled in a Chinese family - based study . C1 and P06681 were measured by pulse wave analysis . P18089 genotypes were determined by polymerase chain reaction . Statistical methods included generalized estimation equations and quantitative transmission disequilibrium test . RESULTS : The II ( 31 . 9 % ) , ID ( 46 . 8 % ) and DD ( 21 . 3 % ) genotype frequencies were in Hardy - Weinberg equilibrium ( P = 0 . 73 ) . The covariates selected by stepwise regression for C1 and P06681 were age , systolic pressure and gender . The population based association analysis showed that C1 and P06681 were not associated with P18089 genotype both before ( C1 : P = 0 . 28 ; P06681 : P = 0 . 27 ) and after ( C1 : P = 0 . 58 ; P06681 : P = 0 . 18 ) the adjustment . The family - based analyses of 128 informative offspring showed that transmission of the D - allele was not associated with C1 or P06681 , both before ( C1 : P = 0 . 42 ; P06681 : P = 0 . 85 ) and after ( C1 : P = 0 . 31 ; P06681 : P = 0 . 82 ) the adjustment . CONCLUSION : The study do not support that the P18089 gene I / D polymorphism has a major gene effect on C1 or P06681 in the Chinese population of current sample size .", "Cellular uptake of Clostridium botulinum P06681 toxin : membrane translocation of a fusion toxin requires unfolding of its dihydrofolate reductase domain . The Clostridium botulinum P06681 toxin is the prototype of the family of binary actin - ADP - ribosylating toxins . P06681 toxin is composed of two separated nonlinked proteins . The enzyme component C2I ADP - ribosylates actin in the cytosol of target cells . The binding / translocation component C2II mediates cell binding of the enzyme component and its translocation from acidic endosomes into the cytosol . After proteolytic activation , C2II forms heptameric pores in endosomal membranes , and most likely , C2I translocates through these pores into the cytosol . For this step , the cellular heat shock protein Hsp90 is essential . We analyzed the effect of methotrexate on the cellular uptake of a fusion toxin in which the enzyme dihydrofolate reductase ( P00374 ) was fused to the C - terminus of C2I . Here , we report that unfolding of C2I - P00374 is required for cellular uptake of the toxin via the C2IIa component . The C2I - P00374 fusion toxin catalyzed ADP - ribosylation of actin in vitro and was able to intoxicate cultured cells when applied together with C2IIa . Binding of the folate analogue methotrexate favors a stable three - dimensional structure of the dihydrofolate reductase domain . Pretreatment of C2I - P00374 with methotrexate prevented cleavage of C2I - P00374 by trypsin . In the presence of methotrexate , intoxication of cells with C2I - P00374 / C2II was inhibited . The presence of methotrexate diminished the translocation of the C2I - P00374 fusion toxin from endosomal compartments into the cytosol and the direct C2IIa - mediated translocation of C2I - P00374 across cell membranes . ___MASK9___ had no influence on the intoxication of cells with C2I / C2IIa and did not alter the C2IIa - mediated binding of C2I - P00374 to cells . The data indicate that methotrexate prevented unfolding of the C2I - P00374 fusion toxin , and thereby the translocation of methotrexate - bound C2I - P00374 from endosomes into the cytosol of target cells is inhibited .", "Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers . Evidence suggests that emotional memory plays a role in the pathophysiology of depression / anxiety disorders . DB00368 crucially modulates emotional memory . Genetic variants involved in noradrenergic signaling contribute to individual differences in emotional memory and vulnerability to psychopathology . A functional deletion polymorphism in the α - 2B adrenoceptor gene ( P18089 ) has been linked to emotional memory and post - traumatic stress disorder . The noradrenaline reuptake inhibitor reboxetine attenuates enhanced memory for negative stimuli in healthy and depressed individuals . We examined whether the effect of reboxetine on emotional memory in healthy individuals would be moderated by P18089 genotype . P18089 deletion carriers demonstrated enhanced emotional memory for negative stimuli compared with deletion noncarriers , consistent with prior studies . DB00234 attenuated enhanced memory for negative stimuli in deletion noncarriers but had no significant effect in deletion carriers . This is the first demonstration of genetic variation influencing antidepressant drug effects on emotional processing in healthy humans .", "Recognition of coagulation factor VIII by P01730 + T cells of healthy humans . Hemophilia A patients treated with coagulation factor ( F ) VIII may develop an anti - FVIII immune response . Anti - FVIII antibodies may occur also in healthy subjects . To understand the extent to which an immune response to FVIII occurs in healthy subjects , we investigated the proliferative response of blood P01730 + T cells from 90 blood donors to FVIII and to pools of overlapping synthetic peptides spanning the sequences of individual FVIII domains ( A1 - A3 , C1 - P06681 ) . Most subjects responded to FVIII and several FVIII domains . Men had stronger responses to FVIII than women , and older subjects than younger subjects . The domain - induced responses were weaker than the FVIII - induced responses , yet their intensity in individual subjects correlated with that of the response to FVIII . We examined whether Th1 and / or Th2 cells responded to FVIII in 68 subjects , by determining the P01730 + T cells that secreted interferon - gamma ( P01579 ) or interleukin ( IL ) - 5 after stimulation with FVIII : 25 subjects had FVIII - specific P01579 - secreting cells , and seven of them had also FVIII - specific P05113 - secreting cells . None had only P05113 - secreting cells . Thus , a P01730 + T cell response to FVIII , which first involves Th1 cells , is common among subjects with a normal procoagulant function .", "[ Sudden cardiac death and polymorphism of genes - candidates of cardiovascular diseases ] . Aim of the study was to elucidate genetic markers associated with elevated risk of sudden cardiac death ( O00767 ) . We collected autopsy material during 1999 - 2001 in a process of forensic medical pathologo - anatomical examination of corpses of 182 men who had died suddenly in Octyabrsky district of Novosibirsk in the age of 25 - 64 years ( mean age 53 , 6 +/- 7 , 9 years ) . We studied polymorphisms of the following genes : angiotensin converting enzyme - , glycoprotein IIb / IIIa - P08514 / IIIa , alpha2b adrenoreceptor - P18089 , beta ( 1 )- adrenoreceptor - P08588 . Control comprised samples of population of men aged 25 - 35 and 55 - 64 years from the same district of Novosibirsk examined within framework of international WHO project MONICA . Comparison of frequencies of genotypes of polymorphism A1 / A2 of P08514 / IIIa gene in combined sample of population and group with O00767 revealed in O00767 group lowering of portion of A2 / A2 homozygotes ( 5 . 0 and 1 . 2 % , respectively , = 0 . 029 ) and elevation of portion of A1 / A2 heterozygotes ( 18 . 7 and 28 . 3 % , respectively , = 0 . 027 ) . Odds ratio for a heterozygote to enter O00767 group was 1 . 71 ( 95 % confidence interval 1 . 0 to 2 . 77 ) . Comparison of frequencies of genotypes and alleles of polymorphism A145G of P08588 gene in combined sample of population and group with O00767 did not reveal any difference . Comparison of frequencies of polymorphism I / D of P12821 gene in combined sample of population and group with O00767 revealed significant lowering of frequencies of genotype I / I in O00767 group ( 22 . 0 and 13 . 8 % , respectively , p = 0 . 033 ) . There were no significant differences between O00767 group and control in frequencies of studied polymorphism of alpha2b - adrenoreceptor gene ." ]

[ "___MASK17___", "___MASK18___", "___MASK23___", "___MASK24___", "___MASK38___", "___MASK45___", "___MASK5___", "___MASK7___", "___MASK9___" ]

[ "Agonist - induced glycogenolysis in rabbit retinal slices and cultures . 1 . The effects of different putative retinal transmitters and / or modulators on glycogenolysis in rabbit retinal slices and in retinal Müller cell cultures were examined . 2 . Incubation of rabbit retinal slices or primary retinal cultures ( either 3 - 5 day - old or 25 - 30 day - old ) in a buffer solution containing [ 3H ] - glucose resulted in the accumulation of newly synthesized [ 3H ] - glycogen . 3 . DB00368 ( NA ) , isoprenaline , vasoactive intestinal peptide ( P01282 ) , 5 - hydroxytryptamine ( 5 - HT ) and 8 - hydroxy - dipropylaminetetralin ( 8 - OH - DPAT ) stimulated the hydrolysis of this newly formed 3H - polymer . The potency order of maximal stimulations was : P01282 greater than NA greater than isoprenaline greater than 5 - HT greater than 8 - OH - DPAT . 4 . The putative retinal transmitters , dopamine , gamma - aminobutyric acid ( GABA ) , glycine and taurine and the muscarinic agonist carbachol ( CCh ) had no effect on [ 3H ] - glycogen content . 5 . The glycogenolytic effects of NA / isoprenaline and 5 - HT / 8 - OH - DPAT appear to be mediated by beta - adrenoceptors and 5 - HT1 receptors ( possibly P08908 ) , respectively while the P01282 - induced response involved another receptor subtype . 6 . Agonists which mediated [ 3H ] - glycogen hydrolysis also stimulated an increase in adenosine 3 ': 5 '- cyclic monophosphate ( cyclic AMP ) formation . Both responses are blocked to a similar extent by the same antagonists and so are probably mediated via the same receptor subtypes . Moreover , dibutyryl cyclic AMP ( db cyclic AMP ) promoted tritiated glycogen breakdown in the three retinal preparations . 7 . Not all receptors linked to cyclic AMP production however promote glycogenolysis . Dopamine and apomorphine stimulated cyclic AMP formation via D1 - receptors without influencing glycogenolysis . These receptors are exclusively associated with neurones .", "Intrathecal 5 - methoxy - N , N - dimethyltryptamine in mice modulates 5 - HT1 and 5 - Q9H205 receptors . The antinociceptive effects of intrathecally administered 5 - methoxy - N , N - dimethyltryptamine ( 5 - MeO - Q08495 ) , a potent 5 - HT receptor agonist , were studied in three behavioral tests in mice : the tail - flick test and the intrathecal DB05875 and N - methyl - D - aspartic acid ( DB01221 ) assays . Intrathecal administration of 5 - MeO - Q08495 ( 4 . 6 - 92 nmol / mouse ) produced a significant prolongation of the tail - flick latency . This action was blocked by 5 - Q9H205 and gamma - aminobutyric acidA ( GABAA ) receptor antagonists but not by 5 - HT2 , P08908 , P28222 or 5 - HT1S receptor antagonists . Binding studies indicated that 5 - MeO - Q08495 had very low affinity for 5 - Q9H205 receptors . 5 - MeO - Q08495 inhibited biting behavior while increasing scratching behavior induced by intrathecally administered DB05875 . The inhibition of biting behavior was antagonized by intrathecal co - administration of P28222 and GABAA receptor antagonists while P08908 , 5 - HT1S , 5 - HT2 and 5 - Q9H205 receptor antagonists had no effect . 5 - MeO - Q08495 - enhanced scratching behavior was inhibited by all the antagonists used except ketanserin and bicuculline , suggesting the involvement of P08908 , P28222 , 5 - HT1S , 5 - Q9H205 and GABAA receptors . DB01221 - induced biting behavior was inhibited by 5 - MeO - Q08495 pretreatment ; this action was antagonized by P28222 , 5 - Q9H205 and GABAA receptor antagonists . The involvement of these receptors in 5 - MeO - Q08495 action suggests that it may promote release of 5 - HT ( 5 - hydroxytryptamine , serotonin ) .", "Activation of the P27361 / 2 signaling cascade by excitotoxic spinal cord injury . The role of the P27361 / 2 signal transduction pathway and related transcription factors in the regulation of gene expression and pain behavior following excitotoxic spinal cord injury ( SCI ) was examined . Specifically , phosphorylation of P27361 / 2 , activation of transcription factors NF - kB , P54762 - 1 , and CREB , and gene expression of the neurokinin - 1 receptor and DB01221 receptor subunits Q9UHB4 and NR - 2A were investigated . Excitotoxic injury was produced by intraspinal injection of quisqualic acid ( QUIS ) in male Sprague - Dawley rats . Western blots were used to evaluate phosphorylation and activation of P27361 / 2 and transcription factors using phospho - specific or total antibodies . Real - time PCR was used to evaluate gene expression of P25103 , NR - 1 , and NR - 2A . Assessment of excessive grooming behavior was used to evaluate the presence of spontaneous pain behavior . Excitotoxic spinal injury resulted in : ( 1 ) increased phosphorylation of P27361 / 2 ; ( 2 ) increased activation of NF - kB and phosphorylation of P54762 - 1 ; and ( 3 ) increased gene expression for the P25103 and Q9UHB4 and NR - 2A subunits of the DB01221 receptor . Blockade of the P29323 cascade with the MEK inhibitor PD98059 inhibited phosphorylation of P54762 - 1 , activation of NF - kB and gene expression of Q9UHB4 , NR - 2A and P25103 , and prevented the development of excessive grooming behavior . The results have shown that excitotoxic spinal injury leads to the injury - induced activation of the P29323 --> P54762 - 1 and NF - kB signaling cascades and transcriptional regulation of receptors important in the development of chronic pain . Blockade of this intracellular kinase cascade prevented the onset of injury - induced pain behavior .", "Co - localization of mu opioid receptor and N - methyl - D - aspartate receptor in the trigeminal dorsal horn . Antagonists acting at the N - methyl - D - aspartate ( DB01221 ) receptor can block the development of tolerance to the analgesic effects of [ mu ] opioid receptor ( MOR ) ligands , such as morphine , and can also enhance the analgesic efficacy of opioids . These findings have led to the hypothesis that interactions between DB01221 receptor and MOR ligands may be due to the co - localization of these receptors on neurons in the dorsal horn . We used dual immunogold and immunoperoxidase immunocytochemistry for P35372 and Q05586 to determine the degree of co - localization of these receptors in neurons of the trigeminal dorsal horn . By use of electron microscopy , we found that both receptors were primarily located in dendrites and to a lesser extent in perikarya , axons , axon terminals , and glia . With regard to the degree of co - localization in dendrites , 63 % of P35372 - labeled dendrites also contained Q05586 , whereas 61 % of Q05586 - labeled dendrites also contained P35372 . Most of the dual - labeled profiles ( 94 % ) were classified as dendrites , with the remainder being axons , axon terminals , or perikarya . These results suggest that direct interactions between MOR and DB01221 receptor ligands are likely mediated through shared dendritic targets in the dorsal horn . Less frequently , we found evidence for modulation of afferents to MOR - containing neurons through presynaptic DB01221 receptors .", "c - jun mRNA expression in the hippocampal formation induced by restraint stress . The effect of restraint stress on c - jun mRNA expression in the hippocampal formation was investigated by in situ hybridization , dot blot and northern blot . c - jun mRNA expression increased after 60 min of forced restraint in the dentate gyrus , P00915 and P07451 regions of the hippocampal formation . The effect in the dentate gyrus was attenuated by pre - stress i . c . v . injection of the anxiolytic benzodiazepine midazolam ( 20 nmol / 2 microl ) or the N - methyl - D - aspartate ( DB01221 ) receptor antagonist 2 - amino - 7 - phosphonoheptanoic acid ( AP - 7 , 5 nmol / 2 microl ) , but not by the P08908 agonist , ( +/- ) 8 - hydroxy - dipropylaminotetralin ( 8 - OH - DPAT , 20 nmol / 2 microl ) . These results suggest that the hippocampal formation is activated during restraint stress , and that this activation is modulated by benzodiazepine / GABA - A or DB01221 receptors .", "Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor - expressing neurons in rat spinal cord . Blockade of local spinal cord inhibition mimics the behavioral hypersensitivity that manifests in chronic pain states . This suggests that there is a pathway capable of mediating allodynia / hyperalgesia that exists but is normally under strong inhibitory control . Lamina I and III neurokinin 1 ( NK1 ) receptor expressing ( P25103 + ) dorsal horn neurons , many of which are projection neurons , are required for the development of this hypersensitivity and are therefore likely to be a component of this proposed pathway . To investigate , whole - cell patch - clamp recordings were made from lamina I and III P25103 + neurons in the spinal cord slice preparation with attached dorsal root . Excitatory postsynaptic currents were recorded in response to electrical stimulation of the dorsal root . Lamina I P25103 + neurons were shown to receive high - threshold ( Adelta / C fiber ) monosynaptic input , whereas lamina III P25103 + neurons received low - threshold ( Abeta fiber ) monosynaptic input . In contrast , lamina I neurons lacking NK1 receptor ( P25103 - ) received polysynaptic A fiber input . Blockade of local GABAergic and glycinergic inhibition with bicuculline ( 10 microm ) and strychnine ( 300 nm ) , respectively , revealed significant A fiber input to lamina I P25103 + neurons that was predominantly Abeta fiber mediated . This novel A fiber input was polysynaptic in nature and required DB01221 receptor activity to be functional . In lamina I P25103 - and lamina III P25103 + neurons , disinhibition enhanced control - evoked responses , and this was also DB01221 receptor dependent . These disinhibition - induced changes , in particular the novel polysynaptic low - threshold input onto lamina I P25103 + neurons , may be an underlying component of the hypersensitivity present in chronic pain states .", "Serotonin inhibits the induction of DB01221 receptor - dependent long - term potentiation in the rat primary visual cortex . An increase in serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] levels in the rat visual cortex is correlated with the developmental decrease in long - term potentiation ( LTP ) , and 5 - HT may play an important role in the closure of the critical period by regulating LTP . The effect of 5 - HT on the induction of N - methyl - D - aspartate receptor ( NMDAR ) - dependent and metabotropic glutamate receptor ( mGluR ) - dependent LTP in visual cortex slices from young rats was investigated . The field potential in layer II / III was recorded by stimulating the underlying layer IV . NMDAR - dependent LTP was induced in slices from 3 - week - old rats by theta - burst stimulation ( TBS ) but not in slices from 5 - week - old rats . However , LTP was induced in 5 - HT - depleted slices from 5 - week - old rats by incubation with para - chloroamphetamine ( 10 microM , 2 h ) , a 5 - HT - depleting agent . The reinstated LTP in 5 - HT - depleted slices was inhibited by the application of D - aminopentanoate , an NMDAR antagonist ( 50 microM ) and 5 - HT ( 10 and 30 microM ) . In contrast , the induction of mGluR - dependent LTP by weak TBS in disinhibited slices with picrotoxin ( 1 microM ) in the bath was not affected by 5 - HT application . The coapplication of P08908 and 5 - HT2 receptor agonists inhibited the induction of NMDAR - dependent LTP in 5 - HT - depleted slices . 5 - HT levels in the visual cortex increased with age . Based on these findings , we conclude that NMDAR - dependent LTP is specifically inhibited by coactivation of P08908 and 5 - HT2 receptors with the increase in 5 - HT levels in the rat visual cortex at the end of the critical period .", "P01308 / P05019 signaling pathways enhances tumor cell invasion through bisecting GlcNAc N - glycans modulation . an interplay with P12830 . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 . We and others have previously demonstrated that P12830 has a role in the regulation of bisecting GlcNAc N - glycans expression , remaining to be determined the P12830 - dependent signaling pathway involved in this N - glycans expression regulation . In this study , we analysed the impact of P12830 expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 ( IGF - IR ) . We demonstrated that exogenous P12830 expression inhibits IR , IGF - IR and P29323 1 / 2 phosphorylation . Stimulation with insulin and P05019 in MDA - MD - 435 cancer cells overexpressing P12830 induces a decrease of bisecting GlcNAc N - glycans that was accompanied with alterations on P12830 cellular localization . Concomitantly , IR / IGF - IR signaling activation induced a mesenchymal - like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 and IR / IGF - IR signaling as major networking players in the regulation of bisecting N - glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 / P05019 signaling play during cancer progression through glycosylation modifications .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK84___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .", "Dorsal horn neurons firing at high frequency , but not primary afferents , release opioid peptides that produce micro - opioid receptor internalization in the rat spinal cord . To determine what neural pathways trigger opioid release in the dorsal horn , we stimulated the dorsal root , the dorsal horn , or the dorsolateral funiculus ( DLF ) in spinal cord slices while superfusing them with peptidase inhibitors to prevent opioid degradation . Internalization of mu - opioid receptors ( MOR ) and neurokinin 1 receptors ( P25103 ) was measured to assess opioid and neurokinin release , respectively . Dorsal root stimulation at low , high , or mixed frequencies produced abundant P25103 internalization but no MOR internalization , indicating that primary afferents do not release opioids . Moreover , capsaicin and DB01221 also failed to produce MOR internalization . In contrast , dorsal horn stimulation elicited MOR internalization that increased with the frequency , being negligible at < 10 Hz and maximal at 500 Hz . The internalization was abolished by the MOR antagonist D - DB00120 - DB00151 - DB00135 - D - DB00150 - DB00125 - DB00156 - Pen - DB00156 - NH2 ( CTAP ) , in the presence of low Ca2 + and by the Na + channel blocker lidocaine , confirming that it was caused by opioid release and neuronal firing . DLF stimulation in \" oblique \" slices ( encompassing the DLF and the dorsal horn of T11 - Q9NP50 ) produced MOR internalization , but only in areas near the stimulation site . Moreover , cutting oblique slices across the dorsal horn ( but not across the DLF ) eliminated MOR internalization in areas distal to the cut , indicating that it was produced by signals traveling in the dorsal horn and not via the DLF . These findings demonstrate that some dorsal horn neurons release opioids when they fire at high frequencies , perhaps by integrating signals from the rostral ventromedial medulla , primary afferents , and other areas of the spinal cord .", "Drug therapy of neuropathic pain : current developments and future perspectives . Understanding mechanism of neuropathic pain is too complex and involves both peripheral and central pathophysiological phenomenon . Accordingly the treatment of neuropathic pain is also very complex and is unsatisfactory . The present review attempts to discuss the currently employed pharmacological agents for the management of neuropathic pain including anti - depressants , anti - convulsants , DB01221 receptor antagonists , topical & local anesthetics , and upload analgesics . However , the existing pharmacotherapy has marginal efficacy and significant side effects . The review also gives an insight into various pharmacological agents with potential neuropathic pain attenuating properties in experimental models that include NSAIDs , corticosteroids , ion channel blockers ( Ca ( 2 +) , Na (+) , K (+) , and TRP channel ) ; ion exchange modulators ( NCE and NHE ) ; ion / molecule transport modulators ( NKCC - 1 and glycine ) ; receptor modulators ( kinin , histamine , P08908 , dopamine , alpha & beta adrenergic , purinergic , excitatory amino acid , sigma , P41146 , endothelin , melanocortin , ephrin and PAR ) ; enzyme inhibitors ( cytosolic kinase , metalloproteinase , protease , vasopeptidase , D - amino acid oxidase , fatty acid amide hydrolase , aldose reductase and sorbitol dehydrogenase ) ; other ligands ( P51606 , RAGEs , neuropeptides , neurotrophic factor , complement cascade , cytokine , glial cell & gap junction , nitrous oxide , growth factor , cell adhesion molecule and neuronal sprouting molecule ) . Moreover , some advanced therapeutic approaches such as neuronal cell transplantation , stem cell therapy , anti - sense oligonucleotide and recombinant therapy have also been dicussed .", "___MASK49___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .", "Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK55___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK55___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .", "5 - HT prolongs ventral root bursting via presynaptic inhibition of synaptic activity during fictive locomotion in lamprey . Locomotor pattern generation is maintained by integration of the intrinsic properties of spinal central pattern generator ( CPG ) neurons in conjunction with synaptic activity of the neural network . In the lamprey , the spinal locomotor CPG is modulated by 5 - HT . On a cellular level , 5 - HT presynaptically inhibits synaptic transmission and postsynaptically inhibits a Ca2 +- activated K + current responsible for the slow afterhyperpolarization ( sAHP ) that follows action potentials in ventral horn neurons . To understand the contribution of these cellular mechanisms to the modulation of the spinal CPG , we have tested the effect of selective 5 - HT analogues against fictive locomotion initiated by bath application of N - methyl - d - aspartate ( DB01221 ) . We found that the P28221 agonist , L694 - 247 , dramatically prolongs the frequency of ventral root bursting . Furthermore , we show that L694 - 247 presynaptically inhibits synaptic transmission without altering postsynaptic Ca2 +- activated K + currents . We also confirm that 5 - HT inhibits synaptic transmission at concentrations that modulate locomotion . To examine the mechanism by which selective presynaptic inhibition modulates the frequency of fictive locomotion , we performed voltage - and current - clamp recordings of CPG neurons during locomotion . Our results show that 5 - HT decreases glutamatergic synaptic drive within the locomotor CPG during fictive locomotion . Thus we conclude that presynaptic inhibition of neurotransmitter release contributes to 5 - HT - mediated modulation of locomotor activity .", "DB00435 induces apoptosis in GM - P04141 - treated eosinophils via caspase - 6 - dependent lamin and DNA fragmentation . Asthma is characterized by accumulation of eosinophils in the lungs and delayed apoptosis may be one mechanism leading to eosinophilia . DB00435 ( NO ) , present in inflamed lungs , has been shown to possess both anti - and proeosinophilic properties . We previously showed that NO induces apoptosis in the presence of survival prolonging cytokine P05113 in human eosinophils . In the present study , we examined the intracellular mechanisms of NO - induced apoptosis in granulocyte macrophage - colony stimulating factor ( GM - P04141 ) - treated eosinophils concentrating on the role of caspases and calpains . Eosinophils were isolated from human blood and apoptosis was determined by relative DNA fragmentation assay , morphological analysis and / or Annexin - V FITC assay . We showed that NO - donor S - nitroso - N - acetyl - d , l - penicillamine ( P60880 ) induced apoptosis in GM - P04141 - treated eosinophils . P60880 - induced DNA fragmentation was totally prevented by an inhibitor of caspase - 6 ( Z - VEID - FMK ) . Decreased levels of caspase - 6 proenzyme and increased amounts of cleaved lamin A / C in P60880 - treated cells indicated activation of caspase - 6 . Furthermore , P60880 - induced lamin A / C and B fragmentation was totally abolished by an inhibitor of caspase - 6 . According to our results , caspase - 6 mediates lamin and DNA fragmentation also in spontaneously dying eosinophils . Inhibitor of calpains prevented most of DNA fragmentation related to spontaneous apoptosis but had no effect in eosinophils undergoing NO - induced apoptosis . In the present study we showed that caspase - 6 is essential for the executive phase involving lamin and DNA fragmentation in both NO - induced and spontaneous eosinophil apoptosis . However , differences in the involvement of calpains suggest that the intracellular signalling in NO - induced apoptosis has specific features at the level of proteases . This study demonstrates new mechanisms for NO - induced and spontaneous apoptosis in human eosinophils .", "Clinical pharmacology of serotonin - altering medications for decreasing alcohol consumption . Variations in serotonin neurotransmission influence alcohol consumption ( AC ) . Levels of 5 - HT and metabolites are low in some brain regions of alcohol preferring rats and in P04141 of alcoholics . Pharmacological treatments which enhance serotonergic neurotransmission ( uptake inhibitors , releasers , agonists ) consistently reduce AC in rats . Serotonin uptake inhibitors ( SUI ; e . g . , citalopram , fluoxetine ) have been studied extensively in humans . In several double - blind randomized , placebo - controlled clinical trials , SUI have consistently decreased AC by averages of 15 % to 20 % in nondepressed mildly / moderately dependent alcoholics who received no other treatment . Effects were dose - dependent and not related to side effects ( few and mild ) or changes in anxiety or depression ( not observed ) . SUI also decreased desire to drink and liking for alcohol , thus suggesting a mechanism for effects . Other drugs acting on the 5 - HT system have been tested in humans , but results are difficult to interpret . For example , buspirone , a P08908 receptor partial agonist , reduced anxiety and alcohol craving , but not AC ; a 5 - HT partial agonist , m - CPP , increased alcohol craving in abstinent alcoholics ; modest reductions in AC were observed with a 5 - Q9H205 antagonist , ondansetron ( 0 . 5 mg / day , but not 4 mg / day ) . The therapeutic potentials of these medications are being studied . For example , SUI effects on AC were enhanced by a brief psychosocial intervention . Since SUI decrease urge to drink , they may be suitable pharmacological adjuncts in relapse prevention strategies . SUI and other serotonin - altering medications are promising new neuropharmacological treatments for reducing AC .", "Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .", "DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK55___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .", "The spino - bulbar - cerebellar pathway : Activation of neurons projecting to the lateral reticular nucleus in the rat in response to noxious mechanical stimuli . It is now well established that the cerebellum receives input from nociceptors which may serve to adjust motor programmes in response to pain and injury . In this study , we investigated the possibility that spinoreticular neurons ( SRT ) which project to a pre - cerebellar nucleus , the lateral reticular nucleus ( LRt ) , respond to noxious mechanical stimulation . Seven adult male rats received stereotaxic injections of the b subunit of cholera toxin in the LRt . Following a 5 day interval , animals were anesthetised with urethane and a noxious mechanical stimulus was applied to the right hind paw . Animals were fixed by perfusion 5min following application of the stimulus . Retrogradely labelled SRT neurons of the lumbar spinal cord were examined for immunoreactivity for phosphorylated P29323 ( pERK ) and the neurokinin - 1 ( NK - 1 ) receptor . Approximately 15 % of SRT cells in deep laminae ( IV - VII and X ) expressed pERK ipsilateral to the site of the stimulus . Around 60 % of SRT cells with the P25103 expressed pERK but 5 % of pERK expressing cells were negatively labelled for NK - 1 . It is concluded that a significant proportion of SRT cells projecting to the LRt respond to noxious mechanical stimuli and that one of the functions of this pathway may be to provide the cerebellum with nociceptive information .", "Neuroprotective effects of serotonin 5 - HT 1A receptor activation against ischemic cell damage in gerbil hippocampus : Involvement of DB01221 receptor Q9UHB4 subunit and P23560 . It is known that the activation of 5 - hydroxytryptamine receptor type 1A ( 5HT ( 1A ) receptor ) may protect against brain damage induced by transient global ischemia . The biochemical mechanisms that underlie this neuroprotective effect remain however to be fully elucidated . Given that serotonergic drugs may regulate N - methyl - d - aspartate ( DB01221 ) receptor function , which is implicated in events leading to ischemia - induced neuronal cell death , and also stimulate the expression of brain - derived neurotrophic factor ( P23560 ) , which is down - regulated in cerebral ischemia , we sought to determine the effects of the selective P08908 receptor agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , on the levels of DB01221 receptor Q9UHB4 subunit and P23560 in gerbil hippocampus after transient global cerebral ischemia . Pretreatment with 8 - OH - DPAT ( 1 mg / kg ) prevented the neuronal loss in P00915 subfield 72 h after ischemia and also the dramatic decrease in P23560 immunoreactivity observed in this area at an earlier time . DB01221 receptor Q9UHB4 levels in whole hippocampus were not affected 24 h after ischemia , but the levels of the subunit phosphorylated at the protein kinase A ( PKA ) site , pNR1 ( Ser897 ) , were significantly increased , and this increase was prevented by the same 8 - OH - DPAT dose , a probable consequence of the increased phosphatase 1 ( P50391 ) enzyme activity found in ischemic gerbils pretreated with the 5 - HT ( 1A ) receptor agonist . The results indicate that both Q9UHB4 subunit phosphorylation and the neurotrophin P23560 account , at least in part , for the neuroprotective effect of 8 - OH - DPAT on cell damage induced by global ischemia in the gerbil hippocampus and support the potential interest of P08908 receptor activation in the search for neuroprotective strategies .", "Obestatin stimulates Akt signalling in gastric cancer cells through beta - arrestin - mediated epidermal growth factor receptor transactivation . Obestatin was identified as a gut peptide encoded by the ghrelin gene that interacts with the G protein - coupled receptor , O43194 . In this work , a sequential analysis of its transmembrane signalling pathway has been undertaken to characterize the intracellular mechanisms responsible for Akt activation . The results show that Akt activation requires the phosphorylation of T308 in the A - loop by the phosphoinositide - dependent kinase 1 ( PDK1 ) and S473 within the HM by the mammalian target of rapamycin ( P42345 ) kinase complex 2 ( mTORC2 : Rictor , Q9BVC4 , mSin1 , P42345 kinase ) with participation neither of G ( i )(/ o )- protein nor Gbetagamma dimers . Obestatin induces the association of O43194 / beta - arrestin 1 / Src signalling complex resulting in the transactivation of the epidermal growth factor receptor ( P00533 ) and downstream Akt signalling . Upon administration of obestatin , phosphorylation of P42345 ( S2448 ) and p70S6K1 ( T389 ) rise with a time course that parallels that of Akt activation . Based on the experimental data obtained , a signalling pathway involving a beta - arrestin 1 scaffolding complex and P00533 to activate Akt signalling is proposed .", "[ Moclobemide ( ___MASK30___ ) , the first P21397 - inhibitor : really something new ? ] .", "5 - Q13049 receptor induces P29323 phosphorylation and proliferation through ADAM - 17 tumor necrosis factor - alpha - converting enzyme ( P78536 ) activation and heparin - bound epidermal growth factor - like growth factor ( HB - P01133 ) shedding in mesangial cells . In this study , we present multiple lines of evidence to support a critical role for heparin - bound P01133 ( epidermal growth factor ) - like growth factor ( HB - P01133 ) and tumor necrosis factor - alpha - converting enzyme ( P78536 ) ( P78536 ) in the transactivation of P01133 receptor ( P00533 ) , P29323 phosphorylation , and cellular proliferation induced by the 5 - HT ( 2A ) receptor in renal mesangial cells . 5 - hydroxy - tryptamine ( 5 - HT ) resulted in rapid activation of P78536 , HB - P01133 shedding , P00533 activation , P29323 phosphorylation , and longer term increases in DNA content in mesangial cells . P29323 phosphorylation was attenuated by 1 ) neutralizing P00533 antibodies and the P00533 kinase inhibitor , AG1478 , 2 ) neutralizing HB - P01133 , but not amphiregulin , antibodies , heparin , or CM197 , and 3 ) pharmacological inhibitors of matrix - degrading metalloproteinases or P78536 small interfering RNA . Exogenously administered HB - P01133 stimulated P29323 phosphorylation . Additionally , P78536 was co - immunoprecipitated with HB - P01133 . Small interfering RNA against P78536 also blocked 5 - HT - induced increases in P29323 phosphorylation , HB - P01133 shedding , and DNA content . In aggregate , this work supports a pathway map that can be depicted as follows : 5 - HT --> 5 - HT ( 2A ) receptor --> P78536 --> HB - P01133 shedding --> P00533 --> P29323 --> increased DNA content . To our knowledge , this is the first time that P78536 has been implicated in 5 - HT - induced P00533 transactivation or in proliferation induced by a G protein - coupled receptor in native cells in culture .", "TATA - driven transcriptional initiation and regulation of the rat serotonin P08908 receptor gene . The transcriptional initiation and regulation of the rat serotonin P08908 receptor gene were characterized . By three types of analyses , a single brain - specific site of transcriptional initiation was localized to - 967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line . This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element , suggesting TATA - driven transcription of the rat P08908 receptor . To identify the promoter activity of the receptor gene , progressive 5 ' deletions of the - 2 , 719 /- 117 - bp fragment of the P08908 promoter linked to luciferase gene were transfected into P08908 - negative ( pituitary GH4C1 , Q9BTT4 myoblast , and P13671 glioma ) and P08908 - positive ( septal SN - 48 and raphe RN46A ) cell lines . Enhancer regions were identified within a fragment between nucleotides - 426 and - 117 that selectively enhanced transcription in P08908 - positive cells . A nonselective enhancer / promoter that mediated expression in all cell lines was located upstream between - 1 , 519 and - 426 bp in a DNA segment containing consensus TATA , CCAAT , SP - 1 , and AP - 1 elements as well as a poly - GT26 dinucleotide repeat . Strong repression of transcription in all cell lines was conferred by the region upstream of - 1 , 519 bp that contains a 152 - bp DNA segment with > 80 % identity to RANTES , tumor necrosis factor - beta , and other immune system genes . Our results indicate that TATA - driven expression of the P08908 receptor is regulated by a novel proximal tissue - specific enhancer region , a nonselective promoter , and an upstream repressor region that is distinct from previously identified neuron - specific repressors .", "Central mechanisms of vomiting . Nausea and vomiting ( emesis ) occur under a variety of conditions in response to activation of one or more emetic triggers . The act of vomiting is coordinated by neuronal circuitry located in the brain stem between the obex and the retrofacial nucleus , including the region extending from the nucleus of the solitary tract through the lateral tegmental field of the reticular formation to the ventrolateral medulla . The area postrema , medullary midline , and certain higher brain centers are also important for vomiting . The sensation of nausea is thought to involve the cerebral cortex . The most effective near - term treatment for combating nausea and vomiting associated with cyclic vomiting syndrome may come from experimental drugs ( P25103 antagonists , P08908 receptor agonists ) or P6 acustimulation , which have been shown to combat nausea and vomiting in response to a broad spectrum of emetic challenges and thus presumably act on central emetic mechanisms .", "Cellular mechanisms in the vulnerability to depression and response to antidepressants . As a testable heuristic , the concept of stress response and adaptation is highly appealing , and the support for the concept is strong . This explanatory model of depression may account for hitherto apparently discordant facts -- contradictory symptoms , antidepressant drugs that act on differing systems , facilitation of antidepressant response by augmentation , and response to psychotherapy and pharmacotherapy . This article has focused narrowly on specific cellular elements of the stress - adaptational mechanisms , including the AC - PKA and P98160 - PKC transductional cascades , together with specific response elements , such as the Q9Y251 axis , P23560 , and DB01221 receptors ; however , other important mechanisms , including specific receptor subtypes ( e . g . , P08908 and NE alpha 2 ) , transmitter systems ( e . g . , acetylcholine and depamine ) , and hormones ( e . g . , thyroid and growth hormones and prolactin ) , which may be important , have not been discussed . As the complex interactions of these systems gradually yield to investigation , not only will new treatments be developed , but better matching of treatment to patient may become an achievable goal .", "Activation of P08908 receptors expressed in NIH - 3T3 cells induces focus formation and potentiates P01133 effect on DNA synthesis . NIH - 3T3 fibroblasts have been transfected with human serotonin P08908 receptors . Clonal cell lines expressed between 40 and 500 fmol receptor / mg . P08908 agonists strongly inhibited nonstimulated - as well as forskolin - or isoproterenol - stimulated adenylyl cyclase . The effects of P08908 receptor activation on cell growth were investigated . P08908 agonists accelerated cell division , generated foci , and increased DNA synthesis . The stimulation of [ 3H ] thymidine incorporation was much stronger when tyrosine kinase receptors were activated concomitantly . DB02527 ( DB02527 ) elevating agents inhibited DNA synthesis induced by all mitogens tested . The mitogenic activity of P08908 agonists did not seem to be linked to adenylyl cyclase inhibition because 1 ) we were not able to measure any decrease in intracellular DB02527 levels under the conditions of DNA synthesis assay and 2 ) 2 ', 5 '- dideoxyadenosine , which strongly inhibited adenylyl cyclase , was not mitogenic and did not modify the mitogenic effects of P08908 agonists . Pertussis toxin completely blocked potentiation of epidermal growth factor effect induced by 8 - hydroxy - di -( n - propyl ) aminotetralin , a P08908 agonist , but only partially blocked the one induced by insulin . In conclusion , in transfected NIH - 3T3 cells , transforming and mitogenic effects of P08908 agonists involve a pertussis toxin - sensitive G protein but do not seem to be linked to adenylyl cyclase inhibition .", "Pharmacological treatments of cerebellar ataxia . The confirmed pharmacological treatment of cerebellar ataxia is still lacking . In a recent preliminary trial , we showed that D - cycloserine , a partial DB01221 allosteric agonist , may relieve the symptoms . In this paper , major clinical trials to relieve ataxic symptoms are reviewed . Previous studies showed some efficacy of physostigmine in ataxic patients . However , physostigmine did not improve the ataxia in a recent double - blind crossover study . The replacement therapy of the deficient cholinergic system with choline or choline derivatives was tried in patients with Friedreich ' s ataxia and other ataxic patients , but the result was not definitive . A levorotatory form of hydroxytryptophan ( a serotonin precursor ) , a serotoninergic P08908 agonist , a serotoninergic 5 - Q9H205 antagonist , and a serotonin reuptake inhibitor were also used for the therapy for ataxia . In a double - blind randomized study , buspirone , a P08908 agonist was active in cerebellar ataxia , but the effect is partial and not major . The effects of the studies with the other serotoninergic drugs were not consistent . The effect of sulfamethoxazole - trimethoprim therapy in spinocerebellar ataxia type3 / Machado - Joseph disease ( P54252 ) was reported , although the therapy improved spasticity or rigidity , rather than ataxia . In contrast to previous studies , sulfamethoxazole - trimethoprim therapy in P54252 had no effect in a 2001 double - blind crossover study . The thyrotropin - releasing hormone , D - cycloserine , and acetazolamide for SCA6 may have some efficacy . However , a well - designed double - blind crossover trial is needed to confirm the effect .", "Effects of psychoactive drugs in the Vogel conflict test in mice . This study examined effects of various psychoactive drugs on the Vogel conflict test , where drinking behavior is punished by electric shocks , in ICR mice to clarify the pharmacological features of this method in mice . A benzodiazepine anxiolytic diazepam and a barbiturate pentobarbital produced significant anticonflict effects , which mean that these drugs increased the number of electric shocks mice received during 40 - min test session . On the other hand , yohimbine ( alpha2 - receptor antagonist ) , caffeine ( adenosine - receptor antagonist ) , scopolamine ( muscarinic cholinergic antagonist ) , cyclazocine ( sigma - receptor antagonist ) , cimetidine ( H2 - receptor antagonist ) , baclofen ( GABA ( B )- receptor agonist ) , MK - 801 ( DB01221 - receptor antagonist ) , buspirone ( P08908 - receptor agonist ) , chlorpromazine ( dopamine - receptor antagonist ) and haloperidol ( dopamine - receptor and sigma - receptor antagonist ) all did not produce anticonflict effects in this test using ICR mice . The results suggest that the Vogel conflict test is applicable to ICR mice and that this test in mice is appropriate as a screening method for drugs that have apparent anti - anxiety actions .", "Cloning , after cloning , knock - out mice , and physiological functions of MAO A and B . Cloning of MAO A and B has demonstrated clearly that MAO A and B are coded by different proteins with 70 % amino acid identity . With the MAO A and B cDNA clones , we showed the tissue distribution and genomic structure of MAO A and B , the latter suggesting that they are derived from the same ancestral gene . The active sites , the role of cysteine residues , the three - dimensional models and the mitochondria targeting domains of both isoenzymes have been established . The transcriptional regulation of MAO A and B has been studied . MAO A KO mice showed increased levels of serotonin ( 5 - HT ) , norepinephrine ( NE ) , dopamine ( DA ) whereas MAO B KO mice showed increased phenylethylamine ( PEA ) levels only . Both MAO A and B KO mice showed increased response to stress . MAO A KO mice showed increased emotional learning and memory and aggressive behavior , but the vesicular monoamine transporter ( Q05940 ) , P08908 , 5 - Q13049 and P28335 receptors were down regulated . 5 - Q13049 antagonist , ketanserin and MDL100907 were able to abolish the aggression , suggesting that the aggressive behavior may be mediated by 5 - Q13049 receptor . In contrast , MAO B KO mice are resistant to MPTP , a toxin which induces Parkinson ' s syndromes . Studies of these mice suggest that MAO A and B have distinct biochemical and physiological functions .", "Association testing of panic disorder candidate genes using Q13308 challenge in healthy volunteers . Despite continuing efforts to determine genetic vulnerability to panic disorder ( PD ) , the studies of candidate genes in this disorder have produced inconsistent or negative , results . Laboratory panic induction may have a potential in testing genetic substrate of PD . In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin - tetrapeptide ( Q13308 ) challenge in healthy subjects . The study sample consisted of 110 healthy volunteers ( 47 males and 63 females , mean age 22 . 2 +/- 5 . 2 ) who participated in Q13308 challenge test . Nine gene - candidates , including 5 - HTTLPR , P21397 VNTR , Q8IWU9 rs1386494 , 5 - P08908 - 1019C - G , 5 - P28223 102T - C , CCKR1 246G - A , CCKR2 - 215C - A , P21728 - 94G - A and P21964 Val158Met , were selected for genotyping based on previous positive findings from genetic association studies in PD . After Q13308 challenge , 39 ( 35 . 5 % ) subjects experienced a panic attack , while 71 subjects were defined as non - panickers . We detected significant differences for both genotypic and allelic frequencies of 1386494A / G polymorphism in Q8IWU9 gene between panic and non - panic groups with the frequencies of G / G genotype and G allele significantly higher in panickers . None of the other candidate loci were significantly associated with Q13308 - induced panic attacks in healthy subjects . In line with our previous association study in patients with PD , we detected a possible association between Q8IWU9 rs1386494 polymorphism and susceptibility to panic attacks . Other polymorphisms previously associated with PD were unrelated to Q13308 - induced panic attacks , probably due to the differences between complex nature of PD and laboratory panic model .", "P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK44___ ) in castrated male and female mice subjected to ___MASK44___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK44___ in mice CPs .", "The effect of zotepine , risperidone , clozapine and olanzapine on MK - 801 - disrupted sensorimotor gating . Dizocilpine ( MK - 801 ; 0 . 3 mg / kg i . p . ) - induced disruption in prepulse inhibition of the acoustic startle response ( PPI ) can be preferentially restored by \" atypical \" antipsychotics . In contrast , some findings indicate that not all of the \" atypical \" antipsychotics , such as clozapine and risperidone , are effective in restoring the DB01221 antagonist - induced deficits in PPI . In our study , we evaluated the effect of four different \" atypical \" antipsychotic drugs on deficits in PPI induced by MK - 801 . DB09225 and risperidone have high affinities to D2 - like and 5 - Q13049 receptors , while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin P08908 , 2A / 2C receptors and muscarinic receptors . Results have shown that MK - 801 disrupted PPI and increased the ASR in rats . Our results showed no effect of zotepine ( 1 and 2 mg / kg ) and risperidone ( 0 . 1 and 1 mg / kg ) on disrupted PPI by MK - 801 . Administration of clozapine ( 5 and 10 mg / kg ) and olanzapine ( 2 . 5 and 5 mg / kg ) restored the deficits in PPI induced by MK - 801 . Additionally , we found a decrease of approximately 46 % in PPI after administration of clozapine ( 5 mg / kg ) and olanzapine ( 2 . 5 and 5 mg / kg ) without MK - 801 treatment . In summary , the four \" atypical \" antipsychotics had different efficacies to restore the disrupted PPI by MK - 801 . Only clozapine and olanzapin restored the MK - 801 - induced deficits in PPI .", "Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells . Epithelial - mesenchymal transition ( EMT ) contributes to the progression of renal tubulointerstitial fibrosis . The N - methyl - d - aspartate receptor ( NMDAR ) , which is present in proximal tubular epithelium , is a glutamate receptor that acts as a calcium channel . Activation of NMDAR induces actin rearrangement in cells of the central nervous system , but whether it helps maintain the epithelial phenotype of the proximal tubule is unknown . Here , knockdown of Q05586 in a proximal tubule cell line ( HK - 2 ) induced changes in cell morphology , reduced P12830 expression , and increased α - SMA expression . Induction of EMT with TGF - β1 led to downregulation of both P12830 and membrane - associated β - catenin , reorganization of F - actin , expression of mesenchymal markers de novo , upregulation of Snail1 , and increased cell migration ; co - treatment with DB01221 attenuated all of these changes . Furthermore , DB01221 reduced TGF - β1 - induced phosphorylation of Erk1 / 2 and Akt and the activation of Ras , suggesting that DB01221 antagonizes TGF - β1 - induced EMT by inhibiting the Ras - MEK pathway . In the unilateral ureteral obstruction model , treatment with DB01221 blunted obstruction - induced upregulation of α - SMA , FSP1 , and collagen I and downregulation of P12830 . Taken together , these results suggest that NMDAR plays a critical role in preserving the normal epithelial phenotype and modulating tubular EMT .", "DB00435 - evoked glutamate release and cGMP production in cerebellar slices : control by presynaptic P28221 receptors . We previously reported that pre - and postsynaptic 5 - hydroxytryptamine ( 5 - HT ) receptors effectively control glutamatergic transmission in adult rat cerebellum . To investigate where 5 - HT acts in the glutamate ionotropic receptors / nitric oxide / guanosine 3 ', 5 '- cyclic monophosphate ( cGMP ) pathway , in the present study 5 - HT modulation of the cGMP response to the nitric oxide donor S - nitroso - penicillamine ( P60880 ) was studied in adult rat cerebellar slices . While cGMP elevation produced by high - micromolar P60880 was insensitive to 5 - HT , 1 microM P60880 , expected to release nitric oxide in the low - nanomolar concentration range , elicited cGMP production and endogenous glutamate release both of which could be prevented by activating presynaptic P28221 receptors . Released nitric oxide appeared responsible for cGMP production and glutamate release evoked by 1 microM P60880 , as both the effects were mimicked by the structurally unrelated nitric oxide donor 2 -( N , N - diethylamino )- diazenolate - 2 - oxide ( 0 . 1 microM ) . Dependency of the 1 microM P60880 - evoked release of glutamate on external Ca2 + , sensitivity to presynaptic release - regulating receptors and dependency on ionotropic glutamate receptor functioning , suggest that nitric oxide stimulates exocytotic - like , activity - dependent glutamate release . Activation of ionotropic glutamate receptors / nitric oxide synthase / guanylyl cyclase pathway by endogenously released glutamate was involved in the cGMP response to 1 microM P60880 , as blockade of DB01221 / non - DB01221 receptors , nitric oxide synthase or guanylyl cyclase , abolished the cGMP response . To conclude , in adult rat cerebellar slices low - nanomolar exogenous nitric oxide could facilitate glutamate exocytotic - like release possibly from parallel fibers that subsequently activated the glutamate ionotropic receptors / nitric oxide / cGMP pathway . Presynaptic P28221 receptors could regulate the nitric oxide - evoked release of glutamate and subsequent cGMP production .", "In vitro prostanoid release from spinal cord following peripheral inflammation : effects of DB05875 , DB01221 and capsaicin . 1 . Spinal prostanoids are implicated in the development of thermal hyperalgesia after peripheral injury , but the specific prostanoid species that are involved are presently unknown . The current study used an in vitro spinal superfusion model to investigate the effect of DB05875 ( SP ) , N - methyl - d - aspartate ( DB01221 ) , and capsaicin on multiple prostanoid release from dorsal spinal cord of naive rats as well as rats that underwent peripheral injury and inflammation ( knee joint kaolin / carrageenan ) . 2 . In naive rat spinal cords , DB00917 and 6 - keto - PGF1alpha , but not TxB2 , levels were increased after inclusion of SP , DB01221 , or capsaicin in the perfusion medium . 3 . Basal DB00917 levels from spinal cords of animals that underwent 5 - 72 h of peripheral inflammation were elevated relative to age - matched naive cohorts . The time course of this increase in basal DB00917 levels coincided with peripheral inflammation , as assessed by knee joint circumference . Basal 6 - keto - PGF1alpha levels were not elevated after injury . 4 . From this inflammation - evoked increase in basal DB00917 levels , SP and capsaicin significantly increased spinal DB00917 release in a dose - dependent fashion . DB06774 - evoked increases were blocked dose - dependently by inclusion of S (+) ibuprofen in the capsaicin - containing perfusate . 5 . These data suggest a role for spinal DB00917 and P25103 activation in the development of hyperalgesia after injury and demonstrate that this relationship is upregulated in response to peripheral tissue injury and inflammation .", "Changes in glutamate receptor subunits within the medulla in goats after section of the carotid sinus nerves . The mechanisms which contribute to the time - dependent recovery of resting ventilation and the ventilatory CO2 chemoreflex after carotid body denervation ( DB09061 ) are poorly understood . Herein we tested the hypothesis that there are time - dependent changes in the expression of specific AMPA , DB01221 , and / or neurokinin - 1 ( P25103 ) receptors within respiratory - related brain stem nuclei acutely or chronically after DB09061 in adult goats . Brain stem tissues were collected acutely ( 5 days ) or chronically ( 30 days ) after sham or bilateral DB09061 , immunostained with antibodies targeting AMPA ( P42261 or P42262 ) , DB01221 ( Q05586 ) , or NK - 1 receptors , and optical density ( OD ) compared . Physiological measurement confirmed categorization of each group and showed ventilatory effects consistent with bilateral DB09061 ( Miller et al . J Appl Physiol 115 : 1088 - 1098 , 2013 ) . Acutely after DB09061 , P42261 OD was unchanged or slightly increased , but P42262 and Q05586 OD were reduced 15 - 30 % within the nucleus tractus solitarius ( P30990 ) and in other medullary respiratory nuclei . Chronically after DB09061 , P42261 was reduced ( P < 0 . 05 ) within the caudal P30990 and in other nuclei , but there was significant recovery of P42262 and Q05586 OD . NK1 OD was not significantly different from control after DB09061 . We conclude that the initial decrease in P42262 and Q05586 after DB09061 likely contributes to hypoventilation and the reduced CO2 chemoreflex . The partial recovery of ventilation and the CO2 chemoreflex after DB09061 parallel a time - dependent return of these receptors to near control levels but likely depend upon additional initiating and maintenance factors for neuroplasticity .", "Identification of novel genes regulated in the developing human ventral mesencephalon . In the human embryo , from approximately 6 weeks gestational age ( GA ) , dopaminergic ( DA ) neurons can be found in the ventral mesencephalon ( VM ) . More specifically , the post - mitotic neurons are located in the ventral part of the tegmentum ( VT ) , whereas no mature DA neurons are found in the neighboring dorsal part . We used Affymetrix HG - U133 GeneChip technology to compare genome - wide expression profiles of ventral and dorsal tegmentum from 8 weeks GA human embryos , in order to identify genes involved in specification , differentiation , and survival of mesencephalic DA ( mDA ) neurons . Known mDA marker genes including P00352 , Q01959 , Q05940 , TH , P05937 , P43354 , P55317 , P48051 , O75364 , P07949 , and P14416 topped the list of 96 genes from HG - U133A with higher expression in VT , validating the experimental set - up . In addition , 28 probes from HG - U133B were identified whereof most are annotated to UniGene clusters with no gene associated or to genes of unknown function . Of these , the fifteen most regulated transcripts , representing changes down to 56 % could be verified by quantitative real - time PCR ( Q - PCR ) on a developmental series of subdissected human embryonic and fetal brain material , resulting in not only a regional but also a temporal expression profile . This revealed a distinct DA - associated profile for in particular a putative transcription factor ( FLJ45455 ) and the uncharacterized transmembrane proteins Q9ULS5 and Q96EP9 . The data presented here may help to device cell replacement and regenerative therapies for Parkinson ' s disease ( PD ) .", "Neurokinin - 1 receptors in the cerebrovascular vasoactive intestinal polypeptide - containing nerves in the rat . Recently , the functions of several putative neurotransmitters such as catecholmines , acetylcholine ( ACh ) and neuropeptides have been elucidated in the cerebrovasculature . The interaction of such neurotransmitters and their receptors , however , has not been sufficiently clarified . The purpose of this study is to explore the relation of recently demonstrated neurokinin - 1 ( NK - 1 ) receptor - containing cerebrovascular nerve fibers with the cerebrovascular vasodilatory nerves by means of the sequential - staining immunohistochemical method . Numerous sites of P25103 immunoreactivities were noted along the nerve fibers with vasoactive intestinal polypeptide ( P01282 ) immunoreactivity in the pial arteries in all regions of the brain . They consisted of fine , delicate varicose fibers and thick bundles without varicosities . After sequential staining with P01282 , P25103 immunoreactive material was demonstrated in the P01282 - positive nerve fibers . The majority of fibers were positive for P01282 alone ( 75 % ) . The number of fibers positive for both P25103 and P01282 was about one - third the number of fibers for P01282 alone ( 22 % ) . Fibers positive for P25103 alone comprised a small population ( 3 % ) . This study demonstrated that NK - 1 receptors are localized in axonal membrane of P01282 - containing parasympathetic nerves . This suggests that the sensory nerves modulate the functions of parasympathetic nerves in peripheral nervous system , such as those on cerebral vessels .", "Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in P04141 of healthy volunteers . BACKGROUND : Concentrations of monoamine metabolites in human cerebrospinal fluid ( P04141 ) have been used extensively as indirect estimates of monoamine turnover in the brain . P04141 monoamine metabolite concentrations are partly determined by genetic influences . METHODS : We investigated possible relationships between DNA polymorphisms in the serotonin 2C receptor ( P28335 ) , the serotonin 3A receptor ( P46098 ) , the dopamine D4 receptor ( P21917 ) , and the dopamine beta - hydroxylase ( P09172 ) genes and P04141 concentrations of 5 - hydroxyindolacetic acid ( 5 - HIAA ) , homovanillic acid ( HVA ) , and 3 - methoxy - 4 - hydroxyphenylglycol ( MHPG ) in healthy volunteers ( n = 90 ) . RESULTS : The P46098 178 C / T variant was associated with 5 - HIAA levels ( p = 0 . 02 ) . The P09172 - 1021 heterozygote genotype was associated with 5 - HIAA ( p = 0 . 0005 ) and HVA ( p = 0 . 009 ) concentrations . Neither the P28335 Cys23Ser variant , nor the P21917 - 521 C / T variant were significantly associated with any of the monoamine metabolites . CONCLUSIONS : The present results suggest that the P46098 and P09172 genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system .", "Pattern and pharmacology of propagating epileptiform activity in mouse cerebral cortex . Multiple extracellular recording electrodes were used to study the intra - and interhemispheric spread of stimulus - evoked epileptiform responses in adult mouse neocortical slices . Bath application of 20 microM bicuculline methiodide induced epileptiform activity that propagated at approximately 0 . 08 m / s over several millimeters in rostro - caudal and medio - lateral direction within the ipsilateral hemisphere and across the corpus callosum to the contralateral hemisphere . A vertical incision from layer II to subcortical regions did not prevent the spread to remote cortical regions , indicating that layer I plays a major role in the lateral propagation of epileptiform activity . The intra - and interhemispheric spread was not influenced by application of an N - methyl - d - aspartate ( DB01221 ) receptor antagonist , but blocked by an antagonist acting at the (+/-)- alpha - amino - 3 - hydroxy - 5 - methylisoxazole - 4 - propionic acid ( AMPA ) - type glutamate receptor . The potential role of potassium channel activation in controlling the generation or spread of epileptiform activity was tested by applying the potassium channel opener cromakalim and the serotonin type 1A ( P08908 ) receptor agonist (+/-)- 8 - hydroxydipropylaminotetralin ( 8 - OH - DPAT ) to the disinhibited slices . Whereas cromakalim reduced the neuronal excitability and blocked all epileptiform responses , 8 - OH - DAPT did not affect the activity pattern . Our results suggest that propagating epileptiform activity in disinhibited neocortical structures is predominantly mediated by activation of AMPA receptors and controllable by activation of a voltage - dependent potassium current .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "Role of different monoamine receptors controlling MK - 801 - induced release of serotonin and glutamate in the medial prefrontal cortex : relevance for antipsychotic action . Several studies have demonstrated that systemically administered N - methyl - d - aspartate ( DB01221 ) receptor antagonists increase serotonin ( 5 - HT ) and glutamate release in the medial prefrontal cortex ( mPFC ) . Previously we showed that the perfusion of clozapine in the mPFC prevented the MK - 801 - induced increase in extracellular glutamate and 5 - HT whereas haloperidol blocked only the effect of MK - 801 on glutamate . To study the contribution of different monoaminergic receptors ( for which clozapine and haloperidol exhibit distinct affinities ) to these effects , here we used in - vivo microdialysis to examine the role of local blockade of dopamine D2 , 5 - Q13049 and alpha1 - adrenergic receptors as well as agonism at dopamine D1 and P08908 receptors in the mPFC on the increased efflux of glutamate and 5 - HT elicited by MK - 801 . The results show that M100907 ( 5 - Q13049 antagonist ) , BAY x 3702 ( P08908 agonist ) and prazosin ( alpha1 - adrenergic antagonist ) blocked the MK - 801 - induced increase of 5 - HT and glutamate in the mPFC . However , raclopride , eticlopride ( dopamine D2 antagonists ) and SKF - 38393 ( dopamine D1 agonist ) were able to prevent the increased efflux of glutamate ( but not that of 5 - HT ) elicited by MK - 801 . We propose that D2 receptor antagonists and D1 agonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC , thus leading to an enhanced cortical inhibition that would prevent an excessive glutamatergic transmission . On the other hand , atypical antipsychotic drugs might further act upon 5 - Q13049 , P08908 and alpha1 - adrenoceptors present in pyramidal cells ( including those projecting to the dorsal raphe nucleus ) , which would directly inhibit an excessive excitability of these cells .", "Behavioral and physiologic effects of genetic or pharmacologic inactivation of the DB05875 receptor ( NK1 ) . Depression and anxiety are among the most common diseases in the United States , thus constituting a substantial financial burden for the health care system . Experimental studies of these affective disorders to date have largely focused on the neurotransmitter pathways with well - established pathophysiologic roles , such as serotonergic , noradrenergic , and gamma - aminobutyric acid ( GABA ) - ergic systems ; agents modulating the activity of these pathways are known to be clinically effective . More recently , the neuropeptide DB05875 ( SP ) and its receptor ( the neurokinin - 1 receptor [ P25103 ] ) have been implicated in the pathophysiology of affective disorders , including depression . Earlier preclinical and clinical studies , though , did not provide a clear consensus on the role of SP in the regulation of affective behavior and related pathologic conditions . Recent studies in mice clearly demonstrate that both the genetic disruption and acute pharmacologic blockade of the P25103 result in marked reduction in anxiety - like behavior and stress - related responses . In parallel with these behavioral effects , physiologic changes , such as an increased firing rate of 5 - hydroxytryptamine ( 5 - HT ) neurons in the dorsal raphe nuclei and a desensitization of presynaptic P08908 inhibitory autoreceptors , were observed . These findings provide further evidence for the regulatory role of the SP - P25103 system in modulation of affective behavior and indicate that its effects are mediated , at least in part , via the serotonergic system . Future studies will attempt to delineate the interaction between the SP - P25103 system and various neurotransmitter pathways in greater detail and to address the specific role ( s ) of this system in different brain regions .", "Serotonin via P34969 receptors activates p38 mitogen - activated protein kinase and protein kinase C epsilon resulting in interleukin - 6 synthesis in human U373 MG astrocytoma cells . Serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes . Previously , it has been demonstrated that 5 - HT may induce interleukin ( IL ) - 6 expression in primary rat hippocampal astrocytes . The present study was undertaken to investigate the molecular pathways underlying this induction of P05231 synthesis . As a model system , we used the human astrocytoma cell line U373 MG , which synthesizes P05231 upon stimulation with various inducers . 5 - HT dose - and time - dependently induced P05231 protein synthesis . We identified several 5 - HT receptors to be expressed on U373 MG cells , including the P28221 , 5 - Q13049 , 5 - Q9H205 and P34969 receptors . In this report , we show that the 5 - HT - induced P05231 release is mediated by the P34969 receptor based on several agonist / antagonists that were used . 5 - HT - induced P05231 synthesis is inhibited by the partially selective P34969 receptor antagonist , pimozide , and the selective antagonist SB269970 . Furthermore , P05231 synthesis was induced by the P34969 receptor agonist carboxamidotryptamin . In addition , we found p38 MAPKs and protein kinase C ( PKC ) epsilon to be involved in 5 - HT - induced P05231 synthesis as specific inhibitors of these enzymes ( SB202190 and RO - 31 - 8425 , respectively ) blocked 5 - HT - induced P05231 synthesis . Furthermore , 5 - HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform . The Q8NFH3 / 44 MAPKs , however , were not involved in 5 - HT - induced P05231 synthesis . This study shows , for the first time , a central role of P34969 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells .", "Discriminative stimulus effects of gamma - hydroxybutyrate ( DB01440 ) and its metabolic precursor , DB04699 ( Q9BVC4 ) in rats . RATIONALE : Gamma - hydroxybutyrate ( DB01440 ) is becoming an increasingly popular drug of abuse . Metabolic precursors of DB01440 , DB04699 ( Q9BVC4 ) and 1 , 4 - butanediol ( BDL ) , are commercially available industrial solvents that may also present potential health risks . Relatively little is known about the neurobehavioral effects of DB01440 and its precursors . OBJECTIVE : The aim of the present investigation was to characterize the discriminative stimulus effects of DB01440 and its precursor , Q9BVC4 . METHODS : Male Sprague - Dawley rats were trained to discriminate DB01440 [ 300 mg / kg , i . g . ; n = 16 ] or Q9BVC4 ( 150 mg / kg , i . p . ; n = 8 ) from vehicle under a fixed ratio 20 ( FR 20 ) schedule of food reinforcement . Stimulus generalization tests were then conducted with several compounds . RESULTS : DB01440 and Q9BVC4 produced cross - generalization and BDL was fully substituted for both DB01440 and Q9BVC4 . Two benzodiazepines , alprazolam and diazepam , and the P08908 agonist , buspirone , did not substitute for either training drug nor did ethanol or the DB01221 antagonists , PCP and ketamine . The DB01440 antagonist , NCS - 382 , and the GABA ( B ) antagonist , CGP - 35348 , blocked the discriminative stimulus effects of DB01440 but not those of Q9BVC4 . CONCLUSIONS : These findings suggest that DB01440 and its metabolic precursors produce similar subjective effects that differ from those of other sedative - hypnotic drugs . Further investigations into the neurochemical actions underlying the subjective effects of these drugs are warranted .", "___MASK6___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .", "DB01221 receptor antagonists block development of tolerance to m - CPP - induced increases in DB01285 concentrations in rats . We have recently demonstrated that a single administration of m - chlorophenylpiperazine ( m - CPP , a preferential P28335 receptor agonist ) produces tolerance to its stimulatory effect on adrenocorticotropic hormone ( DB01285 ) concentrations when challenged 24 h later with the same dose of m - CPP . In the present study , we studied the effects of pretreatment with various N - methyl - D - aspartate ( DB01221 ) receptor antagonists on development of tolerance to m - CPP ' s stimulatory effect on DB01285 concentrations . Pretreatment with various DB01221 receptor antagonists such as 5 . 7 - dichlorokynurenic acid ( 1 . 0 mg / kg ) , 3 - amino - 1 - hydroxy 2 - pyrrolidone ( 1 . 0 mg / kg ) , dizocilpine ( 0 . 1 mg / kg ) and ifenprodil ( 1 . 0 mg / kg ) injected 30 min before the first injection of m - CPP ( 2 . 5 mg / kg ) blocked development of tolerance to m - CPP ' s stimulatory effect on DB01285 concentrations in rats injected 24 h later with the same dose ( 2 . 5 mg / kg ) of m - CPP . These findings suggest that tolerance to postsynaptic P28335 receptor - mediated response is initiated though stimulation of DB01221 receptor complex and , furthermore , demonstrate a functional interaction between the 5 - HT and glutamate systems .", "P23560 released during neuropathic pain potentiates DB01221 receptors in primary afferent terminals . DB01221 receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release . In rats and mice , we found that the ability of intrathecal DB01221 to induce neurokinin 1 receptor ( P25103 ) internalization ( a measure of DB05875 release ) required a previous injection of P23560 . Selective knock - down of DB01221 receptors in primary afferents decreased DB01221 - induced P25103 internalization , confirming the presynaptic location of these receptors . The effect of P23560 was mediated by tropomyosin - related kinase B ( trkB ) receptors and not p75 neurotrophin receptors ( p75 ( NTR ) ) , because it was not produced by proBDNF and was inhibited by the trkB antagonist Q14201 - 12 but not by the p75 ( NTR ) inhibitor TAT - Pep5 . These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full - length trkB in dorsal root ganglion ( Q86YR7 ) neurons . Src family kinase inhibitors blocked the effect of P23560 , suggesting that trkB receptors promote the activation of these DB01221 receptors by Src family kinase phosphorylation . Western blots of cultured Q86YR7 neurons revealed that P23560 increased DB00135 ( 1472 ) phosphorylation of the Q13224 subunit of the DB01221 receptor , known to have a potentiating effect . Patch - clamp recordings showed that P23560 , but not proBDNF , increased DB01221 receptor currents in cultured Q86YR7 neurons . DB01221 - induced P25103 internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide . These effects were decreased by a P23560 scavenger , a trkB receptor antagonist and a Src family kinase inhibitor , indicating that P23560 released by microglia potentiates DB01221 receptors in primary afferents during neuropathic pain .", "Synaptic Q12879 and Q13224 containing DB01221 receptors within the superficial dorsal horn activated following primary afferent stimulation . DB01221 receptors are important elements in pain signaling in the spinal cord dorsal horn . They are heterotetramers , typically composed of two Q05586 and two of four GluN2 subunits : Q12879 - 2D . Mice lacking some of the GluN2 subunits show deficits in pain transmission yet functional synaptic localization of these receptor subtypes in the dorsal horn has not been fully resolved . In this study , we have investigated the composition of synaptic DB01221 receptors expressed in monosynaptic and polysynaptic pathways from peripheral sensory fibers to lamina I neurons in rats . We focused on DB05875 receptor - expressing ( P25103 + ) projection neurons , critical for expression of hyperalgesia and allodynia . EAB - 318 and ( R ) - CPP , Q12879 / B antagonists , blocked both monosynaptic and polysynaptic DB01221 EPSCs initiated by primary afferent activation by ∼ 90 % . Physiological measurements exploiting the voltage dependence of monosynaptic EPSCs similarly indicated dominant expression of Q12879 / B types of synaptic DB01221 receptors . In addition , at synapses between C fibers and P25103 + neurons , DB01221 receptor activation initiated a secondary , depolarizing current . DB08954 , a Q13224 antagonist , caused modest suppression of monosynaptic DB01221 EPSC amplitudes , but had a widely variable , sometimes powerful , effect on polysynaptic responses following primary afferent stimulation when inhibitory inputs were blocked to mimic neuropathic pain . We conclude that Q13224 subunits are moderately expressed at primary afferent synapses on lamina I P25103 + neurons , but play more important roles for polysynaptic DB01221 EPSCs driven by primary afferents following disinhibition , supporting the view that the analgesic effect of the Q13224 antagonist on neuropathic pain is at least in part , within the spinal cord .", "[ Molecular pharmacogenetic studies of drug responses to obsessive - compulsive disorder and six functional genes ] . OBJECTIVE : To investigate the associations between the drug responses to obsessive - pulsive disorder ( OCD ) and six functional genes related with serotonin and dopamine . METHODS : One hundred and thirteen OCD nuclear families were collected . The OCD patients were treated with serotonin reuptake inhibitors ( SRIs ) for 8 weeks and the drug responses were assessed using the Yale - Brown obsessive - compulsive scale ( Y - BOCS ) . The patients were divided into drug responders group and non - responders group according to the reducing rate of Y - BOCS score . The genotypes of six genes were determined with the Amp - DB00712 and Amp - RFLP techniques and analyzed by transmission disequilibrium test ( P04053 ) . The six genes are serotonin 2A receptor ( 5 - Q13049 ) , serotonin transporter ( 5 - HTT ) , dopamine D2 receptor ( P14416 ) , dopamine D4 receptor ( P21917 ) , catechol - O - methyltransferase ( P21964 ) and monoamine oxidase A ( P21397 ) . RESULTS : No association was found between the six genes and different drug responses groups . However , there was significant difference between the drug responders and non - responders in homozygosity at the 5 - Q13049 - 1438G / A locus ( chi ( 2 )= 4 . 69 , P = 0 . 03 ) . CONCLUSION : The results suggested that the 5 - Q13049 may play some roles in the effects of drug treatment on OCD .", "Coupling of serotonergic input to DB01221 receptor - phosphorylation following peripheral nerve injury via rapid , synaptic up - regulation of P03891 . Evidence implicates serotonergic input to spinal dorsal horn neurons in shifting the DB01221 receptor ( NMDAR ) into a high functional output profile after spinal nerve ligation ( Q16658 ) . We investigated the involvement of adaptor protein P03891 ( P03891 ) in NMDAR - phosphorylation and spinal hyperexcitability secondary to peripheral nerve injury . Immunofluorescence for P03891 was found in dorsal horn neurons immunopositive for NMDAR subunit Q9UHB4 . Co - localization of P03891 with postsynaptic marker P78352 was significantly increased 60min after Q16658 ( Rr 0 . 77 vs Rr 0 . 06 in sham controls ; z =- 242 . 85 ; p < 0 . 01 at Fisher ' s exact test ) . Western blot analyses confirmed P03891 up - regulation both in cytoplasmic ( S2 ) and synaptic ( P09131 ) compartments ( p < 0 . 01 at the Student ' s t test ) . Q16658 was followed by increased co - localization of P03891 with the phosphorylated form ( serine 896 ) of Q9UHB4 ( pNMDA ) . Spinal superfusion with P03891 inhibitor rotenone prevented up - regulation of P03891 ( Rr 0 . 06 after rotenone vs Rr 0 . 78 in vehicle - treated controls , z =- 253 . 22 , p < 0 . 01 ) and pNR1 in P09131 . C fiber - evoked dorsal horn field potentials were increased 60min after Q16658 by superfusion with DB01221 agonist cis - ACPD at 100nM ( p < 0 . 01 at the Bonferroni test ) , however cis - ACPD was effective only at 10μM following prior administration of rotenone . Rotenone also abolished enhancement of evoked potentials induced by simultaneous stimulation of DB01221 and 5 - HR2B receptors in uninjured rats . Increased postsynaptic up - regulation of P03891 / pNMDAR 60min after Q16658 was prevented by prior administration of selective P41595 antagonist SB204741 . These results support a pivotal role for P03891 in coupling serotonergic input to NMDAR - activation during neuropathic pain .", "Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type - 1 inhibitor Org - 24461 and risperidone . The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system . The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission , mainly by blockade of D ( 2 ) dopamine receptors . N - methyl - D - aspartate ( DB01221 ) receptor hypofunction in schizophrenia can be reversed by glycine transporter type - 1 ( P48067 ) inhibitors , which regulate glycine concentrations at the vicinity of DB01221 receptors . Combined drug administration with P14416 blockade and activation of hypofunctional DB01221 receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia . To investigate this type of combined drug administration , rats were treated with the atypical antipsychotic risperidone together with the P48067 inhibitor Org - 24461 . Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine , DOPAC , HVA , glycine , glutamate , and serine concentrations were carried out using HPLC / electrochemistry . DB00734 increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples . Org - 24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed . When risperidone and Org - 24461 were added in combination , a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels . Interestingly , the extracellular concentrations of glutamate were also enhanced . Our data indicate that coadministration of an antipsychotic with a P48067 inhibitor may normalize hypofunctional DB01221 receptor - mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication .", "P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .", "Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK15___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .", "ZO - 1 - and ZO - 2 - dependent integration of myosin - 2 to epithelial zonula adherens . For the zonula adherens ( ZA ) to be established by linear arrangement of adherens junctions ( AJs ) in epithelial sheet cells , critical for the epithelial cell sheet formation and intercellular barrier function , myosin - 2 is supposedly integrated into the ZA with the result of overlapping localization of P12830 / actin / myosin - 2 . Here , we immunofluorescently showed that myosin - 2 failed to be integrated into the ZA in cultured epithelial - type Q07157 ( ko )/ 2 ( kd ) Eph4 cells lacking ZO - 1 and - 2 ( zonula occludens - 1 and - 2 ) by knockout and knockdown , respectively . Instead , a linearized but fragmented arrangement of AJs was formed in the way that it was positive for P12830 / actin , but negative for myosin - 2 ( designated prezonula - AJ ) . Transfection of full - length ZO - 1 or ZO - 2 , or ZO - 1 lacking its PDZ ( P78352 / discs large / zonula occludens - 1 ) - 1 / 2 domains ( but not one lacking PDZ - 1 / 2 / 3 ) into Q07157 ( ko )/ 2 ( kd ) Eph4 cells restored the junctional integration of myosin - 2 with prezonula - AJ to establish the ZA . Transfection of dominant - active RhoA or Rho - kinase ( ROCK ) , as well as administration of lysophosphatidic acid or Y27632 , which activates RhoA or inhibits ROCK , respectively , suggested that RhoA regulated the junctional integration of myosin - 2 into ZA in a manner such that ROCK played a necessary but not - sufficient role . Fluorescence resonance energy transfer analyses revealed that spatiotemporal Rho - activation occurred in a ZO - 1 / 2 - dependent way to establish ZA from primordial forms in epithelial cells .", "Effects of inactivation of serotonergic neurons of the median raphe nucleus on learning and performance of contextual fear conditioning . Several studies have shown that the median raphe nucleus ( MRN ) is involved in anxiety . However , no study assessed the role of 5 - HT mechanisms of MRN in both freezing and fear - potentiated startle ( FPS ) within a single form of conditioned learning . In this work we examined the effects of neurotoxic lesions of the MRN with DB01221 on freezing and FPS of rats submitted to a contextual fear conditioning paradigm , in which they were tested in the same chamber where they received foot - shocks 24 h before . Compared to controls DB01221 - injected rats showed a reduction of freezing and FPS in response to contextual cues . Next , we examined the effects of stimulation of P08908 somatodendritic autoreceptors of the MRN with local injections of 8 - OH - DPAT either before training or testing sessions conducted 2 or 24 h post - conditioning . Pre - training injections of 8 - OH - DPAT intra - MRN reduced both freezing and FPS whereas post - training injections reduced only freezing to the aversive context without changing the FPS . Thus , freezing is easily disrupted by post - training MRN injections of 8 - OH - DPAT while memory for FPS remained unchanged . It is proposed that the consolidation of contextual conditioned fear promoting freezing takes place through a slow mechanism of transference of information through 5 - HT mechanisms of the MRN - hippocampus pathway . On the other hand , a rapid fear conditioning process operates for FPS , probably through other pathways .", "Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK51___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .", "Opioid and non - opioid DB01221 - mediated predator - induced analgesia in mice and the effects of parasitic infection . The present study examined the nociceptive responses ( 50 degrees C , hot - plate ) of uninfected and subclinically parasitized male mice exposed to the odor of a predator , an ecologically relevant threatening stimulus . In uninfected mice a 15 - min exposure to 2 - propylthietane , the major component of weasel odor , induced a naloxone - reversible opioid analgesia . A 30 - s exposure elicited a shorter duration and lower amplitude ' non - opioid ' analgesia that was insensitive to naloxone , partially sensitive to either the serotonin - 1A ( P08908 ) agonist , 8 - OH - DPAT , or the GABAA antagonist , bicuculline , and blocked by the competitive N - methyl - D - aspartate ( DB01221 ) antagonist , NPC 12626 . In contrast , mice chronically ( 25 days ) and subclinically infected with the murine nematode , Heligmosomoides polygyrus , failed to show a significant non - opioid analgesia and displayed a markedly lower level of opioid analgesia than uninfected mice . These results suggest that DB01221 receptor mechanisms are potently associated with the expression of the analgesia arising from exposure to the naturally aversive stimulus of predator odor . These findings also demonstrate that parasites , and likely other subchronic infections , can have a significant impact on the display of opioid and non - opioid stress - induced analgesia arising from exposure to the ethologically relevant stimulus of predator odor .", "Study on action mechanism of 1 -( 4 - methoxy - 2 - methylphenyl ) piperazine ( MMPP ) in acquisition , formation , and consolidation of memory in mice . In the present study , the mechanism of action of MMPP ( 1 -( 4 - methoxy - 2 - methylphenyl ) piperazine ) in the acquisition ( pretraining administration ) , formation ( posttraining administration ) , and consolidation ( pretest administration ) of memory was assessed in the passive avoidance test using a short - and long - term memory protocol in mice . MMPP modified avoidance in the acquisition and formation of memory protocols but not in the consolidation protocol . DB00747 ( 0 . 1 mg / kg i . p . ) , dizocilpine ( 0 . 003 mg / kg i . p . ) , and buspirone ( 0 . 1 mg / kg i . p . ) completely inhibited MMPP - induced effects on memory acquisition and partially inhibited memory formation in the short - term but not long - term paradigm . This suggested that cholinergic , N - methyl - D - aspartate ( DB01221 ) and 5 - hydroxytryptamine - 1A ( P08908 ) receptors were implicated in the MMPP - induced improvements in memory . The sedative , anxiolytic , motor impairment , myorelaxant , and anticonvulsive ( pentylenetetrazole - induced seizures ) properties of MMPP were also assessed with the compound only showing a nondose - dependent myorelaxation . These results suggest that MMPP can enhance acquisition and formation , but not consolidation , of memory in short - term and long - term protocol via cholinergic , DB01221 - glutamatergic , and P08908 receptors .", "Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK45___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK45___ who were treated with a single dose of mifepristone .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome ." ]

[ "___MASK15___", "___MASK30___", "___MASK44___", "___MASK45___", "___MASK49___", "___MASK51___", "___MASK55___", "___MASK6___", "___MASK84___" ]

[ "Metabolic stress modulates Alzheimer ' s β - secretase gene transcription via Q96EB6 - PPARγ - P20142 - 1 in neurons . Classic cardio - metabolic risk factors such as hypertension , stroke , diabetes , and hypercholesterolemia all increase the risk of Alzheimer ' s disease . We found increased transcription of β - secretase / P56817 , the rate - limiting enzyme for Aβ generation , in P29474 - deficient mouse brains and after feeding mice a high - fat , high - cholesterol diet . Up - or downregulation of P20142 - 1α reciprocally regulated P56817 in vitro and in vivo . Modest fasting in mice reduced P56817 transcription in the brains , which was accompanied by elevated P20142 - 1 expression and activity . Moreover , the suppressive effect of P20142 - 1 was dependent on activated PPARγ , likely via Q96EB6 - mediated deacetylation in a ligand - independent manner . The P56817 promoter contains multiple Q07869 - RXR sites , and direct interactions among Q96EB6 - PPARγ - P20142 - 1 at these sites were enhanced with fasting . The interference on the P56817 gene identified here represents a unique noncanonical mechanism of PPARγ - P20142 - 1 in transcriptional repression in neurons in response to metabolic signals that may involve recruitment of corepressor NCoR .", "Cluster analysis of risk factor genetic polymorphisms in Alzheimer ' s disease . Multiple genetic variants may contribute to the risk of developing Alzheimer ' s disease . We have analyzed polymorphisms in 9 genes to determine whether particular combinations would contribute to this risk . The genes were P02649 , LDLr , P01034 , P07339 , P01375 , P56817 , P10636 , Q8IWL8 , P29474 , and Q12800 . Three risk groups for the disease were identified . Risk group I was younger , was heterozygous for the P01034 ( GA ) , CTSD2936 ( AG ) , P01375 - 308 ( AG ) genetic variants . Risk group II was older , was homozygous for the - 427 P02649 promoter polymorphism ( TT ) , and heterozygous for the P10636 deletion and for the Q8IWL8 variant ( QR ) . Group III had both the youngest and oldest subjects , were heterozygous for the - 863 ( AC ) and - 1031 ( CT ) P01375 promoter polymorphisms . All three groups carried the P02649 4 allele and were heterozygous for both P56817 polymorphisms . The control groups were carriers of the P02649 3 allele and were homozygous for the P56817 genetic variants .", "Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK95___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .", "P56817 and presenilin / γ - secretase regulate proteolytic processing of P15382 and 2 , auxiliary subunits of voltage - gated potassium channels . P56817 and presenilin ( PS ) / γ - secretase play a major role in Alzheimer ' s disease pathogenesis by regulating amyloid - β peptide generation . We recently showed that these secretases also regulate the processing of voltage - gated sodium channel auxiliary β - subunits and thereby modulate membrane excitability . Here , we report that P15382 and Q9Y6J6 , auxiliary subunits of voltage - gated potassium channels , undergo sequential cleavage mediated by either α - secretase and PS / γ - secretase or P56817 and PS / γ - secretase in cells . Elevated α - secretase or P56817 activities increased C - terminal fragment ( CTF ) levels of P15382 and 2 in human embryonic kidney ( HEK293T ) and rat neuroblastoma ( B104 ) cells . KCNE - CTFs were then further processed by PS / γ - secretase to KCNE intracellular domains . These KCNE cleavages were specifically blocked by chemical inhibitors of the secretases in the same cell models . We also verified our results in mouse cardiomyocytes and cultured primary neurons . Endogenous P15382 - and Q9Y6J6 - CTF levels increased by 2 - to 4 - fold on PS / γ - secretase inhibition or P56817 overexpression in these cells . Furthermore , the elevated P56817 activity increased P15382 processing and shifted P15382 / P51787 channel activation curve to more positive potentials in P29320 cells . P15382 / P51787 channel is a cardiac potassium channel complex , and the positive shift would lead to a decrease in membrane repolarization during cardiac action potential . Together , these results clearly showed that P15382 and Q9Y6J6 cleavages are regulated by P56817 and PS / γ - secretase activities under physiological conditions . Our results also suggest a functional role of KCNE cleavage in regulating voltage - gated potassium channels .", "Novel systemic markers for patients with Alzheimer disease ? - a pilot study . Almost 2 % of the population of western industrialized countries are affected by Alzheimer ' s disease ( AD ) . Nevertheless the pathogenetic process leading to this neurodegenerative disease is widely unknown . Thus , we focus on novel pathophysiological aspects of AD . We hypothesize that AD patients reveal increased levels of peripheral blood mononuclear cells ( PBMCs ) expressing proinflammatory ( P35354 , P01375 , P25942 ) , proapoptotic ( P09874 ) , adhesion - relevant ( P28907 ) or AD associated ( C99 , P56817 , P49768 ) proteins as well as elevated proinflammatory biochemical plasma parameters . Therefore , PBMCs of AD patients and age - matched control subjects were studied by two color fluorescence - activated cell sorter ( FACS ) analysis . Furthermore , concentration of plasma oxidized low - density lipoprotein ( oxLDL ) and P01375 were measured by enzyme - linked immunosorbent assay ( ELISA ) . We found a significantly increased percentage of P01375 , P35354 , P09874 , P28907 , C99 or presenilin - 1 positive PBMCs in AD patients compared with healthy subjects . FACS analyses revealed that the percentage of C99 or presenilin - 1 positive PBMCs , which also express P01375 , P35354 , P09874 or P28907 is also increased in AD patients . Additionally , AD patients had significantly increased plasma oxLDL and P01375 levels . Furthermore , we found positive correlations between plasma oxLDL or P01375 concentrations and the percentage of TNFalpha + , P35354 + or P09874 + , as well as P49768 + , C99 + or P56817 + PBMCs . Our findings suggest that immunocytological investigations , based on immunophenotyping of AD relevant proteins combined with measurement of proinflammatory , proapoptotic and adhesion - relevant proteins in PBMCs may provide more insight into the pathophysiology of AD .", "Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK47___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK47___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK47___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK47___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK47___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK47___ increased the protein expression of hepatic P05181 and ___MASK47___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK47___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK47___ and RFP - induced hepatotoxicity .", "Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK52___ , and 86 % ± 8 % in Q8NE62 - ___MASK52___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK52___ , and 86 % ± 8 % in Q8NE62 - ___MASK52___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 .", "Transcriptional regulation of beta - secretase by p25 / cdk5 leads to enhanced amyloidogenic processing . P12004 - dependent kinase 5 ( cdk5 ) has been implicated in Alzheimer ' s disease ( AD ) pathogenesis . Here , we demonstrate that overexpression of p25 , an activator of cdk5 , led to increased levels of P56817 mRNA and protein in vitro and in vivo . A p25 / cdk5 responsive region containing multiple sites for signal transducer and activator of transcription ( P42224 / 3 ) was identified in the P56817 promoter . P40763 interacts with the P56817 promoter , and p25 - overexpressing mice had elevated levels of pSTAT3 and P56817 , whereas cdk5 - deficient mice had reduced levels . Furthermore , mice with a targeted mutation in the P40763 cdk5 responsive site had lower levels of P56817 . Increased P56817 levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor . These data demonstrate a pathway by which p25 / cdk5 increases the amyloidogenic processing of P05067 through P40763 - mediated transcriptional control of P56817 that could have implications for AD pathogenesis .", "Adulthood nicotine treatment alleviates behavioural impairments in rats neonatally treated with quinpirole : possible roles of acetylcholine function and neurotrophic factor expression . Increases in dopamine D ( 2 ) receptor sensitivity are known to be common in drug abuse and neurological disorders . Past data from this laboratory have shown that long - term increases in D ( 2 ) sensitivity can be produced by quinpirole treatment ( a D ( 2 )/ D ( 3 ) agonist ) during early development . The present investigation was designed to test the hypothesis that nicotine administration in adulthood would reduce both cognitive and skilled reaching impairments produced by increases in D ( 2 ) sensitivity . Female Sprague - Dawley rats were treated with quinpirole ( 1 mg / kg ) or saline from postnatal day 1 ( PD 1 ) to PD 21 . Beginning in adulthood ( PD 61 ) , rats were treated with nicotine ( 0 . 3 mg / kg free base ) or saline twice daily for 14 consecutive days before behavioural testing commenced . Animals neonatally treated with quinpirole demonstrated performance deficits on the Morris water task and a skilled reaching task compared to controls . Deficits on both tasks were completely alleviated by adulthood nicotine treatment . Animals neonatally treated with quinpirole demonstrated a significant 36 % decrease of P28329 in the hippocampus compared to saline controls that was partially eliminated by nicotine . Additionally , neonatal quinpirole produced a significant decrease in hippocampal P01138 content compared to controls , however , nicotine failed to alleviate this decrease in P01138 . The results of this investigation demonstrate that long - term increases in dopamine D ( 2 ) receptor sensitivity produce significant decreases in hippocampal cholinergic and P01138 expression that may result in cognitive impairment . ___MASK11___ alleviates both cognitive and skilled reaching impairments caused by increases in D ( 2 ) sensitivity , but the mechanism through which nicotine is acting is currently unknown .", "Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK25___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .", "A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .", "Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK40___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .", "Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK85___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .", "Inhibition of P05067 trafficking by tau protein does not increase the generation of amyloid - beta peptides . Amyloid - beta , a peptide derived from the precursor protein P05067 , accumulates in the brain and contributes to the neuropathology of Alzheimer ' s disease . Increased generation of amyloid - beta might be caused by axonal transport inhibition , via increased dwell time of P05067 vesicles and thereby higher probability of P05067 cleavage by secretase enzymes residing on the same vesicles . We tested this hypothesis using a neuronal cell culture model of inhibited axonal transport and by imaging vesicular transport of fluorescently tagged P05067 and beta - secretase ( P56817 ) . Microtubule - associated tau protein blocks vesicle traffic by inhibiting the access of motor proteins to the microtubule tracks . In neurons co - transfected with P27918 - tau , P05067 - YFP traffic into distal neurites was strongly reduced . However , this did not increase amyloid - beta levels . In singly transfected axons , P05067 - YFP was transported in large tubules and vesicles moving very fast ( on average 3 microm / s ) and with high fluxes in the anterograde direction ( on average 8 . 4 vesicles / min ) . By contrast , P56817 - P27918 movement was in smaller tubules and vesicles that were almost 2x slower ( on average 1 . 6 microm / s ) with approximately 18x lower fluxes ( on average 0 . 5 vesicles / min ) . Two - colour microscopy of co - transfected axons confirmed that the two proteins were sorted into distinct carriers . The results do not support the above hypothesis . Instead , they indicate that P05067 is transported on vesicles distinct from the secretase components and that amyloid - beta is not generated in transit when transport is blocked by tau .", "Genetic pathway - based hierarchical clustering analysis of older adults with cognitive complaints and amnestic mild cognitive impairment using clinical and neuroimaging phenotypes . Hierarchical clustering is frequently used for grouping results in expression or haplotype analyses . These methods can elucidate patterns between measures that can then be applied to discerning their validity in discriminating between experimental conditions . Here a hierarchical clustering method is used to analyze the results of an imaging genetics study using multiple brain morphology and cognitive testing endpoints for older adults with amnestic mild cognitive impairment ( D6RGH6 ) or cognitive complaints ( CC ) compared to healthy controls ( HC ) . The single nucleotide polymorphisms ( SNPs ) are a subset of those included on a larger array that are found in a reported Alzheimer ' s disease ( AD ) and neurodegeneration pathway . The results indicate that genetic models within the endpoints cluster together , while there are 4 distinct sets of SNPs that differentiate between the endpoints , with most significant results associated with morphology endpoints rather than cognitive testing of patients ' reported symptoms . The genes found in at least one cluster are P08183 , Q02410 , P56817 , Q9Y5Z0 , P10415 , Q07817 , P55210 , P28329 , P01034 , P35462 , P21918 , P05231 , Q07954 , NAT1 , and P49810 . The greater associations with morphology endpoints suggests that changes in brain structure can be influenced by an individual ' s genetic background in the absence of dementia and in some cases ( Cognitive Complaints group ) even without those effects necessarily being detectable on commonly used clinical tests of cognition . The results are consistent with polygenic influences on early neurodegenerative changes and demonstrate the effectiveness of hierarchical clustering in identifying genetic associations among multiple related phenotypic endpoints .", "___MASK46___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK46___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK46___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK46___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK46___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .", "A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK16___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .", "Enhancement of the nonamyloidogenic pathway by exogenous P01138 in an Alzheimer transgenic mouse model . Nerve growth factor ( P01138 ) is an important nerve cell growth regulatory factor and has an indispensable role in the development , survival and regeneration of the cholinergic basal forebrain ( Q03701 ) neurons , and it has multiple targets when used for Alzheimer ' s Disease ( AD ) therapy . In this study , we observed whether P01138 can affect cholinergic neurons to change amyloid - β precursor protein ( P05067 ) metabolism process and reduce amyloidosis in AD brains . P01138 was administered intranasally to P05067 / P49768 double - transgenic mice for 14weeks . We observed an increase in APP695 and O14672 and a decrease in P56817 and P49768 protein levels and , subsequently , a reduction in Aβ1 - 40 and Aβ1 - 42 levels and Aβ burden were present in P01138 - treated mice brains , suggesting that P01138 enhanced the P05067 nonamyloidogenic cleavage pathway and reduced the Aβ generation in the P05067 / P49768 transgenic mice brains .", "Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta - site amyloid precursor protein cleaving enzyme - 1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 ) to increase the synaptic concentrations of serotonin . Beta - site amyloid precursor protein cleaving enzyme - 1 ( P56817 - 1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer ' s disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 - 1 and P31645 . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4 . 2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran - P31645 ' interaction and ' levomilnacipran - P56817 ' interaction were found to be - 7 . 47 and - 8 . 25 kcal / mol , respectively . DB08918 was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 during ' levomilnacipran - P31645 ' interaction . In the case of ' levomilnacipran - P56817 ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 - 1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 and P56817 - 1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 - 1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial .", "Two - dimensional liquid crystalline growth within a phase - field - crystal model . By using a two - dimensional phase - field - crystal ( P27918 ) model , the liquid crystalline growth of the plastic triangular phase is simulated with emphasis on crystal shape and topological defect formation . The equilibrium shape of a plastic triangular crystal ( PTC ) grown from an isotropic phase is compared with that grown from a columnar or smectic - A ( Q13216 ) phase . While the shape of a PTC nucleus in the isotropic phase is almost identical to that of the classical P27918 model , the shape of a PTC nucleus in Q13216 is affected by the orientation of stripes in the Q13216 phase , and irregular hexagonal , elliptical , octagonal , and rectangular shapes are obtained . Concerning the dynamics of the growth process , we analyze the topological structure of the nematic order , which starts from nucleation of + 1 / 2 and - 1 / 2 disclination pairs at the PTC growth front and evolves into hexagonal cells consisting of + 1 vortices surrounded by six satellite - 1 / 2 disclinations . It is found that the orientational and the positional order do not evolve simultaneously ; the orientational order evolves behind the positional order , leading to a large transition zone , which can span over several lattice spacings ." ]

[ "___MASK11___", "___MASK16___", "___MASK25___", "___MASK40___", "___MASK46___", "___MASK47___", "___MASK52___", "___MASK85___", "___MASK95___" ]

[ "Human prostacyclin receptor . DB01240 , a member of the eicosanoid family of lipid mediators , is the major product of arachidonic acid metabolism formed in the marcovascular endothelium . It is a potent vasodilator , antithrombotic , and antiplatelet agent that mediates it effects through a membrane - associated receptor termed the IP . Cloning of the cDNA for IP , from human and other species , indicated its membership of the G protein - coupled receptor superfamily and has allowed detailed examination of the signaling and regulatory pathways utilized by this receptor . This article examines the current state of knowledge of the IP , its signaling and regulation , and its biological role in vivo and examines the possible existence of multiple P43119 sites .", "P43119 induces P42224 and P40763 phosphorylations in human erythroleukemia cells : a mechanism requiring PTX - insensitive G proteins , P29323 and JNK . The ability of the human prostacyclin receptor ( hIP ) to regulate the activities of signal transducers and activators of transcription ( STATs ) has not yet been documented . In the present study , we have delineated the mechanism by which hIP induces P40763 phosphorylations in human erythroleukemia ( HEL ) cells . Stimulation of endogenous hIP by its specific agonist , cicaprost , resulted in P40763 Tyr705 and Ser727 phosphorylations in a time - and concentration - dependent manner . Cicaprost - induced P40763 Tyr705 and Ser727 phosphorylations were resistant to pertussis toxin ( PTX ) treatment , suggesting that these responses were mediated through PTX - insensitive G proteins . In addition , extracellular signal - regulated kinase ( P29323 ) and c - Jun N - terminal kinase ( JNK ) , but not p38 MAPK , were shown to be phosphorylated by cicaprost in a time - and concentration - dependent manner via PTX - insensitive G proteins . The levels of the interaction between P40763 , P29323 and JNK were enhanced by cicaprost treatment . The involvement of P04049 , Q02750 / 2 and JNK in cicaprost - induced phosphorylations of P40763 was illustrated by the use of their selective inhibitors . In contrast , p38 MAPK did not appear to be required . Similar observations were obtained with P42224 upon stimulation by cicaprost . Taken together , these results demonstrate for the first time that hIP activation by cicaprost can lead to P42224 and P40763 phosphorylations via signaling pathways involving PTX - insensitive G proteins , P29323 and JNK .", "Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK37___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .", "Non - prostanoid prostacyclin mimetics . 6 . Derivatives of 2 -[ 3 -[ 2 -( 4 , 5 - Diphenyl - 2 - oxazolyl ) ethyl ] phenoxy ] acetic acid modified beta - to the oxazole ring . 2 -[ 3 -[ 2 -( 4 , 5 - Diphenyl - 2 - oxazolyl ) ethyl ] phenoxy ] acetic acid , 1 , has been described as a non - prostanoid DB01240 mimetic that demonstrates anti - thrombotic properties of long duration in animal models of thrombosis . The effects of substitution and modification of the carbon beta - to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP - induced human platelet aggregation in vitro . Potency was sensitive to both the size of the substituent and the identity of the beta - atom . The carbamates 13c - e demonstrated IC50 ' s of 0 . 28 - 0 . 36 microM and were significantly more potent than the progenitor 1 , IC50 = 1 . 2 microM . The ethyl carbamate 13c displaced [ 3H ] - iloprost from platelet membranes in a concentration - dependent fashion that was half maximal at 20 nM , which compares with IC50 ' s of 171 nM for 1 and 39 nM or unlabelled iloprost . Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for DB01240 , identifying 13c as a partial agonist at the platelet P43119 .", "DB01088 has potent anti - inflammatory properties on human monocyte - derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte - derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT - PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co - culture of DCs with P01730 + CD45RA + T cells was analysed by flow cytometry . RESULTS : Human monocyte - derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL - 12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T - cell priming capacity of DCs : in co - culture experiments of iloprost - treated mDC and naïve CD45RA + T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP - 3beta - induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans .", "Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .", "Interactions between prostaglandin E2 and inhibitors of platelet aggregation which act through cyclic AMP . Prostaglandin ( PG ) E2 potentiates platelet aggregation at low concentrations ( 10 (- 8 )- 10 (- 6 ) M ) . It also inhibits aggregation at a higher concentration ( 10 (- 5 ) M ) , probably by acting through cyclic adenosine 3 ', 5 '- monophosphate ( cyclic AMP ) . The mechanism of this biphasic effect of DB00917 and its implications for thrombosis are not clearly understood . Using a sensitive cyclic AMP assay , in conjunction with platelet aggregation studies , we have examined the interactions between DB00917 and other inhibitors of platelet aggregation which act through cyclic AMP . Low concentrations of DB00917 reversed the inhibition of platelet aggregation and increase in cyclic AMP levels induced by DB01240 , PGD2 and adenosine ( which stimulate adenylate cyclase ( AC ) through separate and specific platelet receptors ) . In contrast , low concentrations of DB00917 added to the inhibition of platelet aggregation and increase in cyclic AMP levels induced by forskolin ( which stimulates AC directly ) and AH - P 719 and DN - 9693 ( which inhibit cyclic AMP phosphodiesterase ( PDE ] . These results suggest that the biphasic effect of DB00917 may be mediated by interaction with two separate platelet receptors . Low concentrations appear to potentiate aggregation by acting at a receptor which is directly coupled to an inhibitory guanine nucleotide - binding protein ( Gi ) , possibly the putative PG endoperoxide receptor . High concentrations of DB00917 appear to inhibit aggregation by acting at an additional receptor , probably the P43119 . The ease with which DB00917 reverses the effects of DB01240 , PGD2 and adenosine , but adds to the effects of AH - P 719 and DN - 9693 , suggests that PDE inhibitors might offer greater potential than these AC stimulators as an anti - thrombotic strategy . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Effect of prostaglandins and thromboxane A2 on the contractility of rabbit splenic capsular smooth muscle . The effect of various prostaglandins ( PGs ) and a thromboxane A2 ( TXA2 ) - generating system on the contractility of rabbit splenic capsular smooth muscle has been investigated . DB01240 as well as higher concentrations of PGE1 and 5 , 6 beta - dihydro - DB01240 inhibit noradrenaline - induced contractions of the smooth muscle preparation . The TXA2 - generating system and high concentrations of PGD2 , on the other hand , increase the contractions . The results support the concept that the hypothetical P43119 on the smooth muscle of the rabbit splenic capsule resembles , in its specificity , the P43119 on platelets .", "Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines . ___MASK76___ and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the P15692 tyrosine kinase receptors 1 , 2 and 3 ( pazopanib ) , and the P00533 and P04626 receptors in a dual manner ( lapatinib ) . ___MASK76___ has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as P09619 and c - kit . Here , we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non - small - cell lung cancer cells . Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases ( such as c - DB00134 ) that were not or only partially affected by either of the two agents alone . We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells , some of which were specific for the combination of both agents . Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up - or downregulation reflected the combined action of pazopanib and lapatinib . Indeed , pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non - small - cell lung cancer cells as well as on unrelated carcinomas . Altogether , these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects . Such combinations may lead to a ' collapse ' of pro - survival signal transduction pathways that leads to apoptotic cell death .", "Estrogen protects the heart from ischemia - reperfusion injury via P35354 - derived DB01240 . There is an accumulating body of data to suggest that estrogen mediates its cardioprotective effects via cyclooxygenase activation and synthesis of prostaglandins ( PG ) , specifically DB01240 . We hypothesized that inhibition of P35354 would prevent estrogen ' s cardioprotective effects after myocardial ischemia - reperfusion . Acute treatment with 17beta - estradiol ( E2 ; 20 microg / rabbit ) increased P35354 protein expression and activity in the myocardium . To determine the effects of P35354 inhibition on infarct size after E2 treatment , New Zealand white rabbits were anesthetized and administered the P35354 inhibitor nimesulide ( 5 mg / kg ) or vehicle intravenously 30 minutes before an intravenous injection of E2 . Thirty minutes after estrogen treatment , the coronary artery was occluded for 30 minutes followed by 4 hours of reperfusion . E2 significantly decreased infarct size as a percent of area at risk when compared to vehicle ( 18 . 9 +/- 3 . 1 versus 47 . 0 +/- 4 . 1 ; P < 0 . 001 ) . Pretreatment with nimesulide nullified the infarct size sparing effect of E2 ( 55 . 8 +/- 5 . 6 ) . Treatment with the P43119 antagonist RO3244794 also abolished the protective effects of E2 ( 45 . 3 +/- 4 . 5 ) . The results indicate that estrogen protects the myocardium from ischemia - reperfusion injury through increased production of P35354 - derived DB01240 . The data indicate that selective P35354 inhibitors might counteract the potential cytoprotective effects of estrogen in premenopausal or postmenopausal women .", "Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats . OBJECTIVE : The aim of this study was to evaluate the possible role of prostacyclin ( DB01240 ) in the pathogenesis of hypertension in spontaneously hypertensive rats ( SHR ) . METHODS : Measurement of mRNA and protein levels of PGH synthase ( PGHS ) - 1 , DB01240 synthase and the P43119 , in the thoracic aorta was performed in SHR aged 5 , 10 , 20 , and 40 weeks old and in age - matched normotensive Wistar - Kyoto ( WKY ) rats with a competitive polymerase chain reaction method and immunoblotting . Aortic production of 6 - keto - PGF1 alpha , the main metabolite of DB01240 , was also measured . RESULTS : Compared with age - matched WKY rats , P23219 mRNA and protein levels in the thoracic aorta of SHR increased with age , reaching three - and twofold higher than WKY rats at 40 weeks old , respectively . DB01240 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old . In contrast , P43119 mRNA levels in SHR were consistently lower than in WKY rats at all ages . CONCLUSIONS : These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites , including PGH2 and DB01240 . They also suggest that the decreased expression of P43119 mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR .", "On the multiplicity of platelet prostaglandin receptors . II . The use of N - 0164 for distinguishing the loci of action for DB01240 , PGD2 , DB00917 and hydantoin analogs . The omega - chain variant analogs of prostacyclin ( DB01240 ) and PGD2 in which n - amyl side - chain has been replaced by a cyclohexyl group have been prepared and their cardiovascular activities have been compared to those of BW - 245C ( Fig . 1 ) a potent anti - aggregatory vasodilator bearing a cyclohexyl - terminated side - chain on a hydantoin skeleton . The cyclohexyl group has little effect on DB01240 , but converts PGD2 to a long lasting hypotensive agent and increases the platelet anti - aggregatory potency of PGD2 by a factor of 8 . The prostaglandin antagonist N - 0164 selectively blocks the anti - aggregatory actions of PGD2 , cyclohexyl - PGD2 , and BW - 245C ; with essentially no effect on DB01240 , cyclohexyl - DB01240 and DB00917 at comparably effective doses . The latter observation is contrary to an earlier report by MacIntyre , but supports the view that the anti - aggregatory effect of high doses of DB00917 ( EC50 = 50 microM ) is mediated by the P43119 . The hydantoin acts at the platelet Q13258 .", "P01375 - alpha decreases surfactant protein B mRNA in murine lung . Respiratory failure secondary to acute lung inflammation is associated with quantitative and qualitative abnormalities of pulmonary surfactant . The surfactant - associated proteins ( SP ) - A , - B , and - C are critical for normal surfactant function , synthesis , and metabolism . P01375 - alpha ( P01375 ) , a primary mediator of acute lung inflammation , decreased SP gene expression in vitro ( 32 , 34 ) . In the present in vivo study , transient T cell activation and P01375 release were initiated by intraperitoneal administration of anti - CD3 antibody 145 - 2C11 . Serum P01375 was elevated 2 h after injection of the antibody . P07988 and - C mRNA were decreased 12 and 24 h after antibody treatment . Intratracheal murine P01375 also resulted in decreased P07988 and P11686 mRNA levels in the bronchiolar and alveolar epithelium of adult FVB / N mice , as demonstrated by S1 nuclease protection and in situ hybridization assays , despite minimal histological inflammation . SP - A mRNA was not significantly altered after anti - CD3 antibody and was only mildly decreased after P01375 . As previously reported , intercellular adhesion molecule - 1 mRNA was elevated after intratracheal P01375 . SP insufficiency contributes to the pathogenesis of pulmonary diseases associated with increased P01375 , such as adult respiratory distress syndrome and pneumonia ( 8 ) . P01375 - mediated decrease in SP gene expression may contribute to the surfactant dysfunction and atelectasis observed in inflammatory lung diseases .", "Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension . Q16647 ( PGIS ) is the final committed enzyme in the metabolic pathway leading to prostacyclin ( DB01240 ) production . Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels , but the importance of this deficiency for lung vascular remodeling remains unclear . We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension . To study this hypothesis , transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3 . 7 - kb human surfactant protein - C ( P11686 ) promoter and the rat PGIS cDNA . Transgenic mice ( Tg + ) and nontransgenic littermates ( Tg - ) were subjected to a simulated altitude of 17 , 000 ft for 5 weeks , and right ventricular systolic pressure ( RVSP ) was measured . Histology was performed on the lungs . The Tg + mice produced 2 - fold more pulmonary 6 - keto prostaglandin F1alpha ( PGF1alpha ) levels than did Tg - mice . After exposure to chronic hypobaric hypoxia , Tg + mice have lower RVSP than do Tg - mice . Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg + mice in comparison with vessel wall hypertrophy in the Tg - mice . These studies demonstrate that Tg + mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia . We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia . This has important implications for the pathogenesis and treatment of severe pulmonary hypertension .", "DB05229 sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium - derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : DB05229 sodium elicited dose - dependent ( 0 . 1 pM - 0 . 1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 ( IP ) antagonist CAY10441 . DB05229 sodium - induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N ( G )- nitro - L - arginine methyl ester ( L - NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H - 1 , 2 , 4 - oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp - 8 - Br - cAMPS were comparable to L - NAME . DB05229 sodium - induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate - sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : DB05229 sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium - dependent and - independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively .", "DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . ___MASK37___ ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .", "Beneficial vasoactive endothelial effects of fluvastatin : focus on prostacyclin and nitric oxide . Statins are believed to exert beneficial effects against cardiovascular disease beyond correction of dyslipidemia . There are however still very sparse data on how individual statins interact with the production of vasoactive eicosanoids and nitric oxide ( NO ) in human vascular endothelial cells . Here we have determined how fluvastatin affects the mRNA expression of genes associated with vascular reactivity as well as the formation of two major vasodilators , prostacyclin ( DB01240 ) and NO , in human endothelial cells . Also , the influence of fluvastatin on arterial resistance was assessed in isolated small arteries . We show that the promoter activity of prostacyclin synthase ( Q16647 ) , the mRNA expression of Q16647 and endothelial nitric oxide synthase ( P29474 ) , and the production of DB01240 and NO are significantly induced by fluvastatin . Also , strong rapid dilatation ex vivo was observed , with the equal contribution of DB01240 and NO . Our findings in cell culture experiments and in isolated human arteries indicate that fluvastatin - evoked endothelium - derived vasodilator production may confer protection of the endothelial cells via both acute and long - term effects of fluvastatin treatment . If these effects take place in vivo , we suggest a protective pleiotropic role of fluvastatin on the cardiovascular system , particularly at the level of the vascular endothelium , to ameliorate the process of atherogenesis and in the acute manner to reduce vascular tone .", "Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK17___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .", "___MASK84___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK84___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK84___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK84___ inhibits activated T cells . We show that in vitro , ___MASK84___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK84___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK84___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK84___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK84___ to treat chronic inflammatory disease .", "The anticoagulant effect of PGI2S and tPA in transgenic umbilical vein endothelial cells is linked to up - regulation of PKA and PKC . The selection of vascular grafts for coronary artery bypass surgery is crucial for a positive outcome . This study aimed to establish a novel line of vascular endothelial cells with a potent anticoagulant effect . A lentiviral vector was used to stably transfect human umbilical vein endothelial cells ( HUVECs ) with PGI2S alone ( HUVEC - PGI2S ) or both PGI2S and tPA ( HUVEC - PGI2S - tPA ) . Both HUVEC - PGI2S and HUVEC - PGI2S - tPA cells over - expressing PGI2S and tPA were compared to mock - transfected cells . The enzyme - linked immuno sorbent assay ( ELISAs ) demonstrated that the anticoagulation components , P01008 and P00747 , were up - regulated and coagulation factor FVIII was down - regulated in both cell lines . QRT - PCR and western blotting demonstrated the vasodilation and platelet disaggregation proteins PKA , PKC , and P43119 were up - regulated in both cell lines , but MAPK expression was not altered in either cell line . However , cell viability and colony formation assays and cell cycle analysis demonstrated that both cell lines had a lower rate of cell growth and induced P55008 phase arrest . HUVEC - PGI2S and HUVEC - PGI2S - tPA cells have a potent anticoagulant effect and their use in vascular heterografts may decrease the risk of thrombosis .", "DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "Inhibition of cyclooxygenases 1 and 2 by the phospholipase - blocker , arachidonyl trifluoromethyl ketone . BACKGROUND AND PURPOSE : Arachidonyl trifluoromethyl ketone ( Q06187 ) is widely used as an inhibitor of cytosolic group IV phospholipase A ( 2 ) ( cPLA ( 2 ) ) and calcium - independent group VI phospholipase A ( 2 ) ( iPLA ( 2 ) ) . Q06187 thus reduces arachidonic acid ( AA ) substrate for cyclooxygenase ( P36551 ; also known as prostaglandin H synthase ) and attenuates prostaglandin ( PG ) synthesis . It has been shown previously , that Q06187 blocks thromboxane B ( 2 ) production induced by exogenous AA in human platelets . It remains , however , unknown whether Q06187 also directly modulates the activity of cyclooxygenase ( P36551 ) . EXPERIMENTAL APPROACH : Time courses for inhibition of P36551 by Q06187 was obtained using osteoblast - like MC3T3 - E1 cells , with exogenous AA as substrate and the pure enzymes P23219 and P35354 . PGE ( 2 ) was measured by GC - MS . KEY RESULTS : Q06187 was a potent inhibitor of P23219 and P35354 with IC ( 50 ) values of 0 . 5 and 0 . 1 microM in MC3T3 - E1 cells and of 1 . 7 and 2 . 6 microM using the pure enzymes . Inhibition was reversible , with slow - and tight - binding characteristics . The arachidonyl carbon chain was essential , as the saturated palmitoyl analogue had no effect . CONCLUSIONS AND IMPLICATIONS : Attenuation of PG synthesis by Q06187 is taken to be the consequence of PLA ( 2 ) inhibition and the findings of many studies are interpreted on that basis . If there are , however , alternative routes for AA liberation ( such as phospholipase C / diacyl glycerol lipase or phospholipase D ) , this interpretation can lead to false conclusions . As Q06187 is a widely used and important pharmacological tool in eicosanoid research , knowledge of its interactions with other major enzymes of the cascade is of considerable importance .", "CNS - specific prostacyclin ligands as neuronal survival - promoting factors in the brain . DB01240 ( DB01240 ) is a critical regulator of the cardiovascular system , via dilatation of vascular smooth muscle and inhibition of platelet aggregation ( Moncada , S . 1982 , Br . J . Pharmacol . , 76 , 3 ) . Our previous studies demonstrated that a novel subtype of P43119 , which is clearly distinct from a peripheral subtype in terms of ligand specificity , is expressed in the rostral region of the brain , e . g . cerebral cortex , hippocampus , thalamus and striatum , and that ( 15R ) - 16 - m - 17 , 18 , 19 , 20 - tetranorisocarbacyclin ( 15R - Q8NDX1 ) and 15 - deoxy - 16 - m - 17 , 18 , 19 , 20 - tetranorisocarbacyclin ( 15 - deoxy - Q8NDX1 ) specifically bind to the central nervous system ( CNS ) - specific P43119 . Here , we report that these CNS - specific P43119 ligands , including DB01240 itself , prevented the neuronal death . They prevented apoptotic cell death of hippocampal neurons induced by high ( 50 % ) oxygen atmosphere , xanthine + xanthine oxidase , and serum deprivation . IC50s for neuronal death were approximately 30 and 300 nM for 15 - deoxy - Q8NDX1 and 15R - Q8NDX1 , respectively , which well correlated with the binding potency for the CNS - specific P43119 . 6 - Keto - PGF1alpha ( a stable metabolite of DB01240 ) , peripheral nervous system - specific DB01240 ligands and other prostaglandins ( PGs ) than DB01240 did not show such neuroprotective effects . In vivo , 15R - Q8NDX1 protected P00915 pyramidal neurons against ischaemic damage in gerbils . These results indicate that CNS - specific DB01240 ligands have neuronal survival - promoting activity both in vitro and in vivo , and may represent a new type of therapeutic drug for neurodegeneration .", "Developmental regulation of prostacyclin synthase and prostacyclin receptors in the ovine uterus and conceptus during the peri - implantation period . This study documents the expression of prostacyclin ( DB01240 ) synthase ( Q16647 ) and DB01240 receptors in the trophoblast and uterus of the ewe at the time of maternal recognition of pregnancy ( i . e . days 7 , 9 , 12 , 14 and 17 ) . The membrane receptor for DB01240 ( P43119 ) and the nuclear receptors , i . e . peroxisome proliferator - activated receptors ( Q07869 ) and their heterodimer partners the retinoid X receptors ( RXR ) , were analysed . In the endometrium , Q16647 transcript and protein were expressed at day 9 of pregnancy and levels declined from days 12 to 17 . Immunohistochemistry and in situ hybridization indicated that Q16647 was mainly located in the luminal epithelium of the endometrium . Endometrial P43119 , Q07869 , P37231 and P48443 expression was regulated during the peri - implantation period whereas Q03181 , P19793 and P28702 were consistently expressed . In the trophoblast , Q16647 transcript levels rose as development progressed and peaked at day 17 . P43119 and Q07869 transcripts peaked before day 12 and then declined and became nearly undetectable by day 17 , whereas Q03181 and P37231 transcript levels rose steadily from days 12 to 17 . Because the PPARs and the RXRs display different expression profiles , we suggest that different heterodimers may form and support distinct functions as development proceeds . Our results also underline the importance of Q16647 and Q03181 in the trophoblast and P43119 in the uterus , suggesting that DB01240 is of both uterine and trophoblastic origin and is involved in a complex signalling pathway at around the time of implantation in the ewe .", "Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre - RT ) , at the fourth week of RT ( mid - RT ) , and 1 month after RT completion ( post - RT ) . Two serial punch biopsies were performed at pre - and mid - RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) - 2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre - RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid - RT ( P30518 ) was greater than 0 . 5 , seven ( 100 % , p = 0 . 0515 ) and five ( 71 . 4 % , p = 0 . 3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre - RT were associated with P30518 ( p = 0 . 0782 ) . For the mid - RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0 . 5 ( p = 0 . 2222 ) . CONCLUSION : The poor mid - RT tumor response was associated with the coexpression of P35354 and P00533 .", "[ Detection of a high - affinity prostaglandin I2 binding site in the human thyroid ] . This study is concerned with the identification and the pharmacological properties of P43119 binding sites on human thyroid membrane fractions . Scatchard analysis is not linear , revealing a high - and a low - affinity receptor binding site . ( 3 H ) DB01088 binding experiments were performed under various clinical conditions : in thyroid cancer the low - affinity binding sites disappear totally and the specific high - affinity binding sites are diminished according to the grade of differentiation of the cancer . An alteration in Bmax and Kd is also observed in cold nodules , in Hashimoto ' s and Riedl ' s thyroiditis and in hyperthyroidism , whereas hot nodules exhibit an increase in both the receptor subpopulations . The data provide evidence for specific DB01240 binding sites and support the suggestion of a direct regulatory key - role of DB01240 in thyroid intermediary metabolism .", "Protein kinase Cdelta and calmodulin regulate epidermal growth factor receptor recycling from early endosomes through Arp2 / 3 complex and cortactin . The intracellular trafficking of the epidermal growth factor receptor ( P00533 ) is regulated by a cross - talk between calmodulin ( P62158 ) and protein kinase Cdelta ( PKCdelta ) . On inhibition of P62158 , PKCdelta promotes the formation of enlarged early endosomes and blocks P00533 recycling and degradation . Here , we show that PKCdelta impairs P00533 trafficking due to the formation of an F - actin coat surrounding early endosomes . The PKCdelta - induced polymerization of actin is orchestrated by the Arp2 / 3 complex and requires the interaction of cortactin with PKCdelta . Accordingly , inhibition of actin polymerization by using cytochalasin D or by overexpression of active cofilin , restored the normal morphology of the organelle and the recycling of P00533 . Similar results were obtained after down - regulation of cortactin and the sequestration of the Arp2 / 3 complex . Furthermore we demonstrate an interaction of cortactin with P62158 and PKCdelta , the latter being dependent on P62158 inhibition . In summary , this study provides the first evidence that P62158 and PKCdelta organize actin dynamics in the early endosomal compartment , thereby regulating the intracellular trafficking of P00533 .", "Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .", "P43119 up - regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1 / 2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven - transmembrane G protein - coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid - receptor signaling in angiogenesis . In this study we examined the temporal - spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT - PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 / 2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin - 1 , and angiopoietin - 2 , in an epidermal growth factor receptor ( P00533 ) - dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 - IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 .", "Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .", "Evidence for distinct prostaglandin I2 and D2 receptors in human platelets . Incubation of human platelet - rich plasma with prostaglandin I2 ( DB01240 ) , results in a marked increase in adenosine 3 ': 5 '- monophosphate ( DB02527 ) that persists for at least 60 min . The persistent stimulation of DB02527 levels by DB01240 can be rapidly reversed by the addition of either prostaglandin E1 or E2 ( PGE1 , DB00917 ) , but not by prostaglandin D2 ( PGD2 ) . Studies of agonist - specific desensitization of DB02527 accumulation show that PGE1 or DB00917 can desensitize for subsequent PGE or DB01240 activation , and that subthreshold levels of DB01240 desensitize for subsequent PGE1 stimulation . PGD2 desensitizes for consequent PGD2 activation , but not for PGE1 , DB00917 or DB01240 , and PGE compounds and DB01240 do not desensitize for subsequent PGD2 activation . Agonist - specific desensitization for DB01240 is not dependent on DB02527 accumulation , but appears to be a consequence of receptor occupation . Support of the desensitization experiments was obtained through the use of the prostaglandin antagonist N - 0164 [ sodium - p - benzyl - 4 -[- oxo - 2 -( 4 - chlorobenzyl )- 3 - phenyl - propyl ] phenyl phosphonate ) . This compound proved to be a potent antagonist of PGD2 and a weak antagonist of DB01240 - stimulated DB02527 accumulation . These data indicate that human platelets have distinct pharmacological receptors for both DB01240 and PGD2 , and that PGE compounds may actually interact with a P43119 .", "A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK53___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .", "Human prostacyclin platelet receptors in diabetes mellitus . Conflicting data have been reported about the impaired sensitivity to the inhibitory effect of prostacyclin ( DB01240 ) in platelets from patients with diabetes . In the present paper we investigated binding of and sensitivity to DB01240 of platelets from insulin dependent ( IDDM ) ( n = 9 ) , non insulin dependent ( NIDDM ) ( n = 8 ) diabetics and two groups of ten healthy subjects of equivalent age in relation to platelet lipidic content . Platelet sensitivity to DB01240 ( DB01240 IC50 ) was found not significantly changed in diabetics as compared to controls ; similarly , no significant differences of the number of high affinity receptors for DB01240 in platelets from patients with IDDM and NIDDM were observed . Platelet sensitivity to DB01240 and DB01240 receptors were found to be significantly related to platelet cholesterol content ( r = 0 . 89 , p less than 0 . 001 and r = - 0 . 80 , p less than 0 . 001 respectively ) . In conclusion platelet P43119 changes are not detectable in diabetics in good metabolic control , but could take place when platelet lipid composition is altered .", "Cellular and molecular biology of prostacyclin synthase . Q16647 ( PGIS ) cDNA comprises 1500 nucleotides coding for a 500 amino acid protein . It is a heme protein with spectral characteristics of cytochrome p450 ( CYP ) . It does not possess the typical CYP mono - oxygenase activity but catalyzes the rearrangement of prostaglandin H2 to form DB01240 . Analysis of its structure - function by molecular modeling and site - directed mutagenesis reveals a long substrate channel lined by hydrophobic residues . DB00151 - 441 has been identified as the proximal axial ligand of heme . DB00135 - 430 is nitrated by peroxynitrite which results in reduced PGIS catalytic activity , suggesting that DB00135 - 430 is located close to the heme pocket . PGIS is constitutively expressed and may be upregulated by cytokines , reproductive hormones , and growth factors . It is physically colocalized with cyclooxygenases and phospholipases , and functionally coupled with these enzymes . PGIS coupling with P35354 has been shown to play an important role in vascular protection , embryo development and implantation , and cancer growth .", "Expression of prostacyclin receptors in luteinizing hormone - releasing hormone immortalized neurons : role in the control of hormone secretion . PGs of the E series are involved in the control of P01148 secretion . The present experiments were conducted to clarify whether DB01240 ( prostacyclin ) might be also involved in such a control , using multiple methodological approaches on immortalized P01148 - secreting neurons . A RT - PCR procedure to detect mouse P43119 ( IP ) messenger RNA was first applied , and the results obtained showed the presence of a specific transcript in two cell lines of immortalized P01148 neurons ( GT1 - 1 and GN11 cell lines ) . Receptor binding assays on membrane preparations from GT1 - 1 cells showed the presence of a single specific and saturable class of binding sites ( Kd = 4 . 6 nM ; 10 , 000 sites / cell ) for [ 3H ] iloprost , a stable analog of DB01240 . Competition experiments showed that the binding sites labeled by [ 3H ] iloprost possess the pharmacological characteristics of IP receptors . In functional studies , DB01240 and its analogs , iloprost and cicaprost , were able to stimulate P01148 release from the GT1 - 1 cells with elevated potencies ( EC50 = 0 . 6 - 4 . 3 nM ) ; PGE1 was only slightly less active ( EC50 = 28 . 5 nM ) , whereas DB00917 , considered the major PG involved in P01148 secretion , was poorly effective ( EC50 = 921 nM ) . The relative potencies ( EC50 ) of these compounds in stimulating the intracellular accumulation of DB02527 were in line with their P01148 - releasing activities . In conclusion , these results indicate that immortalized P01148 - secreting neurons express IP receptors through which DB01240 may exert relevant effects on P01148 release .", "Roles of thromboxane A ( 2 ) and prostacyclin in the development of atherosclerosis in apoE - deficient mice . Production of thromboxane ( TX ) A2 and PG I2 / prostacyclin ( DB01240 ) is increased in patients with atherosclerosis . However , their roles in atherogenesis have not been critically defined . To examine this issue , we cross - bred atherosclerosis - prone apoE - deficient mice with mice deficient in either the TXA receptor ( TP ) or the P43119 ( IP ) . Although they showed levels of serum cholesterol and triglyceride similar to those of apoE - deficient mice , apoE -/- TP -/- mice exhibited a significant delay in atherogenesis , and apoE -/- IP -/- mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone . The plaques in apoE -/- IP -/- mice showed partial endothelial disruption and exhibited enhanced expression of P05362 and decreased expression of platelet endothelial cell adhesion molecule 1 ( P16284 ) in the overlying endothelial cells compared with those of apoE -/- TP -/- mice . Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P16109 expression in platelets of apoE -/- IP -/- and apoE -/- TP -/- mice , respectively , than in those of apoE -/- mice . Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE -/- IP -/- mice than in either apoE -/- TP -/- or apoE -/- mice . We conclude that TXA2 promotes and DB01240 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte - endothelial cell interaction .", "[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK3___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .", "Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .", "The roles of prostanoids in infection and sickness behaviors . A systemic infection in patients causes so - called sickness behaviors , such as fever generation , adrenocorticotropic hormone release , reduced locomotion , loss of social contact , anorexia , and increased sleep . As aspirin - like non - steroidal anti - inflammatory drugs alleviate most of these symptoms , the involvement of prostanoids in the generation of sickness behaviors has been strongly suggested . Prostanoids , consisting of prostaglandins ( PGs ) and thromboxanes ( TXs ) , are a group of lipid mediators formed in response to various stimuli . They include PGD2 , DB00917 , PGF2alpha , DB01240 , and TXA2 . Immediately after synthesis , they are released outside the cells , and exert their actions by binding to a G - protein - coupled rhodopsin - type receptor on the surface of target cells . There are eight types of prostanoid receptors : the Q13258 , four subtypes of PGE receptor , the P43088 , the P43119 , and the TXA receptor . Recently , mice deficient in each of these prostanoid receptors were generated and the examination of these mice in various experimental disease models revealed the important roles of prostaglandin receptor signaling in various pathological processes . In this review , we describe several recent findings that have addressed the mechanisms underlying sickness behaviors and that have identified the critical roles of the signaling of each prostanoid receptor in the elicitation of the stress responses associated with these sickness behaviors .", "Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss - of - function mutations causing X - linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein - Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small - molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug - induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 - 32765 , recently renamed ___MASK74___ , has already entered several clinical trials for various forms of non - Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors .", "Synthetic triterpenoid induces P15428 expression and suppresses inflammation - driven colon carcinogenesis . Colitis - associated colon cancer ( CAC ) develops as a result of inflammation - induced epithelial transformation , which occurs in response to inflammatory cytokine - dependent downregulation of 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) and subsequent suppression of prostaglandin metabolism . Agents that both enhance P15428 expression and suppress cyclooxygenase - 2 ( P35354 ) production may more effectively prevent CAC . Synthetic triterpenoids are a class of small molecules that suppress P35354 as well as inflammatory cytokine signaling . Here , we found that administration of the synthetic triterpenoid 2 - cyano - 3 , 12 - dioxooleana - 1 , 9 ( 11 )- dien - C28 - methyl ester ( CDDO - Me ) suppresses CAC in mice . In a spontaneous , inflammation - driven intestinal neoplasia model , deletion of Q13485 specifically in T cells led to progressive production of inflammatory cytokines , including P01375 - α , IFN - γ , P35228 , P05231 , IL - 1β ; as well as activation of P42224 and P40763 ; along with suppression of P15428 expression . Oral administration of CDDO - Me to mice with Q13485 - deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of P15428 . Induction of P15428 by CDDO - Me was dose dependent in epithelial cells and was abrogated following treatment with TGF - β signaling inhibitors in vitro . Furthermore , CDDO - Me - dependent P15428 induction was not observed in P84022 -/- mice . Similarly , CDDO - Me suppressed azoxymethane plus dextran sodium sulfate - induced carcinogenesis in wild - type animals , highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans .", "On the multiplicity of platelet prostaglandin receptors . I . Evaluation of competitive antagonism by aggregometry . Methods for the evaluation of competitive interactions at receptors associated with platelet activation and inhibition using aggregometry of human PRP have been developed . The evidence supports the suggestion that PGE1 and DB01240 share a common receptor for inhibition of platelet reactivity , but only a portion ( if any ) of the aggregation stimulation associated with DB00917 is the result of DB00917 binding ( without efficacy ) to this receptor . DB00917 ( at . 3 - 20 microM ) is an effective antagonist of PGE1 , DB01240 , and PGD2 producing a shift of about one order of magnitude in the IC50 - values obtained from complete aggregation inhibition dose response curves . The antagonism of PGD2 inhibition is particularly notable , 80 nM DB00917 levels are detectable . This and other actions of DB00917 indicate another platelet receptor for DB00917 . PGE1 acts at both the DB00917 and P43119 . Other substances showing DB01240 - like actions only at high doses ( 1 - 30 microM ) , display additive responses with DB01240 indicative of decreased affinity for the I2 / E1 receptor and the absence of DB00917 - like aggregation stimulation activity . DB01240 methyl ester has intrinsic inhibitory action not associated with in situ ester hydrolysis . The methyl ester is dissaggregatory showing particular specificity for inhibition of release and second wave aggregation .", "Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK30___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .", "DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK83___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .", "The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK84___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .", "P43119 in tumor endothelial cells promotes angiogenesis in an autocrine manner . Molecules highly expressed in tumor endothelial cells ( TEC ) are important for specific targeting of these cells . Previously , using DNA microarray analysis , we found that the prostacyclin receptor ( IP receptor ) gene was upregulated in TEC compared with normal endothelial cells ( NEC ) . Although prostacyclin is implicated in re - endothelialization and angiogenesis , its role remains largely unknown in TEC . Moreover , the effect of the IP receptor on TEC has not been reported . In the present study we investigated the function of the IP receptor in TEC . The TEC were isolated from two types of human tumor xenografts in nude mice , while NEC were isolated from normal counterparts . DB01240 secretion levels in TEC were significantly higher than those in NEC , as shown using ELISA . Real - time RT - PCR showed that the IP receptor was upregulated in TEC compared with NEC . Furthermore , migration and tube formation of TEC were suppressed by the IP receptor antagonist RO1138452 . Immunohistostaining showed that the IP receptor was specifically expressed in blood vessels of renal cell carcinoma specimens , but not in glomerular vessels of normal renal tissue . These findings suggest that the IP receptor is a TEC - specific marker and might be a useful therapeutic target .", "Prostaglandin receptor signaling in disease . Prostanoids , consisting of the prostaglandins ( PGs ) and the thromboxanes ( TXs ) , are a group of lipid mediators formed in response to various stimuli . They include PGD2 , DB00917 , PGF2alpha , DB01240 , and TXA2 . They are released outside of the cells immediately after synthesis , and exert their actions by binding to a G - protein coupled rhodopsin - type receptor on the surface of target cells . There are eight types of the prostanoid receptors conserved in mammals from mouse to human . They are the Q13258 ( DP ) , four subtypes of the PGE receptor ( EP1 , EP2 , EP3 , and EP4 ) , the P43088 ( FP ) , P43119 ( IP ) , and TXA receptor ( TP ) . Recently , mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease . These studies have revealed the roles of PG receptor signaling in various pathological conditions , and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions . Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications .", "Long - term exposure to methotrexate induces immunophenotypic changes , decreased methotrexate uptake and increased dihydrofolate gene copy number in Jurkat T cells . ___MASK37___ ( MTX ) treatment of rheumatoid arthritis may require increasing doses to maintain clinical efficacy . An overall plateau of clinical response is reached after only six months of treatment . To study the immunologic , biochemical and genetic effects of MTX on T cells , the Jurkat T cell line was made MTX - resistant by serial addition of methotrexate sodium into culture medium . Cells proliferated and divided successfully in MTX concentrations ranging to 15 microM . MTX resistance of Jurkat T cells in vitro was accompanied by significantly ( P < 0 . 05 ) decreased expression of P06729 , CD3 , P01730 , P10747 , and Q07108 , P60568 production , and MTX uptake assessed by cell association or disassociation of 3 [ H ]- MTX or fluoresceinated MTX ( FMTX ) , respectively . In addition , there was P00374 gene amplification and increased levels of P00374 in all resistant cell lines . Both permanent and transient phenotypic changes developed in resultant cell lines exposed to increasing concentrations of MTX in vitro . Expression of P01730 and CD25 and sensitivity to MTX returned to near - parental levels after removal of MTX from culture medium , whereas expression of P27487 and MTX uptake were significantly increased . Expression of P06729 , CD3 , Q07108 and P60568 production as well as the P00374 levels did not return to the parental phenotype after removal from MTX . We conclude that MTX - cultured cells express depressed levels of cell - surface markers vital for T cell function and activation . The return of enhancement of these cell - surface markers critical to T cell activation suggests a possible mechanism for the severe flares experienced by rheumatoid arthritis patients when drug treatment is discontinued .", "PGE1 but not DB01240 desensitizes the P43119 - adenylate cyclase complex in human foreskin fibroblasts . In intact cells or in membranes prepared from intact cells that were preincubated with PGE1 , subsequent DB01240 - stimulation is attenuated . Preincubation of cells with DB01240 does not induce desensitization of DB01240 - stimulated adenylate cyclase . These data suggest that HFF cells must be constantly exposed to a biologically active prostaglandin for desensitization to occur . The intrinsic chemical lability of DB01240 may be a biochemical protection mechanism against desensitization in cells that normally respond to DB01240 .", "Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .", "P43119 signaling and early embryo development in the mouse . BACKGROUND : DB01240 ( P06744 ( 2 ) ) plays an important role in mouse embryo development and implantation . However , it is unclear whether its action is mediated via the I prostaglandin receptor ( IP ) . METHODS : We compared the preimplantation development of IP deleted ( IP -/- ) embryos and wild - type ( WT ) embryos . We also evaluated the effect of iloprost , a stable P06744 ( 2 ) analog , and L - 165041 , a peroxisome proliferator activated receptor delta ( PPARdelta ) ligand , on IP -/- versus WT embryos . Finally , we compared the development of heterozygous IP deficient embryos carrying a normal maternal IP allele versus paternal IP allele . RESULTS : Development of IP -/- embryos lagged behind WT embryos and was not enhanced by either the P06744 ( 2 ) analog or the PPARdelta ligand . WT embryos had slightly higher , although statistically not significant , implantation rates than IP -/- embryos . Heterozygous IP deficient embryos carrying a normal maternal IP allele showed better development and responded to the P06744 ( 2 ) analog , unlike those carrying the normal paternal IP allele . CONCLUSIONS : IP receptors play an important role in preimplantation embryo development and mediate the embryo ' s response to exogenous P06744 ( 2 ) . Early embryo development depends on the oocyte IP receptor .", "Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .", "P35354 - derived prostacyclin confers atheroprotection on female mice . Female gender affords relative protection from cardiovascular disease until the menopause . We report that estrogen acts on estrogen receptor subtype alpha to up - regulate the production of atheroprotective prostacyclin , DB01240 , by activation of cyclooxygenase 2 ( P35354 ) . This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice . Deletion of the P43119 removed the atheroprotective effect of estrogen in ovariectomized female mice . This suggests that chronic treatment of patients with selective inhibitors of P35354 could undermine protection from cardiovascular disease in premenopausal females .", "Diverse prostaglandin receptors activate distinct signal transduction pathways in rat myometrium . Attempts were made to identify prostaglandin ( PG ) receptors in rat myometrium , according to the differential rank order of potencies displayed by the natural PGs and their analogues , both at the level of second messenger generation and contraction . In estrogen - treated rat myometrium , PGs [ iloprost = DB01240 greater than DB00917 much greater than 16 , 16 - dimethyl ( DM ) - DB00917 ; sulprostone = misoprostol = 0 ] induced adenosine 3 ', 5 '- cyclic monophosphate generation , indicating the contribution of a P43119 . The generation of inositol phosphates was stimulated by PGs ( PGF2 alpha greater than PGD2 much greater than DB00917 = DM - DB00917 much greater than iloprost greater than sulprostone = misoprostol = 0 ) , reflecting a PGF2 alpha - receptor - mediated process , which was insensitive to pertussis toxin ( PTX ) . Contractions caused by PGF2 alpha were closely correlated to PGF2 alpha - receptor activation associated with the phospholipase C pathway . By contrast , contractions evoked by DB00917 , equally mimicked by sulprostone and misoprostol , were abolished by PTX and were independent of phospholipase C activation . In the pregnant myometrium ( day 21 ) , the latter PGE - receptor - mediated mechanism also contributed to contractions caused by DB00917 ( less than microM concn ) . Phospholipase C activation was coupled not only to PGF2 alpha but also to PGE receptors and could be correlated with contractions induced by PGF2 alpha and DB00917 greater than microM concn ) . All PGs tested were coupled to inhibitory G protein - mediated adenylate cyclase inhibition , displaying an equipotency that did not allow characterization of the inhibitory PG receptors .", "___MASK74___ inhibits P11274 and NF - κB signaling and reduces tumor proliferation in tissue - resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue - resident CLL cells show prominent activation of both B - cell receptor ( P11274 ) and NF - κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 ( Q06187 ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway - specific gene signatures , we detected a rapid and sustained downregulation of P11274 and NF - κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . ___MASK74___ reduced phosphorylation of PLCγ2 and P29323 and decreased nuclear protein expression of NF - κB p50 . ___MASK74___ significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on - target effects of Q06187 inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www . clinicaltrials . gov as # NCT01500733 .", "C . elegans vulval development as a model system to study the cancer biology of P00533 signaling . Molecular genetic studies of C . elegans vulval development have helped to define an evolutionarily conserved signaling pathway from an P01133 - like ligand through P01133 - receptor , Ras and Q96HU1 kinase to the nucleus . Further studies have identified novel positive regulators such as Q8IVT5 - 1 and Q09428 - 8 / Q5T124 - 2 and negative regulators such as cbl / SLI - 1 . The many negative regulatory proteins might serve to prevent inappropriate signaling , and thus are analogous to tumor suppressor genes ." ]

[ "___MASK17___", "___MASK30___", "___MASK37___", "___MASK3___", "___MASK53___", "___MASK74___", "___MASK76___", "___MASK83___", "___MASK84___" ]

[ "DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK59___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .", "Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .", "Significance of Q14764 and P37231 Expression in Lipomatous Soft Tissue Tumors . BACKGROUND : Molecular mechanism of differentiation in lipogenic tumor is still unknown in detail . P01130 - related protein ( Q14764 ) and peroxisome proliferator - activated receptor gamma ( P37231 ) , representative regulatory molecules of lipogenic differentiation , have been reported today as multi - functional molecules and to modulate tumorigenesis in various kind of cancer . To date , diagnostic and therapeutic significance of the expression of these molecules in lipogenic tumors are not defined . METHODS : The immunohistochemical expression status of Q14764 and P37231 in various grades of 54 lipogenic tumors was analyzed . Correlation between the expression levels and the differentiation of the tumors was confirmed . For statistical analyses , the Kruskal - Wallis test , the Steel - Dwass test and the Mann - Whitney U test were used . RESULTS : Q14764 and P37231 expression was detected in 50 ( 92 . 6 % ) and 44 ( 81 . 5 % ) cases , respectively . The expression level in Q14764 was significantly higher in cases with well differentiated liposarcoma , pleomorphic liposarcoma and dedifferentiated liposarcoma than in lipoma . Compared with lipoma or well differentiated liposarcoma , significant elevation in expression level of P37231 was confirmed in myxoid liposarcoma , pleomorphic liposarcoma , dedifferentiated liposarcoma and the differentiated area of dedifferentiated liposarcoma . CONCLUSION : The up - regulation of Q14764 and P37231 in higher grade cases , i . e . less differentiated tumors than in low grade cases was shown , suggesting the candidate role of these molecules as tumor progression modulators rather than regulatory molecules of differentiation in lipogenic tumors .", "ω - 3 fatty acid eicosapentaenoic acid attenuates P25189 +- induced neurodegeneration in fully differentiated human SH - SY5Y and primary mesencephalic cells . DB00159 ( EPA ) , a neuroactive omega - 3 fatty acid , has been demonstrated to exert neuroprotective effects in experimental models of Parkinson ' s disease ( PD ) , but the cellular mechanisms of protection are unknown . Here , we studied the effects of EPA in fully differentiated human SH - SY5Y cells and primary mesencephalic neurons treated with P25189 (+) . In both in - vitro models of PD , EPA attenuated an P25189 (+) - induced reduction in cell viability . EPA also prevented the presence of electron - dense cytoplasmic inclusions in SH - SY5Y cells . Then , possible mechanisms of the neuroprotection were studied . In primary neurons , EPA attenuated an P25189 (+) - induced increase in Tyrosine - related kinase B ( TrkB ) receptors . In SH - SY5Y cells , EPA down - regulated reactive oxygen species and nitric oxide . This antioxidant effect of EPA may have been mediated by its inhibition of neuronal NADPH oxidase and cyclo - oxygenase - 2 ( P35354 ) , as P25189 (+) increased the expression of these enzymes . Furthermore , EPA prevented an increase in cytosolic phospholipase A2 ( P47712 ) , an enzyme linked with P35354 in the potentially pro - inflammatory arachidonic acid cascade . Lastly , EPA attenuated an increase in the bax : bcl - 2 ratio , and cytochrome c release . However , EPA did not prevent mitochondrial enlargement or a decrease in mitochondrial membrane potential . This study demonstrated cellular mechanisms by which EPA provided neuroprotective effects in experimental PD .", "P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK33___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .", "Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK58___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK58___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK58___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK58___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK58___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .", "Akt - dependent heme oxygenase - 1 induction by NS - 398 in P13671 glial cells : a potential role for CO in prevention of oxidative damage from hypoxia . We investigated whether increased heme oxygenase ( HO ) - 1 activity by NS - 398 is responsible for protection against hypoxia - induced damage in P13671 cells . The expression of P09601 was analyzed by Western blot and cell viability was analyzed by lactate dehydroxygease ( LDH ) activity . NS - 398 increased P09601 expression in a concentration - and time - dependent manner during both normoxia and hypoxia ( 95 % N ( 2 )/ 5 % CO ( 2 ) ) , but the latter was much more sensitive . Because induction of P09601 occurred due to hypoxia itself , NS - 398 seemed to potentiate the expression of P09601 . The reduced cell viability due to hypoxia was significantly reversed by either NS - 398 or [ Ru ( CO )( 3 )( Cl )( 2 )]( 2 ) , a CO - donor . Zinc protophorphrin ( ZnPPIX ) , a P09601 inhibitor , inhibited the protective effect of NS - 398 against hypoxia . Treatment with glucose oxidase ( Q9UJM8 , 20 mU / ml ) increased ROS production and caused apoptotic death , as assayed by DCFH - DA and TUNEL , respectively . NS - 398 significantly reduced Q9UJM8 - induced cell death and ROS production ; these effects were reversed by pre - treatment with oxyhemoglobin ( HbO ( 2 ) ) , a CO / NO scavenger , or ZnPPIX . Finally , NS - 398 increased P37231 luciferase activity in transiently P37231 transfected P13671 cells , which was antagonized by ZnPPIX . NS - 398 increased phosphorylation of Akt , and LY - 294002 , a specific PI ( 3 ) kinase inhibitor , inhibited NS - 398 - induced P09601 expression . Taken together , we conclude that therapeutic use of NS - 398 in the treatment of oxidative stress - oriented neuronal disorders would be beneficial through dual actions : P09601 induction and P35354 inhibition .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "Involvement of Rho - kinase in tumor necrosis factor - alpha - induced interleukin - 6 release from P13671 glioma cells . P01375 ( P01375 ) - alpha stimulated interleukin ( IL ) - 6 release and induced the phosphorylation of myosin phosphatase targeting subunit ( MYPT ) - 1 , a Rho - kinase substrate . The P05231 release was significantly suppressed by Y - 27632 and fasudil , Rho - kinase inhibitors . Although IkappaB inhibitor suppressed the P01375 - induced P05231 release , the Rho - kinase inhibitors did not affect the P01375 - induced IkappaB phosphorylation . P01375 induced the phosphorylation of p38 mitogen - activated protein ( Q96HU1 ) kinase , stress - activated protein kinase ( SAPK ) / c - Jun N - terminal kinase ( JNK ) , and Q8TCB0 / Q8NFH3 Q96HU1 kinase . The P01375 - induced P05231 release was suppressed by SB203580 , a p38 MAPK inhibitor , or SP600125 , a SAPK / JNK inhibitor , but not by PD98059 , a Q96HU1 kinase / extracellular signal - regulated kinase kinase inhibitor . The Rho - kinase inhibitors attenuated the P01375 - induced phosphorylation of both p38 Q96HU1 kinase and SAPK / JNK . Rho - kinase , which has been used for the clinical treatment of cerebral vasospasms , may be involved in other central nervous system ( CNS ) disorders such as traumatic injury , stroke , neurodegenerative disease and neuropathic pain . P01375 , a proinflammatory cytokine that affects the CNS through cytokines , such as P05231 , release from neurons , astrocytes and microglia . Therefore , we investigated the involvement of Rho - kinase in the P01375 - induced P05231 release from rat P13671 glioma cells . These results strongly suggest that Rho - kinase regulates the P01375 - induced P05231 release at a point upstream from p38 MAPK and SAPK / JNK in P13671 glioma cells . Therefore , Rho - kinase inhibitor may be considered to be a new clinical candidate for the treatment of CNS disorders in addition to cerebral vasospasms .", "A Nile blue based infrared fluorescent probe : imaging tumors that over - express cyclooxygenase - 2 . The first Golgi - localized cyclooxygenase - 2 ( P35354 ) - specific near - infrared ( Q9Y3T9 ) fluorescent probe , Niblue - P13671 - IMC , able to detect cancer cells , was designed . Importantly , Niblue - P13671 - IMC preferentially labeled the tumors in a mouse tumor model with deep tissue penetration capacity . It may be a promising molecular tool for guiding tumor resection during surgery .", "Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK36___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK36___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .", "Omega - 3 polyunsaturated fatty acids and inflammatory processes : nutrition or pharmacology ? DB00159 ( EPA ) and docosahexaenoic acid ( DB01708 ) are n - 3 fatty acids found in oily fish and fish oil supplements . These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis , adhesion molecule expression and leucocyte - endothelial adhesive interactions , production of eicosanoids like prostaglandins and leukotrienes from the n - 6 fatty acid arachidonic acid , production of inflammatory cytokines and T cell reactivity . In parallel , EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DB01708 give rise to anti - inflammatory and inflammation resolving resolvins and protectins . Mechanisms underlying the anti - inflammatory actions of n - 3 fatty acids include altered cell membrane phospholipid fatty acid composition , disruption of lipid rafts , inhibition of activation of the pro - inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes , activation of the anti - inflammatory transcription factor P37231 ( i . e . peroxisome proliferator activated receptor γ ) and binding to the G protein coupled receptor Q5NUL3 . These mechanisms are interlinked . In adult humans , an EPA plus DB01708 intake greater than 2 g day ⁻ ¹ seems to be required to elicit anti - inflammatory actions , but few dose finding studies have been performed . Animal models demonstrate benefit from n - 3 fatty acids in rheumatoid arthritis ( RA ) , inflammatory bowel disease ( Q9UKU7 ) and asthma . Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta - analyses of the data . Clinical trails of fish oil in patients with Q9UKU7 and asthma are inconsistent with no overall clear evidence of efficacy .", "Expression of P35354 and DB01221 receptor genes at the cochlea and midbrain in salicylate - induced tinnitus . OBJECTIVE / HYPOTHESIS : The expression of the genes for cyclooxygenase ( P36551 ) and DB01221 receptor ( NR ) has seldom been reported in tinnitus . We hypothesized that expression of P35354 and NR was altered in the cochlea and midbrain in salicylate - induced tinnitus . STUDY DESIGN : Experimental study on mice . METHODS : We evaluated the tinnitus score and mRNA expression levels of P35354 and NR subtype 2B ( Q13224 ) in the cochlea and midbrain in response to intraperitoneal injections of salicylate for 4 days . RESULTS : At day 4 of tinnitus induction , the mean weights of the whole body and midbrain did not change greatly in both control and salicylate groups . The tinnitus score was not elevated from day 1 to day 4 in the control group , but increased day by day in the salicylate group . The mRNA expression level of P35354 decreased slightly in the salicylate group in the cochlea ( 1 . 1 ± 0 . 33 vs . 1 . 3 ± 0 . 49 , P = . 0752 ) and in the midbrain ( 0 . 9 ± 0 . 10 versus 1 . 0 ± 0 . 35 , P = . 0489 ) . Inversely , the expression levels of the Q13224 gene increased moderately in the salicylate group in the cochlea ( 3 . 7 ± 0 . 47 versus 2 . 3 ± 1 . 13 , P < 0 . 0001 ) and in the midbrain ( 1 . 6 ± 0 . 64 versus 1 . 0 ± 0 . 44 , P = . 0007 ) . CONCLUSIONS : Salicylate induced tinnitus and altered the expression of the P35354 and Q13224 genes in the cochlea and midbrain of mice . These findings might contribute to further understanding of pathophysiology and therapy of tinnitus .", "___MASK74___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK74___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .", "hGH - V gene expression and promoter activity under glucose and 5 - azacytidine ( 5azaC ) effects . The metabolic conditions affecting placental development depend on nutritional state , genetic constitution and other external factors . The secretion of human placental growth hormone ( hGH - V ) had shown to be dependent of glucose , but the regulatory effects of this metabolite on hGH - V promoter activity and gene expression in presence of 5 - azacytidine had not been studied . In this work we compared the hGH - V promoter activity and the endogenous mRNA expression in human placental choriocarcinoma cell line JAR in the presence of glucose and demethylating genome conditions . High glucose concentration in culture medium diminished hGH - V mRNA endogenous levels in JAR cells whereas the expression of hGH - V from transfected PACs was slightly higher ; but in the presence of 5azaC a higher hGH - V gene expression from both the endogenous and the transfected ones was obtained . A drastic diminution of promoter analysis was shown when cells had no glucose ( J0 cells ) or in presence of 5azaC ; the placental transcription factors that showed modified binding capacity were DB09106 - 2 , P37231 , H4TF - 1 and O75051 - 1 . Our results suggest that in vitro suppressive glucose effect dictates a metabolic context to hGH - V gene expression and promoter regulation whereas a genomic methylation - dependent background is necessary to maintain placental transcription factors able to bind and regulate proximal promoter region of hGH - V in placental cells .", "Toll - like receptor expression in human keratinocytes : nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll - like receptor 2 but not toll - like receptor 4 or platelet activating factor receptor dependent . Cultured primary human keratinocytes were screened for their expression of various members of the toll - like receptor ( TLR ) family . Keratinocytes were found to constitutively express Q15399 , O60603 , O15455 , O60602 , and Q9NR96 but not O00206 , Q9Y2C9 , Q9NYK1 , Q9NR97 , or Q9BXR5 as shown by polymerase chain reaction analysis . The expression of the crucial receptor for signaling of staphylococcal compounds O60603 was also confirmed by immunohistochemistry , in contrast to O00206 , which showed a negative staining pattern . Next , we analyzed the activation of the proinflammatory nuclear transcription factor kappaB by Staphylococcus aureus strain 8325 - 4 . Using nuclear extract gel shifts , RelA staining , and luciferase reporter transfection plasmids we found a clear induction of nuclear factor kappaB translocation by the bacteria . This translocation induced the transcription of nuclear factor kappaB controlled genes such as inducible nitric oxide synthetase , P35354 , and interleukin - 8 . Transcription of these genes was followed by production of increased amounts of interleukin - 8 protein and NO . Inhibition experiments using monoclonal antibodies and the specific platelet activating factor receptor inhibitor CV3988 showed that nuclear factor kappaB activation by S . aureus was O60603 but not O00206 or platelet activating factor receptor dependent . In line , the purified staphylococcal cell wall components lipoteichoic acid and peptidoglycan , known to signal through O60603 , also showed nuclear factor kappaB translocation in human keratinocytes , indicating a crucial role of the staphylococcal cell wall in the innate immune stimulation of human keratinocytes . These results help to explain the complex activation of human keratinocytes by S . aureus and its cell wall components in various inflammatory disorders of the skin .", "Acetylbritannilactone suppresses lipopolysaccharide - induced vascular smooth muscle cell inflammatory response . To investigate the mechanism of action by which a new anti - inflammatory active compound , 1 - O - acetylbritannilactone ( P00519 ) isolated from Inula britannica - F . , inhibits inflammatory responses in vascular smooth muscle cells ( VSMCs ) . Enzyme immunoassay was used to measure the levels of prostandin E ( 2 ) ( PGE ( 2 ) ) production . Immunocytochemistry staining and Western blot analysis were performed to detect the nuclear translocation of nuclear factor - kappaB ( NF - kappaB ) p65 and the expression of IkappaB - alpha , pIkappaB - alpha and cyclooxygenase - 2 ( P35354 ) . Electrophoretic mobility shift assays ( EMSA ) were used to detect DNA - binding activity of NF - kappaB in VSMCs . P00519 ( 5 , 10 , 20 micrommol / l ) had several concentration - dependent effects , including inhibition of lipopolysaccharide ( LPS ) - induced PGE ( 2 ) production and P35354 expression , and blockade of NF - kappaB activation and translocation . These effects were owing to reductions in IkappaB - alpha phosphorylation and degradation induced by LPS . In addition , P00519 directly inhibited the binding of active NF - kappaB to specific DNA cis - element . These results indicate that P00519 is a potent inhibitor of LPS - stimulated VSMC inflammatory responses through blockade of NF - kappaB activity and inhibition of inflammatory gene P35354 expression .", "DB00159 modulates DB00091 - induced proinflammatory cytokine over - expression in osteoblastic cells in vitro . Several adverse outcomes are reported in subjects undergoing long term DB00091 ( DB00091 ) treatment . Severe osteopenia has been described in clinical and experimental reports , while beneficial effects of n - 3 polyunsaturated fatty acids ( PUFAs ) on bone metabolism are recognized . In the present study we investigated the effects of n - 3 versus n - 6 PUFAs on osteoblastic cells treated with DB00091 , evaluating the expression of interleukin ( IL ) - 1 & # 223 ; , interleukin - 6 ( P05231 ) , inducible nitric oxide synthase ( P35228 ) , and cyclooxygenase - 2 ( P35354 ) in two different experimental protocols and the production of P05231 , IL - 1 & # 223 ; , and tumor necrosis factor alpha ( TNFalpha ) in cells challenged simultaneously with DB00091 and eicosapentaenoic acid ( EPA ) for 48h . IL - 1 & # 223 ; and P05231 up - regulation , induced by DB00091 , was counteracted by the addition of EPA in both protocols ; on the contrary , arachidonic acid ( AA ) magnified DB00091 the effects . P35354 and P35228 levels were not modified by DB00091 treatment . These in vitro results , that substantiate clinical reports of DB00091 - induced osteopenia , demonstrate a beneficial effect of EPA on DB00091 - altered cytokine profile , opening new perspectives in the non - pharmacological management of adverse outcomes in DB00091 - treated patients .", "AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK53___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .", "Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20 - ribonucleotide stem - loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus - encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3 '- untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial - encoded transcripts , such as P35354 , a 3 '- UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial - encoded tRNAs , appending the 3 '- UTR localization sequence was essential for efficient fusion - transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders .", "___MASK49___ improves renal ischemia - reperfusion injury by inhibiting the mevalonate pathway . Statins are known to lessen the severity of renal ischemia - reperfusion injury . The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model . Treatment of mice with pravastatin , a widely used statin , improved renal function after renal ischemia - reperfusion without lowering the plasma cholesterol level . Administration of pravastatin with mevalonate , a product of P04035 , eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism . In hypercholestrolemic apolipoprotein E knockout mice with reduced P04035 activity ; the degree of injury was less severe than in control mice , however , there was no protective action of pravastatin on renal injury in the knockout mice . Treatment with a farnesyltransferase inhibitor ( L - 744832 ) mimicked pravastatin ' s protective effect but co - administration with the statin provided no additional protection . Both pravastatin and L - 744832 inhibited the injury - induced increase in plasma P05231 concentration to a similar extent . Our results suggest the protective effect of pravastatin on renal ischemia - reperfusion injury is mediated by inhibition of the mevalonate - isoprenoid pathway independent of its lipid lowering action .", "Differential effects of amfonelic acid on the haloperidol - and clozapine - induced increase in extracellular DOPAC in the nucleus accumbens and the striatum . This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3 , 4 - dihydroxyphenylacetic acid ( DOPAC ) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats . DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes . Amfonelic acid ( 2 . 5 mg / kg s . c . ) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens . ___MASK74___ ( 1 mg / kg s . c . ) increased extracellular DOPAC in both regions . When amfonelic acid was injected 5 min before haloperidol , the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum . Clozapine ( 30 mg / kg i . p . ) increased extracellular DOPAC in both regions , an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum . When ritanserin ( 5 mg / kg i . p . ) , a serotonergic antagonist ( P28223 ) , was co - administered with haloperidol , the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum . The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo . The effects of amfonelic acid on the neuroleptic - induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens . These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms , supporting the view that the regulation of dopamine metabolism differs in the two regions . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Thiazolidinediones : effects on insulin resistance and the cardiovascular system . Thiazolidinediones ( TZDs ) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years . They may delay the development of type 2 diabetes in individuals at high risk of developing the condition , and have been shown to have potentially beneficial effects on cardiovascular risk factors . TZDs act as agonists of peroxisome proliferator - activated receptor - gamma ( P37231 ) primarily in adipose tissue . P37231 receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue , increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor - alpha ( P01375 ) , plasminogen activator inhibitor - 1 ( P05121 ) and interleukin - 6 ( P05231 ) . Clinically , TZDs have been shown to reduce measures of atherosclerosis such as carotid intima - media thickness ( CIMT ) . However , in spite of beneficial effects on markers of cardiovascular risk , TZDs have not been definitively shown to reduce cardiovascular events in patients , and the safety of rosiglitazone in this respect has recently been called into question . Dual Q07869 / gamma agonists may offer superior treatment of insulin resistance and cardioprotection , but their safety has not yet been assured .", "P35354 promotes early atherosclerotic lesion formation in ApoE - deficient and C57BL / 6 mice . Cyclooxygenase ( P36551 ) 2 is expressed in atherosclerotic lesions . We have previously reported that selective inhibition of P35354 reduces early atherosclerosis in P01130 deficient mice . To examine the role of P35354 in atherosclerosis in other mouse models , we studied the effects of selective P35354 inhibition ( by rofecoxib and NS - 398 ) and nonselective P36551 inhibition ( by indomethacin ) on early atherosclerotic lesion formation in apolipoprotein E - deficient ( apoE (-/-) ) mice . Selective P35354 and nonselective P36551 inhibition reduced atherosclerosis in female apoE (-/-) mice by 35 - 38 % and 38 - 51 % in the proximal and en face aortas , respectively . Next we investigated the role of macrophage P35354 by transplanting P35354 (-/-) fetal liver cells into C57BL / 6 mice and challenging the mice with an atherogenic diet . Genetic deletion of P35354 from hematopoietic cells reduced atherosclerosis by 51 % . In addition , LPS activated P35354 (-/-) macrophages had decreased expression of monocyte chemoattractant protein - 1 ( P13500 ) and tumor necrosis factor - alpha ( TNFalpha ) . The results demonstrate that selective inhibition of P35354 and elimination of P35354 from macrophages significantly reduces early atherosclerotic lesion formation in apoE - deficient and C57BL / 6 mice . These results are compatible with P35354 expression by macrophages having a proatherogenic role , and support the potential of anti - inflammatory therapeutic approaches for atherosclerosis .", "___MASK49___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK49___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK49___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .", "___MASK90___ reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin - converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU / ml ) , tissue plasminogen activator ( t - PA ) antigen ( ng / ml ) , and serum P12821 activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37 . 5 mg daily ) and compared them with the values in 15 placebo - treated patients chosen at random . Blood sampling was performed at 07 . 00 h . In the captopril - treated group , serum P12821 activity decreased significantly , from 14 . 0 +/- 0 . 8 to 11 . 5 +/- 1 . 2 IU / L 24 h after captopril therapy ( p < 0 . 01 ) , and those of P05121 activity and t - PA antigen also decreased significantly - from 11 . 9 +/- 2 . 8 to 5 . 5 +/- 2 . 2 IU / ml ( p < 0 . 02 ) and from 9 . 9 +/- 1 . 0 to 7 . 5 +/- 0 . 9 ng / ml ( p < 0 . 05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t - PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .", "Establishment of a double Philadelphia chromosome - positive acute lymphoblastic leukemia - derived cell line , TMD5 : effects of cytokines and differentiation inducers on growth of the cells . A double Philadelphia chromosome ( Ph ) - positive leukemia cell line with common - B cell phenotype , designated TMD5 , was established from the blast cells of a patient with double Ph - positive acute lymphoblastic leukemia . TMD5 cells expressed 190 kDa P11274 / P00519 chimeric protein and 145 kDa P00519 protein . The cells proliferated without added growth factors . Autocrine growth mechanism was not recognized . The addition of growth factors such as DB00099 , GM - P04141 , P08700 , P05231 , or Stem Cell Factor did not affect the growth . Herbimycin A suppressed the growth of TMD5 cells at the low concentration that did not affect Ph - negative cells . It suppressed tyrosine phosphorylation of intracellular proteins in TMD5 cells . Dexamethasone and dibutyryl cyclic AMP also suppressed the growth . They , however , did not affect the phosphorylation significantly . Neither all - trans retinoic acid nor interferon - alpha affected the growth . TMD5 cells , characterized minutely here and rare in that they have double Ph chromosomes , will be a useful tool for the study of Ph - positive leukemia .", "Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK27___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK27___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK27___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK27___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK27___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK27___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK27___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK27___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK27___ in the treatment of changes in hypervigilance following severe stress .", "Levels of NT - proBNP , markers of low - grade inflammation , and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease . P00797 - angiotensin - aldosterone system ( RAAS ) blockade may reduce levels of biomarkers of chronic low - grade inflammation and endothelial dysfunction . We investigated the effect of spironolactone added to standard RAAS blockade on these biomarkers in an analysis of four original studies . MATERIALS AND METHODS : The studies were double - blind , randomised , placebo - controlled studies in 46 type 1 and 23 type 2 diabetic patients with micro - or macroalbuminuria treated with angiotensin - converting enzyme inhibitor ( P12821 inhibitor ) or angiotensin receptor blocker ( ARB ) , and randomised to additional treatment with spironolactone 25 mg and placebo daily for 60 days . OUTCOME MEASURES : Changes in inflammatory ( hsCRP , s - ICAM , P01375 α , P05231 , P10145 , Serum amyloid A , IL1β ) , endothelial dysfunction ( sE - selectin , s - P05362 , s - P19320 , P04275 , p - selectin , s - thrombomodulin ) and NT - proBNP after each treatment period . RESULTS : During spironolactone treatment , u - albumin excretion rate was reduced from 605 ( 411 - 890 ) to 433 ( 295 - 636 ) mg / 24 h , as previously reported . Markers of inflammation and endothelial dysfunction did not change ; only changes in NT - proBNP ( reduced by 14 % , p = 0 . 05 ) and serum amyloid A ( reduced by 62 % , p = 0 . 10 ) were borderline significant . DISCUSSIONS : Our results indicate that the renoprotective effect of spironolactone when added to RAAS blockade is not mediated through anti - inflammatory pathways since markers of inflammation and endothelial dysfunction are not affected during treatment .", "Effects of a Topical Angiotensin - Converting Enzyme Inhibitor and a Selective P35354 Inhibitor on the Prevention of Hypertrophic Scarring in the Skin of a Rabbit Ear .  P12821 ( P12821 ) inhibitors have been reported to inhibit fibrogenesis , and cyclooxygenase - 2 ( P35354 ) inhibitors , to reduce scarring by reducing the initial inflammation . The authors reasoned that the topical application of these 2 agents may have a complementary effect on scar reduction . METHODS : ___MASK90___ ( P12821 inhibitor ) , celecoxib ( P35354 inhibitor ) , or a combination of captopril and celecoxib were topically applied to a skin wound in a rabbit ear , and investigated for the effects on scar formation . RESULTS : The level of scar elevation decreased in the captopril group and the level of infiltration of inflammatory cells decreased in the celecoxib group . In the group where a combination of the 2 drugs was used , the level of scar elevation decreased the most , and collagen deposition and organization returned to normal most rapidly . Celecoxib was found to inhibit the initial inflammation in the ear wound of the rabbit , and captopril inhibited scar elevation . CONCLUSION : Clinical application of these drugs will require further studies with regard to adverse events and their absorptivity as topical agents . However , these findings suggest that the combined topical administration of an P12821 inhibitor and P35354 inhibitor to a skin wound could be an effective treatment for the prevention of hypertrophic scarring .  .", "2 ( 3H )- benzoxazolone and bioisosters as \" privileged scaffold \" in the design of pharmacological probes . The 2 ( 3H )- benzoxazolone heterocycle and its bioisosteric surrogates ( such as 2 ( 3H )- benzothiazolinone , benzoxazinone , etc . ) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template . These heterocycles and pyrocatechol have indeed similar pKa ' s , electronic charge distribution , and chemical reactivity . Therapeutic applications of this template are very broad , and range from analgesic anti - inflammatory compounds ( including P37231 antagonists ) to antipsychotic and neuroprotective anticonvulsant compounds . High affinity ligands have been obtained also for dopaminergic ( D2 and D4 ) , serotoninergic ( P08908 and P28223 ) , sigma - 1 and sigma - 2 receptors . Owing to the high number of positive hits encountered with this heterocycle and its congeners , 2 ( 3H )- benzoxazolone template certainly deserves the title of \" privileged scaffold \" in medicinal chemistry .", "DB00159 inhibits prostaglandin D2 generation by inhibiting cyclo - oxygenase - 2 in cultured human mast cells . BACKGROUND : DB00159 ( EPA ) is catalysed by cyclo - oxygenase ( P36551 ) , as is arachidonic acid , and is a competitive inhibitor of arachidonate metabolism . OBJECTIVES : We examined the effect of EPA on prostaglandin ( PG ) D2 generation in the cultured human mast cells with IgE - anti - IgE challenge incubation . METHODS : Cultured human mast cells were incubated with EPA ( 1 micromol / L ) for 20 h , then challenged with anti - IgE incubation after treatment with IgE . At the same time , P36551 inhibitors were tested to identify P23219 and P35354 activity . PGD2 synthetic activity was also assayed in a cell - free homogenate of cultured mast cells with P36551 inhibitors and EPA . DB11320 in the culture medium and in cells was assayed with the HPLC - fluorescent method . PGD2 and PGD3 were assayed with gas chromatography - mass spectrometry and the stable isotope dilution method . RESULTS : Although EPA incubation did not affect histamine release by cultured human mast cells in response to IgE - anti - IgE challenge incubation , it did decrease PGD2 generation by inhibiting the P35354 pathway . In contrast , in the cell - free homogenate of cultured human mast cells , EPA inhibited both P23219 and P35354 activities . CONCLUSION : Pre - incubation with EPA primarily affects the P35354 pathway in cultured human mast cells and reduces PGD2 generation in response to IgE - anti - IgE challenge incubation . These findings suggest that P23219 and P35354 have different substrate flow systems in mast cells . They also suggest that endogenous EPA diet supplementation would reduce PGD2 production and could serve as an anti - inflammatory substrate in human mast cells .", "The P37231 Agonist 15 - Deoxy - Delta - Prostaglandin J ( 2 ) Attenuates Microglial Production of IL - 12 Family Cytokines : Potential Relevance to Alzheimer ' s Disease . Accumulation of amyloid - beta peptide ( Abeta ) appears to contribute to the pathogenesis of Alzheimer ' s disease ( AD ) . Therapeutic hope for the prevention or removal of Abeta deposits has been placed in strategies involving immunization against the Abeta peptide . Initial Abeta immunization studies in animal models of AD showed great promise . However , when this strategy was attempted in human subjects with AD , an unacceptable degree of meningoencephalitis occurred . It is generally believed that this adverse outcome resulted from a T - cell response to Abeta . Specifically , P01730 (+) Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Abeta immunization in the treatment of AD . Interleukin ( IL ) - 12 and IL - 23 play critical roles in the development of Th1 and Th17 cells , respectively . In the present study , Abeta ( 1 - 42 ) synergistically elevated the expression of IL - 12 and IL - 23 triggered by inflammatory activation of microglia , and the peroxisome proliferator - activated receptor ( Q07869 ) - gamma agonist 15 - deoxy - Delta ( 12 , 14 )- PGJ ( 2 ) ( 15d - PGJ ( 2 ) ) effectively blocked the elevation of these proinflammatory cytokines . Furthermore , 15d - PGJ ( 2 ) suppressed the Abeta - related synergistic induction of P08571 , MyD88 , and O60603 , molecules that play critical roles in neuroinflammatory conditions . Collectively , these studies suggest that P37231 agonists may be effective in modulating the development of AD .", "Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .", "Inhibition of cyclooxygenase - 2 elicits a P21554 - mediated decrease of excitatory transmission in rat P00915 hippocampus . Cannabinoid receptor ( P21554 ) ligands decrease excitatory and inhibitory transmission in the hippocampus , but the influence of endogenously formed cannabinoids ( eCBs ) on basal excitatory transmission remains uncertain . Here , we investigated the influence of eCBs on synaptic transmission in P00915 hippocampus using the slice preparation . Blockade of P21554 with the selective receptor antagonists SR141716 ( rimonabant ) or AM251 augmented synaptic responses evoked upon stimulation of the Schaffer collaterals . This effect persisted in the presence of bicuculline or CGP55845 to block GABA ( A ) or GABA ( B ) receptors , revealing a tonic eCB influence on excitatory transmission . Selective inhibition of cyclooxygenase - 2 ( P35354 ) with meloxicam or NS - 398 decreased excitatory responses partly in a P21554 - dependent manner , independently of GABA ( A ) transmission . Paired - pulse paradigms suggested a presynaptic P21554 mechanism to decrease glutamate release . Inhibition of P23219 or other routes of eCB degradation did not affect synaptic transmission . We conclude that P35354 regulates the formation of P21554 ligands that decrease hippocampal excitatory transmission .", "P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK33___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK33___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .", "Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .", "Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .", "P37231 : a nuclear receptor with affinity for cannabinoids . An increasing number of cannabinoid actions are being reported that do not appear to be mediated by either P21554 or CB2 , the known cannabinoid receptors . One such example is the synthetic analog ajulemic acid ( AJA ) , which shows potent analgesic and anti - inflammatory effects in rodents and humans . AJA binds weakly to P21554 only at concentrations many fold higher than its therapeutic range , and is , therefore , completely free of psychotropic effects in both normal subjects and pain patients suggesting the involvement of a target site other than P21554 . AJA as well as several other cannabinoids appear to have profound effects on cellular lipid metabolism as evidenced by their ability to transform fibroblasts into adipocytes where the accumulation of lipid droplets can be readily observed . Such transformations can be mediated by the activation of the nuclear receptor P37231 . A variety of small molecule ligands including AJA have been shown to induce the activation of P37231 and , in some cases this has led to the introduction of clinically useful agents . It is suggested that P37231 may serve a receptor function for certain actions of some cannabinoids .", "The expression of the solute carriers Q14973 and O75051 - 1 is regulated by cholesterol in HepG2 cells . Drug disposition and response are greatly determined by the activities of drug - metabolizing enzymes and transporters . While the knowledge in terms of CYP enzymes and efflux ABC transporters ( such as P08183 , P - glycoprotein ) is quite extensive , influx transporters are increasingly being unveiled as key contributors to the process of drug disposition . There is little information on the regulation of these proteins in human cells , especially as regards the effect of endogenous compounds . In this study , we analysed the expression of P08684 and three uptake transporters Q14973 ( Q14973 ) , P46721 / P46721 ( P46721 ) and O75051 - 1 ( O15245 ) in HepG2 cells following treatment with cholesterol . While P08684 and P46721 expression was unaffected , cholesterol treatment led to increased levels of Q14973 and O75051 - 1 mRNAs . Alterations in the functional characteristics and / or expression levels of drug transporters in the liver may conceivably contribute to the variability in drug oral bioavailability often observed in the clinical settings .", "High mobility group box protein - 1 promotes cerebral edema after traumatic brain injury via activation of toll - like receptor 4 . Traumatic brain injury ( TBI ) is a major cause of mortality and morbidity worldwide . Cerebral edema , a life - threatening medical complication , contributes to elevated intracranial pressure ( ICP ) and a poor clinical prognosis after TBI . Unfortunately , treatment options to reduce post - traumatic edema remain suboptimal , due in part , to a dearth of viable therapeutic targets . Herein , we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI . Our results demonstrate that high - mobility group box protein 1 ( P09429 ) was released from necrotic neurons via a Q13224 - mediated mechanism . P09429 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice . The detrimental effects of P09429 were mediated , at least in part , via activation of microglial toll - like receptor 4 ( O00206 ) and the subsequent expression of the astrocytic water channel , aquaporin - 4 ( P55087 ) . Genetic or pharmacological ( VGX - 1027 ) O00206 inhibition attenuated the neuroinflammatory response and limited post - traumatic edema with a delayed , clinically implementable therapeutic window . Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal P09429 initiates the microglial release of interleukin - 6 ( P05231 ) in a O00206 dependent mechanism . In turn , microglial P05231 increased the astrocytic expression of P55087 . Taken together , these data implicate microglia as key mediators of post - traumatic brain edema and suggest P09429 - O00206 signaling promotes neurovascular dysfunction after TBI ." ]

[ "___MASK27___", "___MASK33___", "___MASK36___", "___MASK49___", "___MASK53___", "___MASK58___", "___MASK59___", "___MASK74___", "___MASK90___" ]

[ "Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK82___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .", "Interplay between inhibitory ferric and stimulatory curcumin regulates phosphorylation - dependent human cystic fibrosis transmembrane conductance regulator and ΔF508 activity . Curcumin potentiates cystic fibrosis transmembrane conductance regulator ( P13569 ) activation in an DB00171 - independent but phosphorylation - dependent manner . The underlying molecular mechanisms are unclear . Here , P29320 - 293T cells cultured in an Fe ( 3 +)- containing medium were transiently transfected with P13569 constructs , and the role of the inhibitory Fe ( 3 +) bridge between intracellular loop 3 and the regulatory domain of P13569 in this pathway was investigated . The results showed that ethylenediaminetetraacetic acid ( DB00974 ) stimulated phosphorylation - dependent P13569 activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe ( 3 +)- binding interface . Furthermore , curcumin potentiation of P13569 was significantly weakened not only by Fe ( 3 +)- insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N - ethylmaleimide or DB00974 pretreatment that removes Fe ( 3 +) . More importantly , potentiation of P13569 was completely suppressed by sufficient Fe ( 3 +) . Finally , the insertion of Fe ( 3 +)- insensitive H950R / S768R increased the curcumin - independent activity of ΔF508 but weakened its curcumin potentiation . Thus , Fe ( 3 +) homeostasis in epithelia may play a critical role in regulating P13569 activity , and targeting Fe ( 3 +)- chelating potentiators may direct new therapies for cystic fibrosis .", "Q9Y271 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin - intolerant asthma patients . OBJECTIVES : Leukotriene receptor antagonists ( LTRA ) , such as montelukast , have been used as a first - line treatment for patients with aspirin - intolerant asthma ( AIA ) . This study evaluated associations between the clinical requirement for LTRA and genetic polymorphisms of the P09917 , Q16873 , P35354 , Q9Y271 and P21731 genes in the arachidonic acid cascade in the long - term management of 89 AIA patients from a Korean population . METHODS : Asthma control status was monitored for 1 year with maintenance medications of inhaled corticosteroid and oral LTRA , and AIA patients were classified into three groups according to the mean montelukast dose required per month to maintain asthma control for 1 year : group I ( > or = 200 mg montelukast / month ; n = 37 ) , group II ( 5 - 150 mg / month ; n = 25 ) and group III ( < 5 mg / month ; n = 27 ) . Genetic polymorphisms in the arachidonic acid cascade were determined using a single - base extension method . RESULTS : We found that there was a significant difference in the genotype frequency of the Q9Y271 promoter polymorphism - 634C > T among the three groups ( p = 0 . 007 for group I vs group II , p = 0 . 017 for group I vs group III ) , while there were no significant associations between LTRA requirements and polymorphisms of the other genes . The patients with the variant genotype ( CT or TT ) of the - 634C = T Q9Y271 promoter polymorphism showed a higher expression level than those with the common genotype ( CC ) . CONCLUSION : These findings indicate that the Q9Y271 promoter polymorphism is a useful genetic marker for predicting LTRA requirements in the long - term management of AIA patients .", "5 - Lipoxygenase mediates O14788 - induced osteoclast formation via the cysteinyl leukotriene receptor 1 . 5 - Lipoxygenase ( P09917 ) catalyzes the formation of two major groups of leukotrienes , leukotriene B4 and cysteinyl leukotrienes ( CysLTs ) , and it has been implicated as a promising drug target to treat various inflammatory diseases . However , its role in osteoclastogenesis has not been investigated . In this study , we used mouse bone marrow - derived macrophages ( BMMs ) to show that P09917 inhibitor suppresses O14788 - induced osteoclast formation . Inhibition of P09917 was associated with impaired activation of multiple signaling events downstream of Q9Y6Q6 , including P29323 and p38 phosphorylation , and IκB degradation , followed by a decrease in O95644 expression . Ectopic overexpression of a constitutively active form of O95644 partly rescued the antiosteoclastogenic effect of P09917 inhibitor . The knockdown of P09917 in BMMs also resulted in a significant reduction in O14788 - induced osteoclast formation , accompanied by decreased expression of O95644 . Similar effects were shown with CysLT receptor ( CysLTR ) 1 / 2 antagonist and small RNA for Q9Y271 in BMMs , indicating the involvement of CysLT and Q9Y271 in P09917 - mediated osteoclastogenesis . Finally , P09917 inhibitor suppressed LPS - induced osteoclast formation and bone loss in the in vivo mouse experiments , suggesting a potential therapeutic strategy for treating diseases involving bone destruction . Taken together , the results of this study demonstrate that P09917 is a key mediator of O14788 - induced osteoclast formation and possibly a novel therapeutic target for bone - resorption diseases .", "Leukotriene D4 - induced increases in cytosolic calcium in THP - 1 cells : dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists . Agonist - induced changes in intracellular calcium ion concentration ( [ Ca ++] i ) were examined in human monocytic leukemia THP - 1 cells loaded with fura 2 / acetoxymethyl ester ( fura 2 / AM ) . Leukotriene ( LT ) D4 induced a concentration - dependent biphasic response consisting of a transient phase ( up to 5 - fold peak increase ) followed by a sustained phase , showing characteristics of a receptor - operated calcium channel . Homologous desensitization to LTD4 was observed . The responses to LTD4 were reduced by 80 to 90 % in calcium - free buffer . The responses to LTD4 in a calcium - free buffer were dependent upon the duration of prior exposure of the cells to a calcium - free environment . The response at 30 or 60 min after exposure to calcium - free buffer was greater than that at earlier time points ( time - dependent sensitization ) . Similar responses were obtained with THP - 1 cells exposed to DB00974 - containing buffer . It is speculated that such time - dependent sensitization is a result of changes at the receptor level . The responses to LTD4 were blocked by two specific LTD4 antagonists , MK - 0571 and DB00549 , in a concentration - dependent manner . When given after addition of LTD4 , MK - 0571 or DB00549 reversed the sustained phase of the LTD4 - induced response , suggesting that maintenance of the response requires persistent activation of the Q9Y271 . DB00549 was 5 to 10 times more potent than MK - 0571 ( IC50 values of 1 . 1 and 9 . 3 nM , respectively ) , in agreement with results from radioligand binding studies reported separately .", "DB01411 inhibits renal epithelial cyst progression via activation of AMP - activated protein kinase . Q9Y271 ( CysLT1 receptor ) antagonists were found to inhibit chloride secretion in human airway epithelial cells . Since chloride secretion in renal epithelial cells , which shares common mechanisms with airway epithelial cells , plays important roles in renal cyst progression in polycystic kidney disease ( Q15139 ) , this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms . Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney ( MDCK ) cyst models . Mechanisms of actions of CysLT1 receptor antagonists were determined using short - circuit current measurement , assays of cell viability and cell proliferation , and immunoblot analysis of signaling proteins . Of the three drugs acting as CysLT1 receptor antagonists ( montelukast , pranlukast and zafirlukast ) tested , pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability . Its effect was independent of the inhibition of CysLT1 receptors . Instead , it reduced DB02527 - activated chloride secretion and proliferation of MDCK cells in an AMP - activated protein kinase ( AMPK ) - dependent manner and had no effect on P13569 protein expression . Interestingly , pranlukast enhanced AMPK activation via calcium / calmodulin - dependent protein kinase kinase beta ( CaMKKβ ) with consequent activation of acetyl - DB01992 carboxylase ( ACC ) and suppression of mammalian target of rapamycin ( P42345 ) pathway . These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting DB02527 - activated chloride secretion and cell proliferation via CaMKKβ - AMPK - P42345 pathway . Therefore , pranlukast represents a class of known drugs that may have potential utility in Q15139 treatment .", "Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .", "Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK65___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK65___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK65___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .", "___MASK87___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK87___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK87___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK87___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .", "[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK35___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .", "Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK42___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .", "Anti - tumor effects of B - 2 , a novel 2 , 3 - disubstituted 8 - arylamino - 3H - imidazo [ 4 , 5 - g ] quinazoline derivative , on the human lung adenocarcinoma A549 cell line in vitro and in vivo . This study evaluated the selective effects of 2 - isopropyl - 3 - butyl - 8 -( 4 - fluorophenylamino )- 3H - imidazo [ 4 , 5 - g ] quinazoline ( B - 2 ) , a member of a series of quinazolines , on the cell survival and growth of the non - small cell lung cancer ( NSCLC ) cell line A549 in vitro and in vivo . Cytotoxicity assay , hollow fiber assay and cell xenograft model experiment revealed that B - 2 showed selective effects on A549 cell survival or growth in a dose - dependent manner . At a dose of 100mg / kg , B - 2 showed stronger efficacy on tumor growth inhibition in nude mice than ___MASK39___ . Exposure of A549 cells to B - 2 caused inhibition of P00533 - dependent P29323 - MAPK activation . In addition , inhibition of cell cycle progression and induction of mitochondria - dependent apoptosis might contribute to present the multitarget pathway of non - small cell lung cancer treatment of B - 2 .", "Effect of acetazolamide on aquaporin - 1 and fluid flow in cultured choroid plexus . ___MASK54___ ( AZA ) , used in treatment of early or infantile hydrocephalus , is effective in some cases , while its effect on the choroid plexus ( CP ) remains ill - defined . The drug reversibly inhibits aquaporin - 4 ( P55087 ) , the most ubiquitous \" water pore \" in the brain , and perhaps modulation of P29972 ( located apically on CP cells ) by AZA may reduce cerebrospinal fluid ( P04141 ) production . We sought to elucidate the effect of AZA on P29972 and fluid flow in CP cell cultures . CP tissue culture from 10 - day Sprague - Dawley rats and a TRCSF - B cell line were grown on Transwell permeable supports and treated with 100 μM AZA . Fluid assays to assess direction and extent of fluid flow , and P29972 expression patterns by immunoblot , Immuncytochemistry ( ICC ) , and quantitative reverse transcriptase polymerase chain reaction ( qRT - PCR ) were performed . Immunoblots and ICC analyses showed a decrease in P29972 protein shortly after AZA treatment ( lowest at 12 h ) , with transient P29972 reduction mediated by mRNA expression ( lowest at 6 h ) . Transwell fluid assays indicated a fluid shift at 2 h , before significant changes in P29972 mRNA or protein levels . Timing of AZA effect on P29972 suggests the drug alters protein transcription , while affecting fluid flow by a concomitant method . It is plausible that other mechanisms account for these phenomena , as the processes may occur independently .", "Induction of granulocytic differentiation in myeloblasts by hydroquinone , a metabolite of benzene , involves the leukotriene D4 receptor . Chronic exposure of humans to benzene ( BZ ) , a Class I carcinogen , causes acute myelogenous leukemia , possibly via its bone marrow metabolite , hydroquinone ( HQ ) . The ability to alter cytokine - dependent growth and differentiation in hematopoietic stem or progenitor cells appears to be a property of agents with leukemogenic potential . We have previously reported that BZ and HQ specifically stimulate granulopoiesis in mice and cause granulocytic differentiation in normal murine interleukin ( IL ) - 3 - dependent , granulocyte colony - stimulating factor ( DB00099 ) - inducible 32D myeloblasts . BZ induces granulocytic differentiation by upregulating the production of leukotriene D4 ( LTD4 ) , an essential intracellular mediator of G - P04141 signaling . We report here that HQ ( 0 . 5 - 4 . 0 microM ) , as well as LTD4 ( 1 nM - 10 microM ) , causes a concentration - dependent induction of granulocytic differentiation in 32D myeloblasts . Unlike LTD4 , which induces terminal granulocytic differentiation , HQ undergoes a myeloperoxidase - dependent oxidation to bioreactive p - benzoquinone ( BQ ) , which induces differentiation predominantly to the myelocyte stage . Studies with the highly specific Q9Y271 antagonist , MK - 571 , suggest that BQ induces granulocytic differentiation in myeloblasts by activating the Q9Y271 , thus obviating the requirement for LTD4 . This was confirmed by the demonstration that HQ , in the presence of LTD4 , shifts the stage - specific pattern of terminal differentiation induced by LTD4 to the incomplete ( myelocyte ) profile induced by HQ . The inability of HQ to induce a complete program of terminal granulocytic differentiation in myeloblasts , as well as its ability to compete with induction by LTD4 , may have a bearing on the leukemogenic potential of BZ .", "Is Q13304 a P2Y / leukotriene receptor ? examination of uracil nucleotides , nucleotide sugars , and cysteinyl leukotrienes as agonists of Q13304 . The orphan receptor Q13304 has been reported to be activated by UDP , UDP - sugars , and cysteinyl leukotrienes , and coupled to intracellular Ca ( 2 +) mobilization and inhibition of DB02527 accumulation , but other studies have reported either a different agonist profile or lack of agonist activity altogether . To determine if Q13304 is activated by uracil nucleotides and leukotrienes , the hemagglutinin - tagged receptor was expressed in five different cell lines and the signaling properties of the receptor were investigated . In P13671 , 1321N1 , or Chinese hamster ovary ( CHO ) cells stably expressing Q13304 , UDP , UDP - glucose , DB03501 , and cysteinyl leukotriene C4 ( LTC4 ) all failed to promote inhibition of forskolin - stimulated DB02527 accumulation , whereas both UDP and UDP - glucose promoted marked inhibition ( > 80 % ) of forskolin - stimulated DB02527 accumulation in P13671 and CHO cells expressing the Q15391 receptor . Likewise , none of these compounds promoted accumulation of inositol phosphates in COS - 7 or human embryonic kidney 293 cells transiently transfected with Q13304 alone or cotransfected with Gαq / i5 , which links Gi - coupled receptors to the Gq - regulated phospholipase C ( P98160 ) signaling pathway , or PLCε , which is activated by the Gα12 / 13 signaling pathway . Moreover , none of these compounds promoted internalization of Q13304 in 1321N1 - Q13304 cells . Consistent with previous reports , coexpression experiments of Q13304 with cysteinyl leukotriene receptor 1 ( Q9Y271 ) suggested that Q13304 acts as a negative regulator of Q9Y271 . Taken together , these data suggest that UDP , UDP - glucose , DB03501 , and LTC4 are not the cognate ligands of Q13304 .", "Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy . The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model . One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin ( 20 mg / kg per os ) . Three hours after indomethacin , the extent of macroscopically visible gastric damage was determined , and gastric LTB4 synthesis was determined . The compounds tested were PF - 5901 , A - 64077 , nordihydroguaiaretic acid , and L - 698 , 037 . Each compound produced dose - related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin - induced damage . The antioxidant properties of these compounds was assessed using an in vitro assay . There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin - induced gastric damage . In the second part of the study , the effects of intravenous , administration of LTD4 and LTB4 receptor antagonists on indomethacin - induced gastric epithelial damage ( measured by permeability to [ 51Cr ] DB00974 ) were assessed . The two Q9Y271 antagonists ( MK - 571 and DB00549 ) significantly reduced the permeability changes induced by indomethacin , while the two LTB4 antagonists ( SC - 41930 and LY - 255 , 283 ) were without significant effect . Despite the reduction of gastric epithelial injury , blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury . These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs . However , it remains unclear to what extent leukotrienes are involved in the initiation of the injury , as opposed to its amplification .", "Bresol inhibits phosphodiesterase 4 gene expression and modulates the levels of select mediators of inflammation in human monocytic cells . Bresol - a poly - herbal formulation , has been reported to be effective against bronchial asthma and allergic rhinitis in children . In vivo studies have supported the anti - histaminic and anti - anaphylactic action of bresol . However , the mechanism of action of bresol in modulation of inflammation has not been studied at the cellular and molecular level . The present study was aimed to elucidate the mechanism ( s ) of action of bresol at the cellular and molecular levels , using human monocyte leukemia cells . The effects of bresol on phosphodiesterase 4B ( Q07343 ) gene expression were analyzed using human monocytic U937 leukemia cells . The ability of bresol to stimulate DB02527 formation in these cells , as well as its effects on mediators of inflammation like tumor necrosis factor - α ( TNFα ) , nitric oxide ( NO ) , and cycloxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated U937 cells , were also studied . The results here indicated that bresol exhibited potential anti - inflammatory properties by inhibiting LPS - induced Q07343 gene expression in the cells . Bresol also dose dependently activated DB02527 formation , and inhibited TNFα , NO , as well as P35354 formation in the LPS - stimulated cells . Based upon the results , we concluded that the reported anti - inflammatory activity of bresol might be attributed to its abilities to inhibit Q07343 and thus elevate DB02527 levels in human monocytes . The anti - inflammatory effects of bresol might also be a result of the capacity of bresol to modulate the formation of TNFα , NO , and P35354 in monocytes .", "Effects of ozone exposure mediated by BEAS - 2B cells on T cells activation : a possible link between environment and asthma . OBJECTIVE : To explore the possible link between ozone and asthma through analyzing Th1 / Th2 differentiation of T cells following incubation with conditioned medium from the BEAS - 2B cells exposed to ozone in vitro . METHOD : Bronchial epithelial cell line , BEAS - 2B , was cultured using an air - liquid interface culture system in a CO2 incubator and exposed to 0 or 0 . 16 or 0 . 25 mg / m3 of ozone for 8 h . The amounts of IL - 1β , P05231 and RANTES in the cell supernatant were detected . The cell culture supernatants were collected and used as conditioned medium in the next experiment . T cells from children recruited were incubated with conditioned medium for 12 h . Activation rate of Q07108 and Th1 / Th2 / Th17 differentiation were analyzed . RESULTS : BEAS - 2B cells exposed to different ozone concentrations showed morphological changes . Cells exposed to 0 . 16 and 0 . 25 mg / m3 ozone produced higher amounts of IL - 1β , P05231 and RANTES than that in the control group . Children with allergic asthma had upregulated expression of genes related with asthma , including P13500 , CCR4 , P19875 , Q9Y271 , Q99665 , Q14627 , Q13478 , P01584 , P10145 , P25025 and O75888 . Q07108 expression in T cells was significantly elevated irrespective of ozone exposure in children with allergic asthma . Following ozone exposure , in asthmatic children group , expression levels of cytokines of Th1 cells were collectively higher than those from Th2 cells . Ozone - exposed conditioned media could slightly increase all the Th1 , Th2 and Th17 cytokines in T cells from allergic asthmatic children . CONCLUSIONS : Our results suggested that Th1 cells activation might be predominant over Th2 activation upon ozone exposure in asthmatic children , which might help to clarify the mechanisms of asthma related to environmental factors like ozone .", "A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK97___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK97___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .", "Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK56___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism ." ]

[ "___MASK35___", "___MASK39___", "___MASK42___", "___MASK54___", "___MASK56___", "___MASK65___", "___MASK82___", "___MASK87___", "___MASK97___" ]

[ "Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques . OBJECTIVES : To investigate the pharmacokinetics ( PK ) of maraviroc , a P51681 - targeted HIV - 1 entry inhibitor , in rhesus macaques following vaginal administration of various maraviroc - loaded aqueous DB11602 ( O14777 ) gels , and to correlate the PK data with efficacy in a single high - dose vaginal SHIV - 162P3 challenge model . METHODS : DB04835 concentrations in vaginal fluid ( Weck - Cel (®) sponge ) , vaginal tissue ( punch biopsy ) and plasma were assessed over 72 h following single - dose vaginal application of various maraviroc - loaded O14777 gels . The range of maraviroc gel concentrations was sufficiently broad ( 0 . 003 % - 3 . 3 % w / w ) that test gels included both fully solubilized and predominantly dispersed formulations . The efficacy of the O14777 gels against a single high - dose vaginal SHIV - 162P3 challenge was also measured , and correlated with the PK concentrations . RESULTS : DB04835 concentrations in vaginal fluid ( range 10 ( 4 )- 10 ( 7 ) ng / mL ) , vaginal tissue ( 100 - 1200 ng / g ) and plasma ( < 10 ( 2 ) ng / mL ) were highly dependent on maraviroc gel loading , irrespective of the form of the maraviroc component within the gel ( solubilized versus dispersed ) . Fluid and plasma concentrations were generally highest 0 . 5 or 2 h after gel application , before declining steadily through to 72 h . DB04835 concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV - 162P3 challenge . Complete protection was achieved with a 3 . 3 % w / w maraviroc gel . CONCLUSIONS : A high degree of correlation between PK and efficacy was observed . Based on the data obtained with the 3 . 3 % w / w maraviroc gel , maintenance of vaginal fluid and tissue levels in the order of 10 ( 7 ) ng / mL and 10 ( 3 ) ng / g , respectively , are required for complete protection with this compound .", "Differential involvement of Galpha16 in CC chemokine - induced stimulation of phospholipase Cbeta , P29323 , and chemotaxis . Chemokines are known to regulate the chemotaxis of leukocytes and play an important role in immunological processes . Chemokine receptors are widely distributed in hematopoietic cells and are often co - localized with the hematopoietic - specific G ( 16 ) and its close relative , G ( 14 ) . Yet , many chemokine receptors utilize pertussis toxin - sensitive G ( i ) proteins for signaling . Given that both G ( 16 ) and G ( 14 ) are capable of linking G ( i )- coupled receptors to the stimulation of phospholipase Cbeta , we examined the capacity of six CC chemokine receptors ( P32246 , CCR2a , CCR2b , P51677 , P51681 and P32248 ) to interact with G ( 14 ) and G ( 16 ) in a heterologous expression system . Among the CC chemokine receptors tested , P32246 , CCR2b , and P51677 were capable of mediating chemokine - induced stimulation of phospholipase Cbeta via either G ( 14 ) or G ( 16 ) . The G ( 14 )/ G ( 16 )- mediated responses exhibited CC chemokine dose - dependency and were resistant to pertussis toxin ( PTX ) treatment . In contrast , CCR2a , P51681 and P32248 were unable to interact with G ( 14 ) and G ( 16 ) . Under identical experimental conditions , all six CC chemokine receptors were fully capable of inhibiting adenylyl cyclase via G ( i ) as well as stimulating phospholipase Cbeta via 16z44 , a G ( 16 / z ) chimera that possesses increased promiscuity toward G ( i )- coupled receptors . Moreover , P32246 - mediated P27361 / 2 phosphorylation was largely PTX - insensitive in THP - 1 monocytic cells that endogenously express Galpha ( 16 ) . In addition , P32246 agonist was less efficacious in mediating chemotaxis of THP - 1 cells following the knockdown of Galpha ( 16 ) by overexpressing siRNA , indicating the participation of Galpha ( 16 ) in P32246 - induced cell migration . These results show that different CC chemokine receptors can discriminate against G ( 14 ) and G ( 16 ) for signal transduction .", "Improved metastasis - free survival in nonadjuvantly treated postmenopausal breast cancer patients with chemokine receptor 5 del32 frameshift mutations . The CC - chemokine receptor P51681 has been associated with cancer progression and metastasis . P51681 blockers such as DB04835 are tested in metastatic cancer patients . A mutant allele of P51681 , P51681 - delta32 ( CCR5del32 ) , which encodes for a protein with a trans - dominant negative effect on the wildtype protein , is frequently found in populations of northern European origin . We set out to determine if the CCR5del32 genotype is associated with progression of breast cancer . Here , we genotyped 414 breast cancer patients and investigated whether the P51681 genotype had an association with the likelihood to metastasize within specific subgroups of this cohort . The findings were subsequently confirmed in an independent cohort of 1 , 017 breast cancer patients . Specifically within the postmenopausal subgroup of the initial cohort ( n = 325 ) individuals carrying the CCR5del32 genotype exhibited a significantly longer metastasis - free survival ( MFS , p = 0 . 038 ) . In an independent cohort , CCR5del32 genotype was confirmed to be associated with prolonged MFS only in postmenopausal patients ( n = 579 , hazard ratio [ HR ] = 0 . 61 , 95 % confidence interval [ 95 % CI ] = 0 . 38 - 0 . 99 , p = 0 . 044 ) , and not in premenopausal patients ( n = 438 , HR = 1 . 01 , 95 % CI = 0 . 70 - 1 . 48 , p = 0 . 94 ) . Our results indicate that CCR5del32 genotype is associated with good prognosis in postmenopausal breast cancer patients . Considering this result , postmenopausal breast cancer patients who are wildtype for P51681 genotype might benefit from P51681 blockers , such as DB04835 .", "Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( DB02901 ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .", "A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK21___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .", "Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK85___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .", "Recall antigen activation induces prompt release of P51681 ligands from PBMC : implication in memory responses and immunization . P51681 ligands RANTES , macrophage inflammatory protein ( MIP ) - 1alpha and MIP - 1beta are potent and specific inhibitors of strains of human immunodeficiency virus ( HIV ) that use P51681 as a receptor , which are the strains most involved in primary infection . Recently , we observed that release of P51681 ligands is a consistent and reproducible parameter of response to antigen activation in studies using PBMC . In this study , we show that P51681 ligands are released upon antigen [ Fragment C of tetanus toxin ( TTC ) ] stimulation in 81 % ( n = 16 ) of subjects tested , as detected by a standard ELISA in tissue culture supernatants of antigen - activated cells . In contrast , ELISA for other cytokines from the same supernatants revealed that P01579 release could be detected only in 31 % of subjects , P60568 could be detected only in 12 % of the subjects and P05112 was not detectable in any of the subjects tested . Similarly , proliferative responses to TTC , as measured by a standard tritiated thymidine incorporation assay , were detectable in only 56 % of the subjects . Similar observations have been reported in flow cytometric studies , and resonate with previous findings emphasizing the role of P51681 in T cell responses . In addition , the levels of P51681 ligands in supernatants from antigen - activated cells were sufficient to inhibit infection of R5 HIV . Thus , P51681 ligands might play a role in controlling HIV in vivo . Taken together , these observations suggest that P51681 ligands , and in particular MIP - 1alpha and MIP - 1beta , released in the course of memory responses may play a role in protecting P01730 (+) memory T cells from infection .", "Migration of Th1 lymphocytes is regulated by P16410 ( P16410 ) - mediated signaling via P19957 kinase - dependent Akt activation . Efficient adaptive immune responses require the localization of T lymphocytes in secondary lymphoid organs and inflamed tissues . To achieve correct localization of T lymphocytes , the migration of these cells is initiated and directed by adhesion molecules and chemokines . It has recently been shown that the inhibitory surface molecule P16410 ( P16410 ) initiates Th cell migration , but the molecular mechanism underlying this effect remains to be elucidated . Using P01730 T lymphocytes derived from OVA - specific TCR transgenic P16410 - deficient and P16410 - competent mice , we demonstrate that chemokine - triggered signal transduction is differentially regulated by P16410 via phosphoinositide 3 - kinase ( PI3K ) - dependent activation of protein kinase B ( P31749 / Akt ) . In the presence of P16410 signaling , the chemoattractant P13236 selectively induces the full activation of Akt via phosphorylation at threonine 308 and serine 473 in pro - inflammatory Th lymphocytes expressing the cognate chemokine receptor P51681 . Akt signals lead to cytoskeleton rearrangements , which are indispensable for migration . Therefore , this novel Akt - modulating function of P16410 signals affecting T cell migration demonstrates that boosting P16410 or its down - stream signal transduction could aid therapies aimed at sensitizing T lymphocytes for optimal migration , thus contributing to a precise and effective immune response .", "Blockade of lymphocyte chemotaxis in visceral graft - versus - host disease . BACKGROUND : Graft - versus - host disease ( GVHD ) is a major barrier to successful allogeneic hematopoietic stem - cell transplantation ( HSCT ) . The chemokine receptor P51681 appears to play a role in alloreactivity . We tested whether P51681 blockade would be safe and limit GVHD in humans . METHODS : We tested the in vitro effect of the P51681 antagonist maraviroc on lymphocyte function and chemotaxis . We then enrolled 38 high - risk patients in a single - group phase 1 and 2 study of reduced - intensity allogeneic HSCT that combined maraviroc with standard GVHD prophylaxis . RESULTS : DB04835 inhibited P51681 internalization and lymphocyte chemotaxis in vitro without impairing T - cell function or formation of hematopoietic - cell colonies . In 35 patients who could be evaluated , the cumulative incidence rate ( ± SE ) of grade II to IV acute GVHD was low at 14 . 7 ± 6 . 2 % on day 100 and 23 . 6 ± 7 . 4 % on day 180 . Acute liver and gut GVHD were not observed before day 100 and remained uncommon before day 180 , resulting in a low cumulative incidence of grade III or IV GVHD on day 180 ( 5 . 9 ± 4 . 1 % ) . The 1 - year rate of death that was not preceded by disease relapse was 11 . 7 ± 5 . 6 % without excessive rates of relapse or infection . Serum from patients receiving maraviroc prevented P51681 internalization by P13501 and blocked T - cell chemotaxis in vitro , providing evidence of antichemotactic activity . CONCLUSIONS : In this study , inhibition of lymphocyte trafficking was a specific and potentially effective new strategy to prevent visceral acute GVHD . ( Funded by Pfizer and others ; ClinicalTrials . gov number , NCT00948753 . ) .", "Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK71___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .", "[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK25___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .", "The antimicrobial peptide dermaseptin S4 inhibits HIV - 1 infectivity in vitro . Most of HIV - 1 infections are acquired through sexual contact . In the absence of a preventive vaccine , the development of topical microbicides that can block infection at the mucosal tissues is needed . Dermaseptin S4 ( DS4 ) is an antimicrobial peptide derived from amphibian skin , which displays a broad spectrum of activity against bacteria , yeast , filamentous fungi , and herpes simplex virus type 1 . We show here that DS4 inhibits cell - free and cell - associated HIV - 1 infection of P4 - P51681 indicator cells and human primary T lymphocytes . The peptide is effective against R5 and X4 primary isolates and laboratory - adapted strains of HIV - 1 . Its activity is directed against HIV - 1 particles by disrupting the virion integrity . Increasing the number of DS4 - positive charges reduced cytotoxicity without affecting the antiviral activity . The modified DS4 inhibited HIV - 1 capture by dendritic cells and subsequent transmission to P01730 (+) T cells , as well as HIV - 1 binding on O14777 - 1 endometrial cells and transcytosis through a tight epithelial monolayer .", "Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .", "DB09280 - ___MASK56___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .", "Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13 . Autosomal dominant hypophosphatemic rickets ( P30518 ) is an inherited disorder of isolated renal phosphate wasting , the pathogenesis of which is unknown . We performed a genome - wide linkage study in a large kindred to determine the chromosome location of the P30518 gene . Two - point LOD scores indicate that the gene is linked to the markers D12S314 [ Z ( theta ) = 3 . 15 at theta = 0 . 0 ] , vWf [ Z ( theta ) = 5 . 32 at theta = 0 . 0 ] , and P01730 [ Z ( theta ) = 3 . 53 at theta = 0 . 0 ] . Moreover , multilocus analysis indicates that the P30518 gene locus is located on chromosome 12p13 in the 18 - cM interval between the flanking markers D12S100 and D12S397 . These data are the first to establish a chromosomal location for the P30518 locus and to provide a framework map to further localize the gene . Such studies will permit ultimate identification of the P30518 gene and provide further insight into phosphate homeostasis .", "Primary resistance of P51681 - tropic HIV - 1 to maraviroc can not be predicted by the V3 sequence . OBJECTIVES : Resistance of HIV - 1 to P51681 antagonists can occur without coreceptor switching by mutations in envelope glycoproteins that enable virus entry using the inhibitor - bound form of P51681 . We investigated whether mutations in the V3 region of HIV - 1 from subjects naive to maraviroc could be associated with primary resistance to this drug . METHODS : The frequency of P51681 - tropic HIV - 1 subtype B isolates harbouring putative V3 maraviroc resistance mutations was assessed among the HIV tropism database of Toulouse University Hospital , France . Phenotypic assessment of maraviroc susceptibility was performed for 14 isolates representative of the main mutation patterns and 14 controls . V3 mutations were reversed or introduced by site - directed mutagenesis . RESULTS : Ninety - three of 951 ( 9 . 8 % ) isolates harboured V3 mutations assumed to be associated with maraviroc resistance . DB04835 completely blocked virus entry for all but 1 of the 14 isolates harbouring V3 mutations [ IC50 8 . 6 nM ; 95 % CI ( 6 . 6 - 47 . 4 ) ] , as in the 14 control isolates [ IC50 13 . 4 nM ; 95 % CI ( 7 . 7 - 50 . 3 ) ] ( P = 0 . 24 ) . Primary resistance to maraviroc , with a plateau in entry inhibition , was found in one isolate ( harbouring a 20F / 21I genotype ) . Site - directed mutagenesis showed that V3 mutations are necessary but not sufficient to induce maraviroc resistance . CONCLUSIONS : The impact of V3 mutations depended on the env context in which they occurred . Simple assessment of the V3 genotype thus can not accurately predict maraviroc resistance . Rather , phenotypic assessment of virus particles expressing the envelope glycoprotein as a whole is required . This approach revealed that primary resistance of P51681 - tropic HIV - 1 subtype B isolates to maraviroc seems uncommon .", "Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case - control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme - linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0 . 88 ( 95 % CI 0 . 84 - 0 . 93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays .", "P51681 antagonist TD - 0680 uses a novel mechanism for enhanced potency against HIV - 1 entry , cell - mediated infection , and a resistant variant . Regardless of the route of transmission , R5 - tropic HIV - 1 predominates early in infection , rendering P51681 ( P51681 ) antagonists as attractive agents not only for antiretroviral therapy but also for prevention . Here , we report the specificity , potency , and underlying mechanism of action of a novel small molecule P51681 antagonist , TD - 0680 . TD - 0680 displayed the greatest potency against a diverse group of R5 - tropic HIV - 1 and SIV strains when compared with its prodrug , TD - 0232 , the Food and Drug Administration - approved P51681 antagonist DB04835 , and P50750 - 779 , with EC ( 50 ) values in the subnanomolar range ( 0 . 09 - 2 . 29 nm ) . Importantly , TD - 0680 was equally potent at blocking envelope - mediated cell - cell fusion and cell - mediated viral transmission as well as the replication of a P50750 - 779 / DB04835 - resistant HIV - 1 variant . Interestingly , TD - 0232 and TD - 0680 functioned differently despite binding to a similar transmembrane pocket of P51681 . Site - directed mutagenesis , drug combination , and antibody blocking assays identified a novel mechanism of action of TD - 0680 . In addition to binding to the transmembrane pocket , the unique exo configuration of this molecule protrudes and sterically blocks access to the extracellular loop 2 ( ECL2 ) region of P51681 , thereby interrupting the interaction between virus and its co - receptor more effectively . This mechanism of action was supported by the observations of similar TD - 0680 potency against P01730 - dependent and - independent SIV strains and by molecular docking analysis using a P51681 model . TD - 0680 , therefore , merits development as an anti - HIV - 1 agent for therapeutic purposes and / or as a topical microbicide for the prevention of sexual transmission of R5 - tropic HIV - 1 .", "[ DB04835 : clinical trials results ] . Just over a decade after identification of chemokine receptors P51681 and P61073 as coreceptors for HIV , maraviroc ( Celsentri ) , the first P51681 antagonist , has recently obtained its Marketing Authorization in the United States and Europe , for treatment of treatment - experienced adult patients infected with only P51681 - tropic HIV - 1 detectable . P51681 antagonists , after fusion inhibitor enfuvirtide available since 2003 , also belong to entry inhibitors . These molecules , unlike previous antiretrovirals , do not target the virus but its target cell by blocking viral penetration . DB04835 has shown its clinical efficacy in patients failing other antiretroviral classes . Its safety profile was similar to placebo in two large phase III trials . However , careful assessment of both hepatic and immunologic safety of this new therapeutic class is needed . Viral tropism testing has to be investigated before using maraviroc in the clinic , because P51681 antagonists are not active against P61073 viruses . For the moment indicated for the treatment - experienced patient population , maraviroc could in the future benefit to other types of patients , depending on ongoing trials results .", "Coactivators for the orphan nuclear receptor RORalpha . A mutation in the nuclear orphan receptor RORalpha results in a severe impairment of cerebellar development by unknown mechanisms . We have shown previously that RORalpha contains a strong constitutive activation domain in its C terminus . We therefore searched for mammalian RORalpha coactivators using the minimal activation domain as bait in a two - hybrid screen . Several known and putative coactivators were isolated , including glucocorticoid receptor - interacting protein - 1 ( Q9Y3R0 ) and peroxisome proliferator - activated receptor ( Q07869 ) - binding protein ( PBP / Q15648 / Q15648 ) . These interactions were confirmed in vitro and require the intact activation domain of RORalpha although different requirements for interaction with Q9Y3R0 and PBP were detected . Even in the absence of exogenous ligand , RORalpha interacts with a complex or complexes of endogenous proteins , similar to those that bind to ligand - occupied thyroid hormone and vitamin D receptors . Both PBP and Q9Y3R0 were shown to be present in these complexes . Thus we have identified several potential RORalpha coactivators that , in contrast to the interactions with hormone receptors , interact with RORalpha in yeast , in bacterial extracts , and in mammalian cells in vivo and in vitro in the absence of exogenous ligand . Q9Y3R0 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells . Thus , Q9Y3R0 is the first proven coactivator for RORalpha .", "The use of intraallelic variability for testing neutrality and estimating population growth rate . To better understand the forces affecting individual alleles , we introduce a method for finding the joint distribution of the frequency of a neutral allele and the extent of variability at closely linked marker loci ( the intraallelic variability ) . We model three types of intraallelic variability : ( a ) the number of nonrecombinants at a linked biallelic marker locus , ( b ) the length of a conserved haplotype , and ( c ) the number of mutations at a linked marker locus . If the population growth rate is known , the joint distribution provides the basis for a test of neutrality by testing whether the observed level of intraallelic variability is consistent with the observed allele frequency . If the population growth rate is unknown but neutrality can be assumed , the joint distribution provides the likelihood of the growth rate and leads to a maximum - likelihood estimate . We apply the method to data from published data sets for four loci in humans . We conclude that the Delta32 allele at P51681 and a disease - associated allele at P40692 arose recently and have been subject to strong selection . Alleles at PAH appear to be neutral and we estimate the recent growth rate of the European population to be approximately 0 . 027 per generation with a support interval of ( 0 . 017 - 0 . 037 ) . Four of the relatively common alleles at P13569 also appear to be neutral but DeltaF508 appears to be significantly advantageous to heterozygous carriers .", "___MASK40___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK40___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK40___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK40___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK40___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .", "A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .", "Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK99___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "A validated HPLC - MS method for quantification of the P51681 inhibitor maraviroc in HIV + human plasma . DB04835 is a P51681 inhibitor approved in 2007 for treatment of therapy experienced adult patients infected with P51681 - tropic HIV - 1 virus . International guidelines for HIV therapy indicate a plasma concentration cutoff of maraviroc for response . We developed and validated a new HPLC - MS method to quantify maraviroc concentrations in human plasma . 6 , 7 - Dimethyl - 2 , 3 - di ( 2 - pyridyl ) quinoxaline was used as internal standard and added to 100μL of plasma . Samples were then treated with 500μL of acetonitrile for the protein precipitation procedure . An analytical DB00279 Atlantis column ( 150mm × 4 . 6mm i . d . ) with a particle size of 5μm was used to separate the compounds and ions were detected at m / z 257 . 5 and 313 . 3 for maraviroc and quinoxaline respectively . The calibration curve was linear up to 2500ng / mL . The mean recovery of maraviroc was 89 . 1 % . All validation data results were in accordance to Food and Drug Administration and European Medicines Agency requirements . The HPLC - MS method reported here could be used routinely to monitor plasma concentrations of maraviroc in HIV - infected patients .", "DB04835 attenuates trauma - hemorrhage - induced hepatic injury through Q07869 gamma - dependent pathway in rats . DB04835 is a CC - chemokine receptor 5 ( P51681 ) antagonist with potent antiviral and cancer preventive effects . Recent evidence suggests that the co - existence of P51681 in various cell types is involved in inflammation . However , the effects that P51681 antagonists produce in trauma - hemorrhage remain unknown . The peroxisome proliferator - activated receptor gamma ( Q07869 ( γ ) ) pathway exerts anti - inflammatory effects in injury . In this study , we hypothesized that maraviroc administration in male rats , after trauma - hemorrhage , decreases cytokine production and protects against hepatic injury through a Q07869 ( γ )- dependent pathway . Male Sprague - Dawley rats underwent trauma - hemorrhage ( mean blood pressure maintained at approximately 35 - 40 mmHg for 90 minutes ) , followed by fluid resuscitation . During resuscitation , a single dose of maraviroc ( 3 mg / kg , intravenously ) with and without a Q07869 ( γ ) antagonist GW9662 ( 1 mg / kg , intravenously ) , GW9662 or vehicle was administered . Plasma alanine aminotransferase ( ALT ) with aspartate aminotransferase ( Q9NRA2 ) concentrations and various hepatic parameters were measured ( n = 8 rats / group ) at 24 hours after resuscitation . The results showed that trauma - hemorrhage increased hepatic myeloperoxidase activity , intercellular adhesion molecule - 1 and interleukin - 6 levels , and plasma ALT and Q9NRA2 concentrations . These parameters were significantly improved in the maraviroc - treated rats subjected to trauma - hemorrhage . DB04835 treatment also increased hepatic Q07869 ( γ ) expression compared with vehicle - treated trauma - hemorrhaged rats . Co - administration of GW9662 with maraviroc abolished the maraviroc - induced beneficial effects on the above parameters and hepatic injury . These results suggest that the protective effect of maraviroc administration on alleviation of hepatic injury after trauma - hemorrhage , which is , at least in part , through Q07869 ( γ )- dependent pathway .", "Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with P01730 + cell rises in HIV - infected patients . BACKGROUND : DB04835 treatment for HIV - 1 infected patients results in larger P01730 (+) T cell rises than are attributable to its antiviral activity alone . We investigated whether this is due to modulation of T cell activation and inflammation . METHODS AND FINDINGS : Thirty maraviroc - treated patients from the DB04835 versus Efavirenz Regimens as Initial Therapy ( MERIT ) study were randomly selected from among those who had P51681 - tropic ( R5 ) HIV on screening and achieved undetectable HIV RNA ( < 50 copies / mL ) by Week 48 . Efavirenz - treated controls were matched for baseline characteristics to the maraviroc - treated patients selected for this substudy . Changes in immune activation and inflammation markers were examined for associations with P01730 (+) T cell changes . DB04835 treatment tended to result in more rapid decreases in P28907 expression on P01730 (+) T cells and in plasma D - dimer concentrations than did treatment with efavirenz . The proportion of patients with high - sensitivity P02741 > 2 µg / mL increased from 45 % to 66 % in the efavirenz arm , but remained constant in the maraviroc arm ( P = 0 . 033 ) . Decreases in P28907 expression on CD8 (+) T cells were correlated with P01730 (+) T cell rises for maraviroc treatment ( r = - 0 . 4 , P = 0 . 048 ) , but not for treatment with efavirenz . CONCLUSIONS : DB04835 - treated patients had earlier , modest decreases in certain markers of immune activation and inflammation , although in this small study , many of the differences were not statistically significant . Levels of high - sensitivity P02741 remained constant in the maraviroc arm and increased in the efavirenz arm . Decreases in immune activation correlated with increased P01730 (+) T cell gains . TRIAL REGISTRATION : ClinicalTrials . gov NCT00098293 .", "P02771 contributes to THP - 1 cell invasion and chemotaxis via protein kinase and Gi - protein - dependent pathways . P02771 ( AFP ) for long was known as immunomodulator and tumor marker having multifaceted actions on the activity of normal and transformed cells . In present study , we have investigated the involvement of AFP in regulation of THP - 1 cell line invasion and underlying mechanisms . Treatment with human recombinant AFP causes up - regulation of P14780 expression , chemotaxis and calcium mobilization , and increases invasion through Matrigel , with no significant impact on THP - 1 cell growth or viability . Using small molecule inhibitors , we have shown that the rhAFP - induced P14780 expression depends on the activation of P27361 , 2 , JNK and Akt kinases , with the involvement of NFκB and likely , AP - 1 transcription factors . In contrast , inhibition of p38 kinase , but not of JNK , had dramatic suppressive effect on the rhAFP - triggered chemotaxis . In addition , rhAFP - induced P14780 expression and calcium response were completely blocked by pertussis toxin , indicating that Gi - protein - coupled receptor ( s ) has a mediatory role in these processes . P51681 chemokine receptor is the only known Gi - protein binding to AFP . The action of P51681 inhibitor DB04835 results in partial suppression of P14780 up - regulation and calcium response suggesting that P51681 might be involved in these effects .", "Enhancement of OX40 - induced apoptosis by P01375 coactivation in OX40 - expressing T cell lines in vitro leading to decreased targets for HIV type 1 production . OX40 , a member of the tumor necrosis factor receptor ( P01375 - R ) superfamily , has been shown to play an important role in the survival of antigen - specific P01730 (+) T cells . We have previously reported that stimulation of the OX40 - expressing and HIV - 1 chronically infected T cell line , ACH - 2 / OX40 , with either P23510 ( P23510 ) - expressing cells or with P01375 resulted in the activation of HIV - 1 followed by apoptotic cell death . In the present study we found that costimulation via OX40 and P01375 - R in OX40 - expressing HIV - 1 - infected T cell lines leads to a marked reduction of HIV - 1 production associated with rapid cell death . Since HIV - 1 - negative OX40 (+) T cell lines underwent rapid apoptotic cell death after P23510 and P01375 stimulation , it was reasoned that the ACH - 2 / OX40 cell death was unlikely to be due to HIV - 1 infection . Furthermore , we found that the OX40 - mediated apoptosis of the P01730 (+) T cell line , Molt - 4 / P51681 - OX40 ( M / R5 - OX40 ) , required ( 1 ) signals mediated via the cytoplasmic tail of OX40 , ( 2 ) activation of the caspase cascade , including caspase - 8 and caspase - 3 , and ( 3 ) induction of endogenous P01375 , but not of P01374 , P48023 , or P50591 ( P50591 ) , suggesting that this apoptosis occurred indirectly via the P01375 / P01375 - R system . Finally , a fraction of primary activated P01730 (+) T cells , expressing high levels of OX40 , underwent apoptosis , as revealed by annexin V staining , after cocultivation with P23510 (+) cells . These results suggest a new biological role of the P23510 / OX40 system in controlling the fate of activated P01730 (+) T cells and of controlling HIV - 1 infection in inflammatory environments .", "In vitro cell death of activated lymphocytes in Omenn ' s syndrome . Omenn ' s syndrome ( OS ) is characterized by erythrodermia , hepatosplenomegaly , lymphadenopathy , hypereosinophilia and elevated IgE levels associated with increased susceptibility to severe infections . Peripheral blood T cells , though usually present in normal number , show an activated phenotype ( including an increased expression of CD95 / Fas ) , a Th2 pattern of cytokine secretion and defective proliferative response to mitogens . In this report , we demonstrate that T cells from patients with OS undergo an excessive cell death in vitro resulting from two mechanisms . First , a substantial number of peripheral blood lymphocytes from OS patients die in unstimulated cultures ( p = 0 . 009 vs . healthy controls ) . This spontaneous apoptosis is associated with reduced expression of bcl - 2 gene product ( p < 0 . 05 ) and can be prevented by addition of interleukin ( IL ) - 2 ( which also prevents down - modulation of bcl - 2 ) , while is independent from CD95 signaling . Second , lymphocytes from OS patients are highly susceptible to activation - induced cell death ( AICD ) induced with mitogens . This mechanism is largely independent from P60568 , while it can be significantly inhibited blocking CD95 with an IgG2b monoclonal antibody ( mAb ) . The dependence of AICD from signals transduced via CD95 was confirmed showing that cross - linking CD95 with an IgM mAb induces a higher cell death in purified P01730 + CD45R0 + cells from OS patients than in controls ( comparable for CD95 expression ) . Both mechanisms of cell death observed in this study result from lymphocyte hyperactivation occurring in vivo in these patients and may contribute to functional T cell defects of OS .", "P05231 trans - signaling via P40763 directs T cell infiltration in acute inflammation . Interleukin ( IL ) - 6 signaling through its soluble receptor ( P05231 transsignaling ) directs transition between innate and acquired immune responses by orchestrating the chemokine - directed attraction and apoptotic clearance of leukocytes . Through analysis of mononuclear cell infiltration in WT and P05231 - deficient mice during peritoneal inflammation , we now report that P05231 selectively governs T cell infiltration by regulating chemokine secretion ( P02778 , P13236 , P13501 , P51671 , and Q92583 ) and chemokine receptor ( P51677 , CCR4 , P51681 , and P49682 ) expression on the CD3 + infiltrate . Although blockade of P05231 trans - signaling prevented chemokine release , chemokine receptor expression remained unaltered suggesting that this response is regulated by P05231 itself . To dissect the signaling events promoting T cell migration , inflammation was established in knock - in mice expressing mutated forms of the universal signal - transducing element for P05231 - related cytokines P40189 . In mice ( gp130Y757F / Y757F ) deficient in SHP2 and O14543 binding , but presenting hyperactivation of P42224 / 3 , T cell recruitment and P13501 expression was enhanced . Conversely , both of these parameters were suppressed in mice with ablated P40189 - mediated P42224 / 3 activation ( gp130DeltaSTAT / DeltaSTAT ) . T cell migration was related to P40763 activity , because monoallelic deletion of Stat3 in P40189 ( Y757F / Y757F ) mice ( gp130Y757F / Y757F : Stat3 +/- ) corrected the exaggerated responses observed in gp130Y757F / Y757F mice . Consequently , P40763 plays a defining role in P05231 - mediated T cell migration .", "A validated high - performance liquid chromatography - ultraviolet method for quantification of the P51681 inhibitor maraviroc in plasma of HIV - infected patients . DB04835 is the first commercialized P51681 inhibitor for HIV therapy . A new high - performance liquid chromatography - ultraviolet method to quantify maraviroc concentrations in human plasma was developed and validated . The method is based on a protein precipitation procedure , with an acidic solution of acetonitrile ( trifluoroacetic acid 0 . 1 % ) and quinoxaline as internal standard . The analytes were eluted using a gradient run in 15 minutes on an analytical C18 Luna column ( 150 mm x 4 . 6 mm ID ) with a particle size of 5 mum . DB04835 and internal standard were detected by UV at 193 nm and 352 nm , respectively . The calibration curve was linear up to 2500 ng / mL . The mean recovery of maraviroc was 96 % . All validation data were in accordance with U . S . Food and Drug Administration requirements . The new high - performance liquid chromatography - ultraviolet method reported here could be used routinely to monitor plasma concentrations of maraviroc in healthy volunteers and HIV - infected patients .", "Computational study on the interaction between P51681 and HIV - 1 entry inhibitor maraviroc : insight from accelerated molecular dynamics simulation and free energy calculation . P51681 ( P51681 ) is the co - receptor of human immunodeficiency virus type 1 ( HIV - 1 ) and plays an important role in HIV - 1 virus infection . DB04835 has been proved to be effective for anti - HIV - 1 by targeting P51681 . Understanding the detailed interaction mechanism between P51681 and DB04835 will be of great help to the rational design of a more potential inverse agonist to block HIV - 1 infection . Here , we performed molecular dynamics ( MD ) simulation and accelerated MD simulation ( aMD ) to study the interaction mechanism between P51681 and DB04835 based on a recently reported crystal structure . The results of MD simulation demonstrate that DB04835 can form stable hydrogen bonds with residues Tyr37 ( 1 . 39 ) , Tyr251 ( 6 . 51 ) and Glu283 ( 7 . 39 ) . The results of aMD simulation indicate that the carboxamide moiety is more flexible than the tropane group of DB04835 in the pocket of P51681 . The electrostatic potential analysis proves that DB04835 can escape from the pocket of P51681 along the negative electrostatic potential pathway during the dissociation process . The free energy calculation illustrates that there exist three binding pockets during the dissociation process of DB04835 . Our results will be useful for understanding the interaction mechanism between P51681 and DB04835 as well as for the rational design of a more potent inverse agonist .", "Multifaceted mechanisms of HIV inhibition and resistance to P51681 inhibitors PSC - RANTES and DB04835 . Small - molecule P51681 antagonists , such as maraviroc ( MVC ) , likely block HIV - 1 through an allosteric , noncompetitive inhibition mechanism , whereas inhibition by agonists such as PSC - RANTES is less defined and may involve receptor removal by cell surface downregulation , competitive inhibition by occluding the HIV - 1 envelope binding , and / or allosteric effects by altering P51681 conformation . We explored the inhibitory mechanisms of maraviroc and PSC - RANTES by employing pairs of virus clones with differential sensitivities to these inhibitors . Intrinsic PSC - RANTES - resistant virus ( YA versus RT ) or those selected in PSC - RANTES treated macaques ( M584 versus P09131 - 4 ) only displayed resistance in multiple - cycle assays or with a P51681 mutant that can not be downregulated . In single - cycle assays , these HIV - 1 clones displayed equal sensitivity to PSC - RANTES inhibition , suggesting effective receptor downregulation . Prolonged PSC - RANTES exposure resulted in desensitization of the receptor to internalization such that increasing virus concentration ( substrate ) could saturate the receptors and overcome PSC - RANTES inhibition . In contrast , resistance to MVC was observed with the MVC - resistant HIV - 1 ( R3 versus S2 ) in both multiple - and single - cycle assays and with altered virus concentrations , which is indicative of allosteric inhibition . MVC could also mediate inhibition and possibly resistance through competitive mechanisms .", "DB04835 reduces the regulatory T - cell frequency in antiretroviral - naive HIV - infected subjects . BACKGROUND : DB04835 is the first antiretroviral ( O00253 ) drug to target a human protein , the P51681 coreceptor ; however , the mechanisms of maraviroc - associated immunomodulation in human immunodeficiency virus ( HIV ) - infected subjects remain to be elucidated . Regulatory T cells ( Tregs ) play a key role in HIV - associated immunopathology and are susceptible to maraviroc - mediated P51681 blockade . Our aim was to evaluate the effect of maraviroc on Tregs . METHODS : We compared the effect of maraviroc - containing or - sparing combination O00253 ( cART ) on Tregs in O00253 - naive , HIV - infected subjects . Tregs were characterized as P01730 (+) CD25 ( hi ) FoxP3 (+) on day 0 , 8 , and 30 . Additional analysis on week 48 was performed in a subgroup of patients . The potential reduction in the frequency of Tregs among maraviroc - treated peripheral blood mononuclear cells ( PBMCs ) was also tested in vitro . The suppressive function of Tregs was also analyzed in maraviroc - treated Tregs . RESULTS : We found that maraviroc significantly reduced the Treg frequency in both the short term and 1 year after treatment initiation . In vitro experiments showed a dose - dependent reduction in the Treg frequency after treatment of PBMCs with maraviroc , although their in vitro suppressive function was not altered . CONCLUSIONS : These findings partially explain maraviroc - associated immunomodulatory effects and open new therapeutic expectations for the development of Treg - depleting immunotherapies .", "Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK52___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK52___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK52___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .", "DB04835 concentrations in cerebrospinal fluid in HIV - infected patients . OBJECTIVE : To determine maraviroc ( MVC ) concentrations in cerebrospinal fluid ( P04141 ) in HIV - infected patients . METHODS : Twelve P51681 + HIV - 1 adult antiretroviral - experienced patients receiving MVC - containing regimens for at least 1 month were enrolled . Both P04141 and blood samples were taken around 12 hours after the last MVC dose . liquid chromatography tandem mass spectrometry was used to determine MVC concentrations , and HIV - 1 viral load was determined by real - time polymerase chain reaction , ( LOD , 40 copies / mL ) . RESULTS : Twelve blood and 12 P04141 samples were collected . Median P01730 count was 281 ( 120 - 759 ) cells per microliter , and median HIV - 1 viral load was < 40 copies per milliliter . Median time on MVC was 13 . 5 weeks ( 4 - 60 ) . Nucleoside analogues ( tenofovir / didanosine ) were given in only 1 case . Median MVC concentrations in plasma were 124 . 75 ( 7 . 3 - 517 ) ng / mL . In all except one , P04141 sample - receiving an erroneous MVC dose while taking concomitantly nevirapine - MVC concentrations [ 2 . 58 ( < 0 . 5 - 7 . 22 ) ng / mL ] were within the EC ( 90 ) range ( 0 . 06 - 10 . 70 ) . Median MVC P04141 : plasma ratio was 0 . 022 ( 0 . 004 - 0 . 17 ) , and when the free MVC plasma concentration was used , 0 . 094 ( 2 . 58 - 27 . 44 ) . P04141 viral load was < 40 copies per milliliter in all 9 patients with undetectable plasma viral load . CONCLUSIONS : MVC achieves concentrations within the EC ( 90 ) range in P04141 . All patients with undetectable plasma viral load although receiving nucleoside - sparing regimens including new drugs showed viral suppression in P04141 .", "Retinoblastoma protein induction by HIV viremia or P51681 in monocytes exposed to HIV - 1 mediates protection from activation - induced apoptosis : ex vivo and in vitro study . We have previously described an antiapoptotic steady - state gene expression profile in circulating human monocytes from asymptomatic viremic HIV (+) donors , but the mechanism associated with this apoptosis resistance remains to be fully elucidated . Here , we show that Rb1 activation is a dominant feature of apoptosis resistance in monocytes exposed to HIV - 1 in vivo ( as measured ex vivo ) and in vitro . Monocytes from asymptomatic viremic HIV (+) individuals show a positive correlation between levels of hypophosphorylated ( active ) Rb1 and VL in conjunction with increases in other p53 - inducible proteins associated with antiapoptosis regulation , such as P38936 and P05121 ( P05121 ) , when compared with circulating monocytes from uninfected donors . Monocytes exposed in vitro to HIV - 1 R5 isolates but not X4 isolates showed lower caspase - 3 activation after apoptosis induction , indicating a role for the P51681 signaling pathway . Moreover , monocytes exposed to R5 HIV - 1 or MIP - 1 β induced Rb1 and P38936 expression and an accumulation of autophagy markers , LC3 and Beclin . The inhibition of Rb1 activity in HIV - 1 R5 viral - exposed monocytes using siRNA led to increased apoptosis sensitivity , thereby confirming a central role for Rb1 in the antiapoptotic phenotype . Our data identify Rb1 induction in chronic asymptomatic HIV - 1 infection as a mediator of apoptosis resistance in monocytes in association with protective autophagy and contributing to monocyte survival during immune activation and / or HIV - 1 viremia .", "Developing clinical role of a P51681 co - receptor antagonist in HIV - 1 infection . BACKGROUND : DB04835 is the only approved P51681 coreceptor antagonist on the market for treatment of HIV - 1 infection . It uses a previously untargeted step in the HIV - 1 replication cycle necessary for viral entry into the host cell . OBJECTIVE : This review will describe and evaluate recent clinical literature regarding maraviroc , focusing on safety , efficacy , and mechanisms of treatment failure . METHODS : A search of the primary literature and conference abstracts was conducted using the keywords P51681 antagonist , maraviroc , and UK - 427857 . Resulting articles were then compiled and analyzed in this review . CONCLUSION : DB04835 is a potent inhibitor of HIV - 1 replication and contributes to effective viral suppression in combination with traditional antiretroviral medications . Due to its numerous drug interactions , potential for severe adverse events , and relative paucity of clinical data in long - term randomized , controlled trials , maraviroc should be one of the final agents utilized in salvage therapy in combination with other active antiretroviral agents .", "Hepatic safety and tolerability in the maraviroc clinical development program . DB04835 is the first P51681 antagonist to be approved for the treatment of HIV - 1 infection . It is generally well tolerated , with a similar side - effect profile to placebo in controlled studies . Many agents used to treat HIV disease are associated with the potential for hepatotoxicity . The hepatic effects of maraviroc were analyzed across all Pfizer - sponsored maraviroc clinical trials , in which 2350 volunteers received maraviroc . Although sporadic hepatic enzyme abnormalities were reported in 34 phase 1 / 2a studies of up to 28 - day duration , they demonstrated no dose relationship or association with hyperbilirubinemia . In the four phase 2b / 3 studies in antiretroviral - naive and antiretroviral - experienced patients , there was no significant imbalance in hepatic enzyme abnormalities or hepatobiliary adverse events in maraviroc versus comparator arms up to week 96 . The findings were similar in patients coinfected with hepatitis B and / or C virus , although the number of coinfected patients was small . No patient met the strict definition for Hy ' s Law . Two participants reported severe hepatotoxicity and although other potential causes were present , the contribution of maraviroc to these events could not be excluded . This analysis suggests that maraviroc does not present significant risks to hepatic safety when taken at the recommended doses in the populations studied .", "DB04835 does not affect humoral response to the pandemic influenza A - H1N1v 2009 adjuvanted vaccine in HIV - 1 - infected patients . Immune changes induced by the P51681 antagonist maraviroc raise the question of an impairment of responses to vaccines . We evaluated the immunogenicity of the adjuvanted pandemic influenza A - H1N1v 2009 vaccine in HIV - 1 - infected patients with suppressed HIV viremia with or without a maraviroc - containing regimen . Seroprotection , seroconversion , and geometric mean titer ratio of specific antibody titers did not differ between groups . These results suggest that maraviroc does not significantly affect the immune response to this adjuvanted vaccine .", "DB04835 . DB04835 is a specific , slowly reversible , noncompetitive , small - molecule antagonist of the P51681 chemokine receptor , which also serves as an HIV - 1 coreceptor . By acting as an antagonist at the P51681 coreceptor , maraviroc inhibits HIV - 1 from entering host cells . Clinical data for maraviroc are available from two large , well designed , ongoing phase IIb / III trials ( MOTIVATE - 1 and MOTIVATE - 2 ) conducted in patients infected with R5 - tropic HIV - 1 who had previously received at least one agent from three of the four classes of antiretroviral drugs and / or were triple - class resistant . According to 24 - week interim results of the MOTIVATE - 1 and - 2 trials , a significantly greater reduction in viral load occurred in patients receiving maraviroc 150 or 300mg ( depending on optimised background therapy [ OBT ] ) twice daily plus OBT compared with placebo plus OBT . This significant difference was maintained at 48 weeks in MOTIVATE - 1 . In the MOTIVATE - 1 and - 2 trials , a significantly greater proportion of patients receiving maraviroc plus OBT achieved an HIV - 1 RNA level < 400 and < 50 copies / mL compared with those receiving placebo plus OBT . In addition , the P01730 + cell count was increased to a significantly greater extent with maraviroc plus OBT compared with placebo plus OBT . The 48 - week results of MOTIVATE - 1 also report a significant difference in favour of maraviroc for all these endpoints . In general , maraviroc at dosages of up to 300mg twice daily was well tolerated in treatment - experienced patients infected with R5 - tropic HIV - 1 .", "Optimizing management of treatment - naïve and treatment - experienced HIV + patients : the role of maraviroc . DB04835 is the first P51681 antagonist approved for the treatment of HIV - 1 infection . It specifically inhibits the replication of R5 viruses by blocking viral entry . HIV - 1 tropism can be estimated accurately and predict viral response to maraviroc . Genotypic tools are increasingly replacing phenotypic assays in most places . The favorable pharmacokinetic properties and the good safety profile of maraviroc may support an earlier use of the drug in HIV - 1 infection , as well as favor its consideration as part of switch strategies in patients under suppressive antiret - roviral regimens containing less - well - tolerated drugs . Moreover , a particular immune benefit of maraviroc might encourage its use as part of intensification strategies in HIV - infected patients with impaired P01730 gains despite prolonged suppression of HIV replication with antiretroviral therapy . However , the long - term consequences of using maraviroc must be carefully checked , given its particular mechanism of action , blocking a physiologic cell receptor .", "Development and bioanalytical validation of a liquid chromatographic - tandem mass spectrometric ( LC - MS / MS ) method for the quantification of the P51681 antagonist maraviroc in human plasma . BACKGROUND : DB04835 is a P51681 antagonist that has been utilized as a viral entry inhibitor in the management of HIV - 1 . Current clinical trials are pursuing maraviroc drug efficacy in both oral and topical formulations . Therefore , in order to fully understand drug pharmacokinetics , a sensitive method is required to quantify plasma drug concentrations . METHODS : DB04835 - spiked plasma was combined with acetonitrile containing an isotopically - labeled internal standard , and following protein precipitation , samples were evaporated to dryness and reconstituted for liquid chromatographic - tandem mass spectrometric ( LC - MS / MS ) analysis . Chromatographic separation was achieved on a Waters BEH Q99618 , 50 × 2 . 1 mm UPLC column , with a 1 . 7 μm particle size and the eluent was analyzed using an DB00058 4000 mass analyzer in selected reaction monitoring mode . The method was validated as per FDA Bioanalytical Method Validation guidelines . RESULTS : The analytical measuring range of the LC - MS / MS method is 0 . 5 - 1000 ng / ml . Calibration curves were generated using weighted 1 / x ( 2 ) quadratic regression . Inter - and intra - assay precision was ≤ 5 . 38 % and ≤ 5 . 98 % , respectively ; inter - and intra - assay accuracy ( % DEV ) was ≤ 10 . 2 % and ≤ 8 . 44 % , respectively . Additional studies illustrated similar matrix effects between maraviroc and its internal standard , and that maraviroc is stable under a variety of conditions . Method comparison studies with a reference LC - MS / MS method show a slope of 0 . 948 with a Spearman coefficient of 0 . 98 . CONCLUSIONS : Based on the validation metrics , we have generated a sensitive and automated LC - MS / MS method for maraviroc quantification in human plasma .", "An LC - MS - MS method for quantitative determination of maraviroc ( UK - 427 , 857 ) in human plasma , urine and cerebrospinal fluid . DB04835 is a first - in - class P51681 antagonist that shows potent anti - HIV - 1 activity in vitro and in vivo and is well tolerated in both healthy volunteers and HIV - 1 - infected patients . The method for determination of maraviroc ( UK - 427 , 857 ) and its major metabolite ( UK - 408 , 027 ) in human plasma consists of a protein - precipitation procedure and analysis by liquid chromatography / tandem mass spectrometry using positive ion TurboIonSpray ® ionization and multiple reaction monitoring . The assay has been validated over a concentration range of 0 . 500 - 500 ng / mL for both analytes . The determinations of maraviroc in human cerebrospinal fluid ( 0 . 500 - 500 ng / mL ) and in urine ( 5 . 00 - 5000 ng / mL ) have also been validated but do not include measurement of the metabolite . The validations included extraction recovery , intra - assay and inter - assay precision and accuracy , stability of stock and spiking solutions , freeze - thaw stability , matrix stability , processed - extract stability , and evaluation of potential interferences from selected medications in plasma or urine .", "Lessons from maraviroc clinical trials . Evaluation of : Gulick RM , Lalezari J , Goodrich J et al . DB04835 for previously treated patients with R5 HIV - 1 infection . N . Engl . J . Med . 359 , 1429 - 1441 ( 2008 ) . DB04835 is the first commercially available HIV chemokine receptor antagonist targeting HIV that utilizes the P51681 chemokine receptor ( R5 tropic ) . The DB04835 versus Optimized Therapy in Viremic Antiretroviral Treatment - Experienced Patients ( MOTIVATE ) trials were two randomized , placebo - controlled studies designed to demonstrate the activity of maraviroc in triple - class - experienced HIV individuals , with a primary end point of viral load suppression at 48 weeks . DB04835 outperformed the placebo plus optimized background ( OBT ) arm , and exhibited a favorable safety profile with low discontinuation rates , which equaled those of the placebo plus OBT group . The results of these trials led to maraviroc receiving regulatory approval for the treatment of HIV .", "[ P51681 antagonists : a new class of antiretrovirals ] . A decade after identification of the chemokine receptor P51681 as a coreceptor for human immunodeficiency virus ( HIV ) , the first P51681 antagonist has recently been approved by the European Medicines Evaluation Agency ( EMEA ) for treatment of HIV infected patients . DB04835 ( Celsentri is a small molecule that specifically inhibits P51681 and thereby blocks HIV entry into its target cells . Viral tropism testing is mandatory before prescribing maraviroc , due to its unique mode of action limited to P51681 - tropic viruses . DB04835 is administered orally , twice daily . Daily dose must be adapted in case of association with a cytochrome P450 inducer or inhibitor . Efficacy of maraviroc has been demonstrated in patients failing other antiretroviral classes . Its potential for first line or switch therapy has to be proven in future trials .", "Genotypic and functional properties of early infant HIV - 1 envelopes . BACKGROUND : Understanding the properties of HIV - 1 variants that are transmitted from women to their infants is crucial to improving strategies to prevent transmission . In this study , 162 full - length envelope ( env ) clones were generated from plasma RNA obtained from 5 HIV - 1 Clade B infected mother - infant pairs . Following extensive genotypic and phylogenetic analyses , 35 representative clones were selected for functional studies . RESULTS : Infant quasispecies were highly homogeneous and generally represented minor maternal variants , consistent with transmission across a selective bottleneck . Infant clones did not differ from the maternal in env length , or glycosylation . All infant variants utilized the P51681 co - receptor , but were not macrophage tropic . Relatively high levels ( IC₅₀ ≥ 100 μg / ml ) of autologous maternal plasma IgG were required to neutralize maternal and infant viruses ; however , all infant viruses were neutralized by pooled sera from HIV - 1 infected individuals , implying that they were not inherently neutralization - resistant . All infant viruses were sensitive to the HIV - 1 entry inhibitors DB00109 and soluble P01730 ; none were resistant to DB04835 . Sensitivity to human monoclonal antibodies 4E10 , 2F5 , b12 and 2G12 varied . CONCLUSIONS : This study provides extensive characterization of the genotypic and functional properties of HIV - 1 env shortly after transmission . We present the first detailed comparisons of the macrophage tropism of infant and maternal env variants and their sensitivity to DB04835 , the only P51681 antagonist approved for therapeutic use . These findings may have implications for improving approaches to prevent mother - to - child HIV - 1 transmission .", "P01375 - induced apoptosis in neonatal lymphocytes : TNFRp55 expression and downstream pathways of apoptosis . Previously we have shown decreased Fas - mediated apoptosis in cord blood lymphocyte subsets . In this study , we compared tumor necrosis factor ( P01375 ) - alpha - induced apoptosis in T lymphocytes and their subsets between cord blood and peripheral blood from healthy young controls . The expression of P01375 receptor I ( P19438 ) was assessed by flow cytometry and quantitative RT - PCR . The expression of adapter molecules P01375 receptor - associated death domain ( Q15628 ) , Fas - associated death domain ( Q13158 ) and P01375 - associated factor - 2 ( TRAF - 2 ) and caspase 3 was analyzed by Western blotting . The activity of caspase 3 and caspase 8 was measured by colorimetric assay . The susceptibility of P01730 + and CD8 + T cells to P01375 - induced apoptosis was measured by terminal deoxytidyl transferase - mediated dUTP nick end labelling ( TUNEL ) assay . Both P01730 + and CD8 + T cell subsets from cord blood demonstrated decreased susceptibility to P01375 - induced apoptosis that was associated with decreased activation of both caspase 8 and caspase 3 as compared to T cell subsets in peripheral blood . Furthermore , expression of P19438 , Q15628 and caspase 3 was decreased in cord blood lymphocytes as compared to peripheral blood lymphocytes . The significance of these observations is discussed .", "A validated stability - indicating UPLC method for the determination of impurities in DB04835 . DB04835 is an antiretroviral drug in the P51681 receptor antagonist class , which is used in the treatment of HIV . DB04835 has six impurities . A novel , stability - indicating reversed - phase ultra - performance liquid chromatography ( RP - UPLC ) method has been developed for the quantitative determination of maraviroc in active pharmaceutical ingredients , along with its six impurities . The method is applicable to the quantification of related compounds and the assay of maraviroc . Efficient chromatographic separation was achieved on a BEH Shield RP - 18 column , 100 × 2 . 1 mm , 1 . 7 µm , in isocratic elution within 12 min . The mobile phase was 0 . 01 M ammonium acetate in water and acetonitrile in the ratio of 63 : 37 ( v / v ) . The flow rate was 0 . 4 mL / min , column oven temperature was maintained at 40 ° C and detection was conducted at 210 nm . Stress degradation conditions were established for maraviroc by subjecting it to acid , base , oxidation , water , humidity , thermal and photolysis stress . The stress samples were assayed against a qualified reference standard and the mass balance was close to 98 . 0 % . The developed UPLC method was validated according to the current International Conference on Harmonization guidelines for specificity , detection limit , quantitation limit , linearity , accuracy , precision , intermediate precision and robustness . The resolution between maraviroc and its six impurities was greater than 3 . 0 . A regression analysis showed that the correlation coefficient value was greater than 0 . 999 for maraviroc and its six impurities .", "Polymorphisms of chemokine receptors and P29474 in Brazilian patients with sickle cell disease . Sickle cell disease ( O00767 ) is an inherited disorder that presents extremely variable clinical manifestations . For the past few decades , it has been approached as an inflammatory disorder , and several researchers have tried to determine the factors involved in such characteristic . In order to contribute to the identification of the genetic differences underlying this phenotypic diversity in O00767 , we proposed to study the distribution of polymorphic variants of the genes encoding the chemokine receptors P41597 and P51681 , as well as three polymorphisms in the NOS3 gene , in Brazilian O00767 patients . These genes are involved in the development of inflammatory immune reactions , a feature believed to be of extreme importance in O00767 pathology . Our results indicate that the polymorphisms studied here are not directly associated with severe clinical manifestations in O00767 patients . Nevertheless , we observed a tendency for the development of a severe clinical course in carriers of the variant alleles P41597 - 64I and CCR5delta32 and in homozygotes for the - 786C variant of the NOS3 gene . Further studies should be carried out in order to assess the role of such variants in the clinical picture of O00767 .", "Desmopressin ( ___MASK21___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK21___ ) also has strong vasodilatory effects . ___MASK21___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK21___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK21___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK21___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK21___ - induced vasodilation .", "Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK44___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK44___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK44___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .", "5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK71___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .", "Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) ." ]

[ "___MASK21___", "___MASK25___", "___MASK40___", "___MASK44___", "___MASK52___", "___MASK56___", "___MASK71___", "___MASK85___", "___MASK99___" ]

[ "P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .", "[ Fundamental study of magnetization transfer contrast ( P04629 ) effect : optimization of MT pulse condition using experimental phantom ] . Magnetization transfer contrast ( P04629 ) was evaluated by changing the off - set frequency and pulse intensity of P04629 with the spoiled gradient echo ( SPGR ) sequence ( P24752 *- weighted image ) using an experimental phantom that included olive oil , protein , fiber , collagen , and pure water . The intensity of pure water reached a constant level just above the off - set frequency ( 1200 Hz ) regardless of MT pulse power . The contrast - to - noise ratio ( P21554 ) in each of the phantom materials was maximal at the MT pulse power of 2500 degrees ( equivalent flip angle ) . The P21554 and image noise obtained by body coil were inferior to those obtained with an extremity coil . In clinical application , the P04629 effect on chondrosarcoma was higher ( MT ratio , ROI - 1 : 0 . 448 , ROI - 2 : 0 . 382 ) than those of other cases in this study . Since the image contrast was improved between the malignant fibrous histiocytoma ( Q9H334 , MT ratio , ROI - 1 : 0 . 282 , ROI - 2 : 0 . 289 ) and peripheral tissues , extraskeletal extension could be observed more easily than without P04629 imaging . In conclusion , the effects of P04629 might be in providing useful information , in presuming composed tissues , differential diagnoses , and extent to the surrounding structures because of changing the image contrast to surrounding tissues corresponding to the rate of included bound water .", "___MASK16___ : a phenylamino - pyrimidine derivative with activity against P11274 - P00519 , P10721 and P09619 kinases . The P11274 - P00519 kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia ( CML ) . However , mutations within the P00519 kinase domain interfering with drug binding have been identified as the main mechanism of resistance to imatinib . Multiple distinct P11274 - P00519 kinase mutant isoforms conferring varying degrees of resistance to tyrosine kinase inhibitors have been reported . ___MASK16___ is a tyrosine kinase inhibitor 30 - fold more potent than imatinib against P11274 - P00519 kinase . ___MASK16___ is active against a wide range of imatinib - resistant P11274 - P00519 mutant isoforms , except for T315I . Results from Phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy have shown a favorable toxicity profile and confirmed the high efficacy of nilotinib in this setting . Studies addressing the activity of nilotinib in newly - diagnosed patients with CML are underway . Furthermore , nilotinib is a potent inhibitor of P10721 and P09619 kinases . Here , we review the preclinical development of nilotinib and the activity of this agent in patients with CML and in tumors driven by P10721 and / or P09619 mutant kinases , such as gastrointestinal stromal tumors and some forms of clonal hypereosinophilia .", "Involvement of the P10721 / KITL signaling pathway in 4 - vinylcyclohexene diepoxide - induced ovarian follicle loss in rats . Repeated daily dosing of rats with the occupational chemical 4 - vinylcyclohexene diepoxide ( VCD ) depletes the ovary of primordial and primary follicles through an increase in the natural process of atresia . Additionally , in vitro exposure of Postnatal Day 4 ( P01160 4 ) rat ovaries to VCD causes similar follicular depletion . This study was designed to investigate survival signaling pathways that may be associated with VCD - induced ovotoxicity in small preantral follicles . Female Fischer 344 rats ( P01160 28 ) were dosed daily ( 80 mg / kg / day VCD i . p . ; 12 days in vivo ) , and P01160 4 ovaries were cultured ( VCD 20 or 30 microM ; 8 days in vitro ) . Microarray analysis identified a subset of 14 genes whose expression was increased or decreased by VCD in both experiments ( i . e . , via both exposure routes ) . Particularly , the analysis showed that relative to controls , VCD did not affect mRNA expression of growth and differentiation factor 9 ( Gdf9 ) , whereas there were decreases in mRNA encoding bone morphogenic protein receptor 1a ( Bmpr1a ) and Kit . To confirm findings from microarray , the genes Gdf9 , Bmpr1a , and Kit were further examined . When growth factors associated with these pathways were added to ovarian cultures during VCD exposure , O60383 and P12644 had no effect on VCD - induced ovotoxicity ; however , KITL attenuated this follicle loss . Additionally , there was a decrease in Kit and an increase in Kitl expression ( mRNA and protein ) following VCD exposure , relative to control . These results support that VCD compromises P10721 / KITL signaling , which is critical for follicular survival in primordial and primary follicles .", "Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .", "Reinvestigation of carrier transport properties in liquid crystalline 2 - phenylbenzothiazole derivatives . We have reinvestigated the charge carrier transport properties in a liquid crystal of 2 -( 4 '- heptyloxyphenyl )- 6 - dodecylthiobenzothiazole ( 7O - P10721 - P28222 ) , for which the electronic conduction was first established in rodlike liquid crystals and for which the highest hole mobility in the smectic A ( SmA ) phase ever achieved was reported . We found that 7O - P10721 - P28222 exhibited three crystal phases , one of which appeared in a limited temperature range of 10 degrees just below the phase transition temperature from the SmA phase . In this crystal phase , nondispersive transient photohole currents were observed in time - of - flight experiments , and its hole mobility was determined to be 8 x 10 (- 3 ) cm ( 2 )/ Vs , slightly higher than that reported previously in the SmA phase . For the SmA phase , however , the hole mobility was 1 x 10 (- 4 ) cm ( 2 )/ Vs . Furthermore , we established the electron transport in the SmA phase of purified 7O - P10721 - P28222 , whose mobility was the same as the hole mobility in that phase . In order to confirm generality of the new findings in 7O - P10721 - P28222 , we investigated the carrier transport properties of its derivative having a short hydrocarbon chain , 2 -( 4 '- heptyloxyphenyl )- 6 - butylthiobenzothiazole ( 7O - P10721 - S4 ) , and obtained comparable results . The present results correct a mistake in the previous report and give an idea of what a typical mobility in the SmA phase is . On the basis of these results , we discuss what determines the charge carrier mobility in smectic mesophases .", "The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK86___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .", "Chromosome 8p as a potential hub for developmental neuropsychiatric disorders : implications for schizophrenia , autism and cancer . Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia . Presumably , owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult . However , the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established . There are 484 annotated genes located on 8p ; many are most likely oncogenes and tumor - suppressor genes . Molecular genetics and developmental studies have identified 21 genes in this region ( ADRA1A , O15013 , Q15822 , Q15825 , Q05901 , Q9UBT3 , Q16555 , Q06889 , O60258 , Q9NP95 , P11362 , FZD3 , LDL , NAT2 , P07197 , Q02297 , PCM1 , P00750 , P48454 , Q8N474 and P54219 / P54219 ) that are most likely to contribute to neuropsychiatric disorders ( schizophrenia , autism , bipolar disorder and depression ) , neurodegenerative disorders ( Parkinson ' s and Alzheimer ' s disease ) and cancer . Furthermore , at least seven nonprotein - coding RNAs ( microRNAs ) are located at 8p . Structural variants on 8p , such as copy number variants , microdeletions or microduplications , might also contribute to autism , schizophrenia and other human diseases including cancer . In this review , we consider the current state of evidence from cytogenetic , linkage , association , gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease . We also describe how a mutation in an 8p gene ( Fgf17 ) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex . We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer , despite the shortcomings of this evidence .", "DB09078 : first global approval . DB09078 ( Lenvima ™ ) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial - derived growth factor receptors 1 , 2 and 3 , fibroblast growth factor receptors 1 , 2 , 3 and 4 , platelet - derived growth factor receptor α , P07949 and P10721 . In addition to their role in normal cellular function , these kinases have been implicated in pathogenic angiogenesis , tumour growth and cancer progression . DB09078 is being developed by Eisai Co . Ltd for the treatment of solid tumours , primarily for differentiated thyroid cancer , and other malignancies . A capsule formulation of the drug has received approval in the USA for use in locally recurrent or metastatic , progressive , radioactive iodine - refractory differentiated thyroid cancer . DB09078 is in pre - registration for this indication in the EU , Australia , Brazil , Canada , Japan , South Korea , Russia , Singapore and Switzerland , and is in phase 3 development in Argentina , Chile and Thailand . DB09078 has orphan designation in the EU and Japan for use in differentiated thyroid cancer . In addition , an ongoing global , phase 3 trial is evaluating the use of lenvatinib as first - line treatment in unresectable hepatocellular carcinoma . This article summarizes the milestones in the development of lenvatinib leading to this first approval in locally recurrent or metastatic , progressive , radioactive iodine - refractory differentiated thyroid cancer .", "Antitumor activity of lenvatinib ( e7080 ) : an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models . Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor ( P15692 ) signaling pathway is a promising therapeutic strategy for thyroid cancer . DB09078 mesilate ( lenvatinib ) is a potent inhibitor of P15692 receptors ( P17948 - 3 ) and other prooncogenic and prooncogenic receptor tyrosine kinases , including fibroblast growth factor receptors ( P11362 - 4 ) , platelet derived growth factor receptor α ( PDGFRα ) , P10721 , and P07949 . We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice . Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer ( DTC ) , 5 anaplastic thyroid cancer ( ATC ) , and 1 medullary thyroid cancer ( P04629 ) xenograft models . DB09078 also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts , while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines : that is , RO82 - W - 1 and TT cells . Western blot analysis showed that cultured RO82 - W - 1 cells overexpressed P11362 and that lenvatinib inhibited the phosphorylation of P11362 and its downstream effector Q8WU20 . DB09078 also inhibited the phosphorylation of P07949 with the activated mutation C634W in TT cells . These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and P07949 signaling pathway in preclinical human thyroid cancer models .", "Comparison of two polymer - based immunohistochemical detection systems : ENVISION + and ImmPRESS . The non - specific background reaction produced in avidin - biotin - based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non - avidin - biotin systems , yet there are few reports comparing the performance of non - avidin - biotin , polymer - based methods . In this study we compare two of these methods , ENVISION + trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin - fixed , paraffin - embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut - 1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION + or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION + trade mark in 16 / 18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION + trade mark . Based on these results , ImmPRESS is a good polymer - based detection system for routine immunohistochemistry .", "Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .", "Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK38___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK38___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .", "Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .", "Thymoma patients treated in a phase I clinic at MD Anderson Cancer Center : responses to P42345 inhibitors and molecular analyses . BACKGROUND : Thymomas and thymic carcinoma are rare tumors with no approved therapies . Our purpose was to analyze the molecular features and outcomes of patients referred to the Clinical Center for Targeted Therapy ( Phase I Clinic ) . METHODS : We retrospectively reviewed the medical records of consecutive referred patients with advanced / metastatic thymoma or thymic carcinoma RESULTS : Twenty - one patients were identified ( median age 52 years ; 10 women ; median number of prior systemic therapies = 2 ) . Six of 10 patients ( 60 % ) treated with P42345 inhibitor combination regimens achieved stable disease ( SD ) ≥ 12 months or a partial response ( PR ) . For patients treated on P42345 inhibitor regimens ( N = 10 ) , median time to treatment failure ( Q15669 ) was 11 . 6 months versus 2 . 3 months on last conventional regimen prior to referral ( p = 0 . 024 ) . Molecular analyses ( performed by next generation sequencing in seven patients and single polymerase chain reaction ( PCR ) - based assays in an additional six patients ) showed diverse actionable mutations : P42336 ( 1 of 12 tested ; 8 % ) ; P00533 ( 1 of 13 ; 8 % ) ; P07949 ( 1 of 7 ; 14 % ) ; and P31749 ( 1 of 7 ; 14 % ) . Of two patients with P42336 or P31749 mutations , one was treated with an P42345 inhibitor - based regimen and achieved 26 % regression with a Q15669 of 17 months . CONCLUSION : Patients with advanced / metastatic thymoma or thymic carcinoma demonstrated prolonged Q15669 on P42345 inhibitor - based therapy as compared to prior conventional treatment . Heterogeneity in actionable molecular aberrations was observed , suggesting that multi - assay molecular profiling and individualizing treatment merits investigation .", "Timing of the hepatic arterial phase at DB08884 - enhanced hepatic dynamic Q9BWK5 : comparison of the test - injection and the fixed - time delay method . PURPOSE : To compare the fixed - time - and the test - injection method with respect to the image quality of hypervascular hepatocellular carcinoma ( HCC ) and the adequacy of timing of the hepatic arterial phase ( HAP ) in DB08884 ( EOB ) enhanced Q9BWK5 . MATERIALS AND METHODS : We studied 63 patients with computed tomography ( CT ) - proven hypervascular HCC : 30 ( group 1 ) were scanned HAP using the fixed - time delay method ( protocol 1 ) ; in the other 33 ( group 2 ) , we applied the test - injection method ( protocol 2 ) . We compared the protocols with respect with tumor - to - liver contrast ( TLC ) , contrast - to - noise - ratio ( P21554 ) , and relative enhancement of the liver and tumor ( Q04864 , P07949 ) during HAP . Two radiologists compared the adequacy of HAP , image contrast , image noise , and overall image quality . RESULTS : Under protocol 2 , TLC , P21554 , and Q04864 and P07949 of hypervascular HCC were significantly higher ( P < 0 . 01 ) . The proportion of optimal HAP was significantly higher for protocol 2 than protocol 1 ( P < 0 . 01 ) . The visual score of the image contrast and the overall image quality were significantly higher in group 2 than group 1 ( P = 0 . 02 and P = 0 . 01 , respectively ) . CONCLUSION : At EOB - enhanced hepatic dynamic Q9BWK5 , the test - injection method yielded better image quality of hypervascular HCC and improved adequacy of timing of HAP .", "The P08908 - receptor agonist flibanserin reduces drug - induced dyskinesia in O75916 - deficient mice . Drug - induced dyskinesia is a major complication of dopamine replacement therapy in advanced Parkinson ' s disease consisting of dystonia , chorea and athetosis . Agonists at P08908 - receptors attenuate levodopa - induced motor complications in non - human primates . Mice with increased dopamine D2 receptor ( P14416 ) signalling due to the lack of expression of the regulator of G - protein signalling 9 ( O75916 ) also develop dyskinesia following levodopa treatment . We investigated whether the P08908 - receptor agonist flibanserin compared with buspirone reduces motor abnormalities induced by levodopa or quinelorane , a selective dopamine D2 - receptor agonist . Following dopamine depletion via reserpine , 40 mice ( 20 wild - type and 20 O75916 knock - out ) were treated with flibanserin or buspirone in combination with levodopa or quinelorane . Motor behaviour was analysed using open field analysis . O75916 knock - out mice displayed significantly more drug - induced dystonia ( p < 0 . 04 ; t test ) than wild type . In quinelorane - treated wild - type mice flibanserin as well as buspirone significantly reduced dystonia ( p < 0 . 05 ) . In O75916 knock - out animals again both reduced quinelorane - induced dystonia . However , flibanserin was significantly more effective ( p = 0 . 003 ) . Following reserpine pretreatment and administration of levodopa wild - type and Q99697 9 knock - out mice showed mild to moderate dystonia . Surprisingly , 10 mg / kg buspirone increased dystonia in both animal groups , whereas it was decreased by 10 mg / kg flibanserin . However , compared with levodopa alone only the increase of dystonia by buspirone was significant ( p < 0 . 04 ) . ___MASK51___ showed promising antidyskinetic effects in a model of drug - induced dyskinesia . Our data underline the possible benefit of P08908 agonists in drug - induced dyskinesia .", "DB00741 response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . DB00741 is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post - stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress - coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro - hypertrophic nuclear factor of activated T - cell ( NFAT ) signaling ] and increased P15692 gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild - type European brown trout , Salmo trutta . A positive correlation between post - stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post - stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well - known from mammalian cardiology .", "P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK2___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .", "Nicotinic acetylcholine receptors containing the α6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons . ___MASK68___ and alcohol are often co - abused suggesting a common mechanism of action may underlie their reinforcing properties . Both drugs acutely increase activity of ventral tegmental area ( VTA ) dopaminergic ( DAergic ) neurons , a phenomenon associated with reward behavior . Recent evidence indicates that nicotinic acetylcholine receptors ( nAChRs ) , ligand - gated cation channels activated by ACh and nicotine , may contribute to ethanol - mediated activation of VTA DAergic neurons although the nAChR subtype ( s ) involved has not been fully elucidated . Here we show that expression and activation of nAChRs containing the α6 subunit contribute to ethanol - induced activation of VTA DAergic neurons . In wild - type ( WT ) mouse midbrain sections that contain the VTA , ethanol ( 50 or 100 mM ) significantly increased firing frequency of DAergic neurons . In contrast , ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express Q15825 , the gene encoding the α6 nAChR subunit ( α6 knock - out ( KO ) mice ) . DB00898 - induced activity in WT slices was also reduced by pre - application of the α6 subtype - selective nAChR antagonist , α - conotoxin MII [ E11A ] . When co - applied , ethanol potentiated the response to ACh in WT DAergic neurons ; whereas co - application of ACh and ethanol failed to significantly increase activity of DAergic neurons in α6 KO slices . Finally , pre - application of α - conotoxin MII [ E11A ] in WT slices reduced ethanol potentiation of ACh responses . Together our data indicate that α6 - subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons . These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement , providing a potential common therapeutic molecular target to reduce nicotine and alcohol co - abuse .", "Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .", "Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .", "Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .", "Blockade of cannabinoid receptors reduces inflammation , leukocyte accumulation and neovascularization in a model of sponge - induced inflammatory angiogenesis . OBJECTIVE : Angiogenesis depends on a complex interaction between cellular networks and mediators . The endocannabinoid system and its receptors have been shown to play a role in models of inflammation . Here , we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis . MATERIALS AND METHODS : Polyester - polyurethane sponges were implanted in C57Bl / 6j mice . Animals received doses ( 3 and 10 mg / kg / daily , s . c . ) of the cannabinoid receptor antagonists SR141716A ( P21554 ) or SR144528 ( CB2 ) . Implants were collected at days 7 and 14 for cytokines , hemoglobin , myeloperoxidase , and N - acetylglucosaminidase measurements , as indices of inflammation , angiogenesis , neutrophil and macrophage accumulation , respectively . Histological and morphometric analysis were also performed . RESULTS : Cannabinoid receptors expression in implants was detected from day 4 after implantation . Treatment with P21554 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation , although P21554 receptor antagonist were more effective at blocking leukocyte accumulation . There was a reduction in P01375 - α , P15692 , P09341 / KC , P13500 / JE , and P10147 / MIP - 1α levels , with increase in P13501 / RANTES . Both treatments reduced neovascularization . Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis . CONCLUSIONS : Blockade of cannabinoid receptors reduced leukocyte accumulation , inflammation and neovascularization , suggesting an important role of endocannabinoids in sponge - induced inflammatory angiogenesis both via P21554 and CB2 receptors .", "P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .", "Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK51___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK51___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .", "Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK30___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .", "Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .", "Tyrosine kinase blockers : new hope for successful cancer therapy . Tyrosine kinases ( TKs ) are attractive targets for cancer therapy , as quite often their abnormal signaling has been linked with tumor development and growth . Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair , apoptosis , and cell proliferation . During the last few years , thorough analysis of the mechanism underlying tyrosine kinase ' s activity led to novel cancer therapy using TKs blockers . These drugs are remarkably effective in the treatment of various human tumors including head and neck , gastric , prostate and breast cancer and leukemias . The most successful example of kinase blockers is Imatinib ( Imatinib mesylate , Gleevec , STI571 ) , the inhibitor of Bcr / Abl oncoprotein , which has become a first - line therapy for chronic myelogenous leukemia . The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed . Others kinase inhibitors used recently in cancer therapy include Dasatinib ( BMS - 354825 ) specific for P00519 non - receptor cytoplasmic kinase , Gefitinib ( DB00317 ) , Erlotinib ( DB00530 , Tarceva ) and DB01268 ( SU 11248 , Sutent ) specific for P15692 receptor kinase , AMN107 ( ___MASK16___ ) and INNO - 406 ( NS - 187 ) specific for c - P10721 kinase . The following TK blockers for treatment of various human tumors are in clinical development : DB01259 ( DB01259 ditosylate , DB01259 , GW - 572016 ) , Canertinib ( DB05424 ) , DB05294 ( DB05294 ) , DB04879 ( PTK787 / ZK 222584 ) , DB00398 ( Bay 43 - 9006 , Nexavar ) , and Leflunomide ( SU101 , DB01097 ) . Herein , we discuss the chemistry , biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes . Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein . In the thyroid , the Q06710 - P37231 fusion is present in the neoplastic lesions that have a follicular architecture - follicular thyroid carcinoma ( FTC ) and follicular variant of papillary thyroid carcinoma ( FVPTC ) , and less frequently in follicular thyroid adenoma ( DB00499 ) , while the presence of P07949 / PTC fusions are largely restricted to papillary thyroid carcinoma ( PTC ) . The ability to detect fusion genes is relevant for a correct diagnosis and for therapy . We have developed a new fusion gene microarray - based approach for simultaneous analysis of all known and predicted fusion gene variants . We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls - one thyroid cancer cell line ( TPC - 1 ) and two PTCs with known Q16204 - P07949 ( alias P07949 / Q13635 ) fusion gene , using this microarray . Within the thyroid tumors tested , only well known , previously reported fusion genes in thyroid oncology were identified . Our results reinforce the pathogenic role played by P07949 / Q13635 , P07949 / PTC3 , and Q06710 - P37231 fusion genes in thyroid tumorigenesis .", "Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization . DB09078 is an oral multikinase inhibitor that selectively inhibits vascular endothelial growth factor ( P15692 ) receptors 1 to 3 and other proangiogenic and oncogenic pathway - related receptor tyrosine kinases . To elucidate the origin of the potency of lenvatinib in P15692 receptor 2 ( P35968 ) inhibition , we conducted a kinetic interaction analysis of lenvatinib with P35968 and X - ray analysis of the crystal structure of P35968 - lenvatinib complexes . Kinetic analysis revealed that lenvatinib had a rapid association rate constant and a relatively slow dissociation rate constant in complex with P35968 . Co - crystal structure analysis demonstrated that lenvatinib binds at its DB00171 mimetic quinoline moiety to the DB00171 binding site and to the neighboring region via a cyclopropane ring , adopting an DB00128 - DB00120 - DB00145 ( DFG ) - \" in \" conformation . These results suggest that lenvatinib is very distinct in its binding mode of interaction compared to the several approved P35968 kinase inhibitors .", "[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK8___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .", "Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large - scale Genome - Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2 , 047 subjects of European descent ( 1 , 062 cases and 985 controls ) . ___MASK68___ dependence was assessed with multiple smoking measures , including the Fagerström Test for ___MASK68___ Dependence , the Diagnostic and Statistical Manual for Mental Disorders - IV ( DSM - IV ) nicotine dependence , the ___MASK68___ Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single - item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM - V .", "Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK42___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .", "Comparison of genetic and epigenetic alterations at 11 tumor suppressor loci in pulmonary sclerosing hemangioma and adenocarcinoma . Pulmonary sclerosing hemangioma ( SH ) is an unusual tumor of pneumocytic origin . Morphologically , SH can mimic pulmonary adenocarcinomas . Here , the authors compared genetic and epigenetic aberrations in SH with those in pulmonary adenocarcinoma . Clinicopathologic characteristics , microsatellite alterations , and CpG island methylation were analyzed in pulmonary SHs ( n = 24 ) and adenocarcinomas ( n = 34 ) to compare their patterns of molecular abnormalities . SHs were also analyzed immunohistochemically to characterize the expression status of proteins involved in basic biologic processes . The clinical presentation of SH cases was generally benign . Both cell types of SH stained positive for thyroid transcription factor 1 ( Q15669 - 1 ) , epithelial membrane antigen ( P15941 ) , β - catenin , P12830 , and vascular endothelial growth factor ( P15692 ) . Allelic imbalances in D3S1283 , D3S1234 , D3S1300 , D3S1285 , P04637 , D17S938 , and D9S179 were less frequent in SH than in adenocarcinoma ; rates of allelic imbalances in D20S170 and D21S1446 were not significantly different . In SH , CpG island methylation frequencies of p16 ( INK4a ) ( 0 . 0 % ) and RASSF1A ( 12 . 5 % ) were significantly lower than those in adenocarcinoma ( 29 . 4 % and 38 . 2 % , respectively ) ; the frequencies of HOX D9 , D11 , and D13 gene methylation in SH were 37 . 5 % , 33 . 3 % , and 33 . 3 % , respectively . The results show that pulmonary SH and adenocarcinoma share similar genetic and epigenetic aberrations , but also exhibit significant differences , especially in tumor suppressor genes ." ]

[ "___MASK16___", "___MASK2___", "___MASK30___", "___MASK38___", "___MASK42___", "___MASK51___", "___MASK68___", "___MASK86___", "___MASK8___" ]

[ "Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK23___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .", "Low levels of insulin - like growth factor - I in cerebrospinal fluid in children with autism . Autism is a behaviourally defined syndrome characterized by disturbances of social interaction and communication and restrictions of behaviour patterns and imagination . The pathogenesis of autism is unknown but it is suspected that a number of genetic factors may be involved . Neurotrophic factors such as insulin - like growth factor - I ( P05019 ) play a role in early brain development . The aim of this study was to determine whether P05019 levels might be associated with the development of autism . P05019 levels were measured in the P04141 of 11 children with autism ( 4 females , 7 males ; mean age 3 . 8 years , SD 1 . 1 ) using a sensitive radioimmunoassay method and compared with levels in 11 control participants ( 6 females , 5 males ; mean age 3 . 8 years ) . Levels of P05019 in the P04141 were statistically significantly lower in the children with autism than in the control children ( p = 0 . 03 ) . P05019 may play a role in pathogenetic mechanisms of autism and the role of neurotrophic factors in autism and other neurodevelopmental diseases should be studied further .", "Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1 / 2 pluripotent cells through an androgen receptor - mediated pathway . DB00624 supplementation increases skeletal muscle mass and decreases fat mass ; however , the underlying mechanisms are unknown . We hypothesized that testosterone regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage . Mouse C3H 10T1 / 2 pluripotent cells were treated with testosterone ( 0 - 300 nM ) or dihydrotestosterone ( DB02901 , 0 - 30 nM ) for 0 - 14 d , and myogenic conversion was evaluated by immunocytochemical staining for early ( MyoD ) and late ( myosin heavy chain II ; MHC ) myogenic markers and by measurements of MyoD and MHC mRNA and protein . Adipogenic differentiation was assessed by adipocyte counting and by measurements of peroxisomal proliferator - activated receptor gamma 2 ( Q07869 gamma 2 ) mRNA and Q07869 gamma 2 protein and CCAAT / enhancer binding protein alpha . The number of MyoD + myogenic cells and MHC + myotubes and MyoD and MHC mRNA and protein levels increased dose dependently in response to testosterone and DB02901 treatment . Both testosterone and DB02901 decreased the number of adipocytes and down - regulated the expression of Q07869 gamma 2 mRNA and Q07869 gamma 2 protein and CCAAT / enhancer binding protein alpha . P10275 mRNA and protein levels were low at baseline but increased after testosterone or DB02901 treatment . The effects of testosterone and DB02901 on myogenesis and adipogenesis were blocked by bicalutamide . Therefore , testosterone and DB02901 regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor - mediated pathway . The observation that differentiation of pluripotent cells is androgen dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men .", "P10275 promotes the migration and invasion of upper urinary tract urothelial carcinoma cells through the upregulation of P14780 and P35354 . Dysregulated androgen receptor ( AR ) signaling is implicated in several types of tumor , including carcinomas of the prostate , breast , liver and bladder . However , the contribution of AR to the progression of upper urinary tract urothelial carcinomas ( UUTUC ) has not been fully investigated . In the present study , we demonstrated that the AR is involved in the metastasis and invasiveness of UUTUC cells . We investigated the role of the AR in UUTUC by using UUTUC - derived BFTC 909 cells . The overexpression of AR promotes the migration and invasion of BFTC 909 cells . Expression of migration / invasion - related genes was increased in BFTC 909 cells overexpressing AR determined by qPCR and western blot analyses . The results showed that AR - enhanced migration and invasion of UUTUC cells are linked to the upregulation of the matrix - degrading enzyme P14780 and cyclooxygenase ( P36551 ) - 2 . Subsequently , the blocking of P14780 and P35354 signaling by inhibitors suppressed AR - enhanced cell migration and invasion . The results of the present study provide evidence for the first time of the role of AR in the motility and invasion of UUT cancer cells and support the hypothesis that the AR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia of UUT . Thus , the AR may also serve as a novel biomarker and potential therapeutic target for UUT cancer .", "P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( DB02901 ) in castrated male and female mice subjected to DB02901 replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by DB02901 in mice CPs .", "Cyclooxygenases in rat Leydig cells : effects of luteinizing hormone and aging . Previous studies suggested that increased Leydig cell cyclooxygenase ( P36551 ) 2 expression may be involved in the reduced testosterone production that characterizes aged Leydig cells . Our objective herein was to further elucidate the relationships among LH stimulation , Leydig cell P35354 and P23219 expression , aging , and testosterone production . Incubation of Leydig cells from young or aged rats with LH or dibutyryl DB02527 resulted in increases in both intracellular P35354 protein expression and testosterone production . P23219 expression did not respond to LH or dibutyryl DB02527 . Incubation of adult cells with a protein kinase A inhibitor suppressed the stimulatory effects of LH on P35354 and testosterone production . Short - term incubation of Leydig cells with TGF - alpha or IL - 1beta also increased P35354 protein levels ; P05019 had no effect . In vivo , LH also was found to stimulate both P35354 and testosterone , but not P23219 . As reported previously , P35354 expression was greater in old than in young cells , and old Leydig cells responded to inhibition of P35354 in vitro with increased testosterone production . However , the effects of the P35354 inhibitors were not restricted to old cells ; young Leydig cells also responded to P35354 inhibition with increased testosterone production . This and the observation that the incubation of young or old cells with LH resulted in increased P35354 and testosterone production in both cases suggests that the relationship between P35354 and testosterone production is not unique to aged Leydig cells . Moreover , the close correlation between increases in P35354 and testosterone in LH - stimulated young and aged Leydig cells is difficult to reconcile with the contention that the increased expression of P35354 in aged cells is responsible for age - related suppression of Leydig cell testosterone production .", "Sarpogrelate HCl , a selective 5 - Q13049 antagonist , retards the progression of atherosclerosis through a novel mechanism . Although sarpogrelate HCl is widely used for the prevention of arterial thrombosis , its effect on atherosclerosis is unknown . Accordingly , we here investigated the effects of sarpogrelate HCl on a rabbit model of atherosclerosis . Male rabbits were fed a 0 . 5 % cholesterol diet ( HCD ) ( Gp 1 ) , HCD with vitamin E ( Gp 2 ) , HCD with vitamin E and sarpogrelate ( Gp 3 ) , or HCD with sarpogrelate alone ( Gp 4 ) for 8 weeks . The atherosclerotic area was decreased by feeding of vitamin E and sarpogrelate ( 16 . 9 +/- 2 . 0 % in Gp 1 vs . 8 . 2 +/- 2 . 0 % in Gp 3 ) . Tone - related basal NO release was higher in Gps 3 and 4 . DB03128 - induced relaxation tended to be improved in Gp 3 . The amount of P29474 mRNA was increased in Gp 4 , and aortic cyclic GMP concentration showed the same tendency . O ( 2 )(-) release tended to be decreased in Gps 2 and 3 . The matrix metalloproteinase - 1 ( P03956 ) - positive area was decreased , and the percentage ratio of cell numbers of smooth muscle cells / macrophages in the plaque was increased in Gp 3 . The results demonstrated that sarpogrelate HCl retards the progression of atherosclerosis in rabbits , and that this effect is enhanced by concomitant administration of vitamin E . Although upregulation of P29474 may play a role as one of the underlying mechanisms , our results suggest that an additional mechanism - possibly involving the antiproliferative effects of sarpogrelate HCl on smooth muscle cells and macrophages - may also play an important role .", "P10275 signaling induced by supraphysiological doses of dihydrotestosterone in human peripheral blood lymphocytes . Anabolic androgenic steroids , a class of steroid hormones related to testosterone , are natural ligands of androgen receptor ( AR ) , a member of the nuclear receptor superfamily of ligand - activated transcription factors . AR binds specific DNA elements , known as androgen - response elements . DB00624 , the main male sexual hormone , binds AR directly and indirectly , through conversion into dihydrotestosterone ( DB02901 ) , its more active metabolite . Anabolic androgenic steroids are frequently detected in the urine of doped athletes ; their consumption is also growing among sport amateurs and adolescents . The effects of androgens can differ depending on the target cells and / or tissues . To gain insight into transcription activation mechanisms of AR , we investigated AR protein signaling in human peripheral blood lymphocytes treated with supraphysiological doses of DB02901 . We performed a comparative proteomic analysis and we identified about 30 differentially expressed proteins . At least five species contained a consensus androgen - response elements sequence in the promoter region of related coding genes . The analysis also revealed that high doses of DB02901 activate the drug detoxification process , could stimulate an increase in cell motility and exert a prosurvival effect rather than an apoptotic one .", "P10275 in Sertoli cells is not required for testosterone - induced suppression of spermatogenesis , but contributes to Sertoli cell organization in Utp14b jsd mice . DB00624 acting through the androgen receptor ( AR ) maintains the arrest of spermatogonial differentiation in juvenile spermatogonial depletion ( jsd mutation in the Utp14b gene ) mutant adult male mice . It is not known which of the somatic cell types expressing AR mediates this inhibition . To determine whether Sertoli cells are responsible , we selectively eliminated AR in Sertoli cells in jsd mice containing a floxed - Ar gene and an anti - Müllerian hormone - Cre transgene . In these Sertoli AR - knockout ( SCARKO ) - jsd mice , spermatogonial differentiation did not recover . However , the normal organization of Sertoli cell nuclei was drastically disrupted in SCARKO - jsd mice compared with SCARKO or jsd mice . In addition , the extent of ectoplasmic specializations was reduced ; tight junctions were not found ; vinculin , an anchoring protein found in ectoplasmic specializations , became uniformly distributed in the cytoplasm ; and the adult Sertoli cells showed excess heterochromatin subjacent to their nuclear envelope . Despite the abnormalities in Sertoli cells in SCARKO - jsd mice , global suppression of testosterone action and levels was still effective in restoring the differentiated germ cells , and this was accompanied by an improved arrangement of Sertoli cell nuclei . We conclude that Sertoli cells are not targets for the testosterone - mediated inhibition of spermatogonial differentiation in jsd mice , and that both AR in Sertoli cells and the presence of differentiated germ cells contribute to maintaining the organization of Sertoli cells within the seminiferous tubules .", "P10275 in human placental villi . In studies with a synthetic androgen , R 1881 , an androgen - binding component was found in the cytosol of human placental villi . Kinetic analysis indicated that the Kd value of this component was 1 . 4 nM at 0 - 4 degrees C and that binding of R 1881 amounted to 277 +/- 73 fmol / mg protein . glycerol density gradient ultracentrifugation showed a peak of binding activity in the 8S region in a medium of low ionic strength , but in the 4 . 5S region in a medium containing 9 . 5 M DB00761 . The R 1881 - binding component was inactivated by mild heat - or trypsin - treatment , but not by treatment with DNase or RNase . Most of the R 1881 - binding activity was sedimented at 20 to 40 % saturation of ammonium sulfate . These findings indicate that the R 1881 - binding component in human placental cytosol is quite similar in its characteristics to androgen receptors , which are present in various androgen - responsive organs . DB00624 was a more potent competitor of R 1881 - binding than DB02901 or cyproterone acetate . Scatchard plots indicated that the binding site of testosterone was identical with that of R 1881 . These findings suggest that the androgen receptor in placental cytosol is specific for testosterone . The Kd value for testosterone was calculated to be 3 . 2 nM .", "Regulation of androgen receptor mRNA in rat Sertoli and peritubular cells . Regulation of 9 . 5 - kb androgen receptor mRNA concentrations in Sertoli and peritubular cells from 20 - day - old rats was studied by Northern blot analysis . Treatment of cells in vitro for 1 - 7 days with 300 ng / ml DB00094 increased androgen receptor mRNA up to 4 - fold in Sertoli cells but not in peritubular cells . DB00624 ( 100 ng / ml ) had no effect or slightly decreased androgen receptor mRNA in Sertoli and peritubular cells . P10275 mRNA concentrations in Sertoli and peritubular cells from rats killed 15 days after hypophysectomy were elevated 4 - 5 - fold over those in cells from intact rats . The androgen receptor mRNA concentration was decreased in both Sertoli and peritubular cells isolated from hypophysectomized animals treated with 500 micrograms / day testosterone propionate in vivo and subsequently with 100 ng / ml testosterone in vitro . DB00094 treatment ( 100 micrograms / day in vivo , followed by 300 ng / ml in vitro ) did not increase androgen receptor mRNA over that in cells from hypophysectomized controls but rather decreased its concentration to varying degrees in Sertoli and peritubular cells . The rise in androgen receptor mRNA in both Sertoli and peritubular cells isolated from hypophysectomized animals is attributable , at least in part , to the absence of the inhibitory influence of testosterone . Other data in the literature suggest positive regulation of Sertoli cell androgen receptor protein by DB00094 and androgens . Consequently , complex mechanisms involving transcriptional , translational , and post - translational regulation probably control androgen receptor concentrations in the cells of the rat seminiferous tubule .", "Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK28___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .", "P01308 - like growth factor - I receptor signaling and resistance to trastuzumab ( Herceptin ) . BACKGROUND : ___MASK22___ ( Herceptin ) , an anti - P04626 / neu receptor monoclonal antibody that inhibits growth of ErbB2 - overexpressing breast cancer , is used to treat such cancers . Development of resistance to trastuzumab , however , is common . We investigated whether insulin - like growth factor - I ( P05019 ) , which activates cell survival signals , interferes with the growth - inhibitory action of trastuzumab . METHODS : MCF - 7 / P04626 - 18 and SKBR3 human breast cancer models were used to assess cell proliferation , colony formation in soft agar , and cell cycle parameters . Throughout , we used trastuzumab at a dose of 10 microg / mL and P05019 at a dose of 40 ng / mL . All statistical tests were two - sided . RESULTS : ___MASK22___ inhibited the growth of MCF - 7 / P04626 - 18 cells , which overexpress P04626 / neu receptors and express P05019 receptors ( IGF - IRs ) , only when IGF - IR signaling was minimized . For example , in 1 % fetal bovine serum ( FBS ) , trastuzumab reduced cell proliferation by 42 % ( P =. 002 ) ; however , in 10 % FBS or P05019 , trastuzumab had no effect on proliferation . In SKBR3 cells , which overexpress P04626 / neu receptor but express few IGF - IRs , trastuzumab reduced proliferation by 42 % ( P =. 008 ) regardless of P05019 concentration . When SKBR3 cells were genetically altered to overexpress IGF - IRs and cultured with P05019 , trastuzumab had no effect on proliferation . However , the addition of IGF - binding protein - 3 , which decreased IGF - IR signaling , restored trastuzumab - induced growth inhibition . CONCLUSIONS : In breast cancer cell models that overexpress P04626 / neu , an increased level of IGF - IR signaling appears to interfere with the action of trastuzumab . Thus , strategies that target IGF - IR signaling may prevent or delay development of resistance to trastuzumab .", "Androgen receptors . DB00624 and its active metabolite dihydrotestosterone exert their influence on target cells through a specific intracellular protein receptor . Structural abnormalities of this receptor lead to a diminished androgen action within the cell and result in the syndrome of androgen insensitivity . Androgen insensitivity is classified on the basis of whether the insensitivity is complete or partial and whether the androgen receptor is normally present ( AR (+) ) , absent ( AR (-) ) or diminished ( AR (+/-) ) . All patients with androgen insensitivity have normal or high plasma levels of testosterone and elevated serum LH . Patients with complete androgen insensitivity are phenotypically female . The clinical presentation of partial androgen insensitivity is variable , ranging from a minimal amount of virilization to a completely masculine appearance . All patients described with a syndrome of androgen insensitivity are infertile . The influence of androgen receptor function in the pathogenesis of benign prostatic hypertrophy is being investigated . P10275 content is also being studied as a possible marker of responsiveness to hormonal therapy in prostatic carcinoma .", "The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK76___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .", "Altered levels of angiopoietin 1 and tie 2 are associated with androgen - regulated vascular regression and growth in the ventral prostate in adult mice and rats . The involution of the rat ventral prostate gland after castration could be caused by primary changes in the vasculature . To explore the mechanisms , we studied the effects of castration and testosterone treatment on the vasculature in the ventral prostate in adult rats and mice . P10275 expression , vascular morphology , and the expression of angiopoietin ( ang ) 1 and 2 and their receptor tie 2 were examined 1 , 3 , and 7 d after castration and after testosterone treatment of castrated animals using stereological methods , immunohistochemistry , laser capture microdissection , and Western blotting . One day after castration , the percentage of blood vessels covered with smooth muscle actin , endothelial cell proliferation , and vascular volume had decreased , whereas endothelial cell apoptosis had increased . Simultaneously , ang 1 and tie 2 protein levels decreased . Nuclear expression of androgen receptor was observed not only in glandular and stroma smooth muscle cells but also in the mural cells of prostate arteries and veins and was markedly down - regulated already 1 d after castration . DB00624 administration of castrated mice and rats reversed all the observed effects . At the mRNA level , tie 2 was exclusively , but ang 1 predominantly , expressed in the stroma , compared with the epithelial compartment . Local delivery of soluble tie 2 during testosterone - stimulated growth , inhibited vascular maturation and increased vascular volume and leukocyte infiltration compared with controls . We conclude that androgens may regulate the prostate vasculature by direct effects on mural vascular cells and by influencing the secretion of the angiopoietins , in above all , the stroma cells .", "P10275 ( CAG ) n polymorphism and androgen levels in women with systemic lupus erythematosus and healthy controls . Systemic lupus erythematosus ( SLE ) is an autoimmune disorder that affects mainly females . Therefore , interrelations between the reproductive and immune system have been assumed . Considering the complex influence of hormones and receptors , we aimed to investigate the influence of androgens and androgen receptor ( AR ) polymorphism in women with SLE . One hundred and sixteen patients and 44 healthy women were investigated . DB00624 , sex hormone - binding globulin ( P04278 ) , dehydroepiandrosterone - sulphate ( DHEAS ) concentrations and AR ( CAG ) n polymorphism were determined . SLE patients had significantly lower levels of total and free testosterone and DHEAS in comparison with the controls . No differences in the CAG repeat length between the groups were established . Women with two alleles carrying more than 22 CAG repeats had significantly higher levels of P04278 ( 101 . 51 ± 61 . 81 vs . 69 . 22 ± 45 . 93 nmol / l , p = 0 . 015 ) and DHEAS ( 3 . 11 ± 2 . 65 vs . 2 . 11 ± 3 . 06 μmol / l , p = 0 . 007 ) and a tendency to higher testosterone concentrations ( 2 . 35 ± 2 . 10 vs . 1 . 71 ± 1 . 70 nmol / l , p = 0 . 056 ) in comparison with other women . The CAG repeat length in the relatively longer ( CAG ) n allele was inversely related to the Systemic Lupus International Collaborating Clinics / P10323 index ( r = - 0 . 258 , p = 0 . 009 ) . In conclusion , the androgen receptor ( CAG ) n polymorphism is not related to the development of SLE , but it could modulate the severity of the lupus chronic damages as well as the androgen levels in women .", "Axotomy transiently down - regulates androgen receptors in motoneurons of the spinal nucleus of the bulbocavernosus . DB00624 is an important trophic factor for motoneurons in the spinal nucleus of the bulbocavernosus ( SNB ) , and SNB motoneurons are more responsive to testosterone than are other motoneurons . Axonal injury during early postnatal life prevents the normal development of steroid - sensitivity by adult SNB motoneurons . Axonal injury also causes changes in the expression by motoneurons of a wide range of proteins , including the up - regulation of trophic factor receptors . We have used a polyclonal antibody ( PG - 21 ; G . S . Prins ) to study the expression of androgen receptors in SNB motoneurons after axonal injury . PG - 21 labeled motoneuronal nuclei in the lower lumbar spinal cord of rats in a pattern that matched autoradiographic reports of androgen accumulation in this region of the nervous system . A population of numerous , small cells located dorsal to the central canal also showed evidence of androgen receptor expression . Cutting the axons of SNB motoneurons in adulthood or in development caused a decrease in androgen receptor immunoreactivity in SNB motoneurons . This is the first report that a trophic factor receptor in motoneurons is down - regulated after axonal injury , and is interesting in light of reports that testosterone treatment can facilitate motoneuronal regeneration after nerve cut . P10275 levels subsequently returned to normal , regardless of the age at axotomy , providing no evidence for a lasting effect of developmental axotomy on androgen receptor levels in SNB motoneurons . Thus , axotomy - induced down - regulation of androgen receptors does not underlie the inability of SNB motoneurons to respond to androgen treatment several months after pudendal nerve cut in development .", "P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .", "Sex steroid regulation of chin - marking behavior in male New Zealand rabbits . Chin - marking behavior ( chinning ) was evaluated daily in nine intact adult male rabbits . All subjects ( Ss ) displayed chinning ( mean of means +/- SE = 61 +/- 7 marks / 10 min ) but the frequency of this behavior varied largely across them ( range of mean chinning frequency = 19 - 84 marks / 10 min ) . Chinning frequency showed abrupt variations at intervals of 2 - 3 days , but periodogram analysis did not reveal the existence of an endogenous rhythm in this behavior . Castration significantly decreased ( mean of means +/- SE = 29 +/- 9 marks / 10 min ; p < 0 . 01 ) . but did not suppress chinning . DB00624 propionate ( TP ; 1 mg / day for 16 days ) restored chinning in castrated Ss to slightly below precastration levels ( mean +/- S . E . V 53 +/- 13 marks / 10 min ) . The daily administration of 1 microgram estradiol benzoate ( EB ) plus 1 mg dihydrotestosterone propionate ( DHTP ) stimulated chinning within 2 days ( mean increase = 147 % ; p < 0 . 005 ) . DHTP ( 1 mg / day ) given alone stimulated chinning only after 11 days of treatment ( mean increase = 475 % ; p < 0 . 01 ) . At higher doses , both DHTP ( 10 mg / day ) and EB ( 10 or 50 micrograms / day ) stimulated chinning by 450 % , 80 % , and 100 % , respectively , over baseline values . Results indicate that chinning largely depends on testicular steroids . P10275 occupation by T or DB02901 , which is enhanced by E , optimally activates chinning .", "Recent androgen receptor antagonists in prostate cancer . P10275 has been shown to promote prostate cell growth and carcinogenesis of prostate cancer by up - regulating its target genes . DB00624 and dihydrotestosterone are two major hormones which bind to and activate androgen receptor . Targeting both the androgen receptor and the enzymes catalyzing the biosynthesis of testosterone and dihydrotestosterone has been shown to be clinically beneficial in the treatment of prostate cancer . Prostate cancer can become castration - resistant after long term treatment with chemo drugs , so efforts in finding compounds with improved efficiency to castration - resistant prostate cancer are urgently needed . In this review we summarized the studies on recent progress in the development of small molecular AR antagonists for the treatment of prostate cancer .", "A transcriptional repressor co - regulatory network governing androgen response in prostate cancers . Transcriptional corepressors are frequently aberrantly over - expressed in prostate cancers . However , their crosstalk with the P10275 ( AR ) , a key player in prostate cancer development , is unclear . Using ChIP - Seq , we generated extensive global binding maps of AR , ERG , and commonly over - expressed transcriptional corepressors including Q13547 , Q92769 , O15379 , and Q15910 in prostate cancer cells . Surprisingly , our results revealed that ERG , HDACs , and Q15910 are directly involved in androgen - regulated transcription and wired into an AR centric transcriptional network via a spectrum of distal enhancers and / or proximal promoters . Moreover , we showed that similar to ERG , these corepressors function to mediate repression of AR - induced transcription including cytoskeletal genes that promote epithelial differentiation and inhibit metastasis . Specifically , we demonstrated that the direct suppression of P18206 expression by ERG , Q15910 , and HDACs leads to enhanced invasiveness of prostate cancer cells . Taken together , our results highlight a novel mechanism by which , ERG working together with oncogenic corepressors including HDACs and the polycomb protein , Q15910 , could impede epithelial differentiation and contribute to prostate cancer progression , through directly modulating the transcriptional output of AR .", "Effects of short - and long - term risperidone treatment on prolactin levels in children with autism . BACKGROUND : The effects of short - and long - term risperidone treatment on serum prolactin were assessed in children and adolescents with autism . METHODS : Patients with autism ( N = 101 , 5 - 17 years of age ) were randomized to an 8 - week trial of risperidone or placebo and 63 then took part in a 4 - month open - label follow - up phase . Serum samples were obtained at Baseline and Week - 8 ( N = 78 ) , and at 6 - month ( N = 43 ) and 22 - month ( N = 30 ) follow - up . Serum prolactin was determined by immunoradiometric assay ; dopamine type - 2 receptor ( P14416 ) polymorphisms were genotyped . RESULTS : Baseline prolactin levels were similar in the risperidone ( N = 42 ) and placebo ( N = 36 ) groups ( 9 . 3 +/- 7 . 5 and 9 . 3 +/- 7 . 6 ng / ml , respectively ) . After 8 weeks of risperidone , prolactin increased to 39 . 0 +/- 19 . 2 ng / ml , compared with 10 . 1 +/- 8 . 8 ng / ml for placebo ( p < . 0001 ) . P01236 levels were also significantly increased at 6 months ( 32 . 4 +/- 17 . 8 ng / ml ; N = 43 , p < . 0001 ) and at 22 months ( N = 30 , 25 . 3 +/- 15 . 6 ng / ml , p < . 0001 ) . P01236 levels were not associated with adverse effects and P14416 alleles ( Taq1A , - 141C Ins / Del , C957T ) did not significantly influence baseline levels or risperidone - induced increases in prolactin . CONCLUSIONS : ___MASK28___ treatment was associated with two - to four - fold mean increases in serum prolactin in children with autism . Although risperidone - induced increases tended to diminish with time , further research on the consequences of long - term prolactin elevations in children and adolescents is needed .", "A new model of cell cycle - regulated transcription : repression of the cyclin A promoter by P05231 - 1 and anti - repression by E2F . Cell cycle regulation of the cyclin A gene is determined by a bipartite repressor binding site in the region of the basal promoter , termed CDE - CHR , which also controls the expression of cell cycle genes upregulated in S or G2 ( such as cdc25C ) . The CDE - CHR in the cyclin A promoter is recognized by both E2F complexes and P05231 - 1 , but the contribution of each of these factors in cell cycle regulation is unknown . In the present study , we have introduced mutations into the cyclin A promoter which lead to either a loss or enhancement of E2F binding , while having only marginal effects on the interaction with P05231 - 1 . Unlike mutants deficient for P05231 - 1 binding , promoter variants lacking E2F binding showed an unchanged repression in G0 , thus identifying P05231 - 1 as the principal repressor of the cyclin A gene . The same mutants did show , however , a delayed derepression while a mutation leading to increased E2F binding resulted in premature up - regulation . These findings clearly suggest that E2F contributes to the correct timing of cyclin A transcription , presumably by acting as an anti - repressor . In agreement with this conclusion , we find that the cyclin A promoter only poorly interacts with Q16254 , which is the major E2F family member in G0 cells , while a clear binding is seen with Q01094 and - 3 , which are up - regulated in late P55008 .", "Epigenetic repression of miR - 31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression . P10275 signaling plays a critical role in prostate cancer pathogenesis . Yet , the regulation of androgen receptor signaling remains elusive . Even with stringent androgen deprivation therapy , androgen receptor signaling persists . Here , our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA , miR - 31 , and androgen receptor signaling . We examined primary and metastatic prostate cancer and found that miR - 31 expression was reduced as a result of promoter hypermethylation , and importantly , the levels of miR - 31 expression were inversely correlated with the aggressiveness of the disease . As the expression of androgen receptor and miR - 31 was inversely correlated in the cell lines , our study further suggested that miR - 31 and androgen receptor could mutually repress each other . Upregulation of miR - 31 effectively suppressed androgen receptor expression through multiple mechanisms and inhibited prostate cancer growth in vivo . Notably , we found that miR - 31 targeted androgen receptor directly at a site located in the coding region , which was commonly mutated in prostate cancer . In addition , miR - 31 suppressed cell - cycle regulators including Q01094 , Q14209 , Q9UQ84 , Q08050 , and MCM2 . Together , our findings suggest a novel androgen receptor regulatory mechanism mediated through miR - 31 expression . The downregulation of miR - 31 may disrupt cellular homeostasis and contribute to the evolution and progression of prostate cancer . We provide implications for epigenetic treatment and support clinical development of detecting miR - 31 promoter methylation as a novel biomarker .", "P10275 and invasion in prostate cancer . Activation of androgen receptor ( AR ) stimulates the growth of not only androgen - dependent but also of androgen - refractory prostate cancer . However , neither the role of AR in invasion / metastasis nor the relationship between invasiveness and androgen - refractory status has been established . In this study , we used the androgen - dependent prostate cancer cell line MDA PCa 2b , derived from a human bone metastasis , to generate an invasive subline ( MDA - I ) using a Matrigel chamber . MDA - I cells expressed higher levels of AR and prostate - specific antigen than their less invasive parental cells . Blocking AR function or removal of androgen suppressed the invasion of MDA - I cells , whereas stimulating AR increased invasion . In addition , forced AR overexpression increased the invasiveness of MDA PCa 2b cells . Next , we showed that an androgen - refractory subline ( MDA - hr ) of MDA PCa 2b cells also expressed higher levels of AR and were more invasive than their parental androgen - dependent cells . Blocking AR function suppressed the invasiveness of MDA - hr cells . Gelatin zymography indicated that matrix metalloproteinase 2 ( P08253 ) and P14780 activities were regulated by AR signaling and closely correlated with the invasiveness of the androgen - dependent and androgen - refractory prostate cancer cells . These data suggest that AR promotes the invasiveness of both androgen - dependent and androgen - refractory prostate cancer and that a more invasive phenotype might develop through AR activation during cancer progression . These findings potentially support the use of adjuvant hormonal therapy and the future development of more potent androgen blockade therapy .", "___MASK23___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK23___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .", "P10275 is widely expressed in bovine placentomes and up - regulated during differentiation of bovine trophoblast giant cells . OBJECTIVES : In cattle no biological role has been definitely identified for placental estrogens and progesterone . However , in the bovine trophoblast androgens may also be produced and have local effects . Thus , the aims of this study were to identify androgen receptor ( AR ) expressing cells and to monitor testosterone tissue concentrations in bovine placentomes throughout gestation . METHODS : Placental AR expression was characterized at the mRNA and protein level applying conventional and real - time RT - qPCR , western blot and immunohistochemistry . DB00624 was measured by radioimmunoassay . RESULTS : AR - mRNA was qualitatively detected from day 50 of gestation until term . Mean relative gene expression levels were constant between day 100 and late gestation . A slight non - significant increase was observed in the prepartal period . With immunohistochemistry distinct nuclear signals were predominantly observed in invasive trophoblast giant cells ( P21980 ) from day 80 until term . In mature P21980 of the trophoblast , immature P21980 and uninucleated trophoblast cells , stromal cells of the chorionic villi , caruncular epithelial and stromal cells immunoreactive score values were low at early and midgestation but increased significantly ( p < 0 . 01 ) during late gestation and remained high until parturition . With western blot in placentomal tissue a specific band of approximately 110 kDa was detected as it was the case in epididymis used as a positive control . DB00624 concentrations increased from 0 . 70 ± 0 . 29 pmol / g wet tissue between days 60 - 220 to 4 . 22 ± 1 . 29 pmol / g during late gestation ( p < 0 . 001 ) . DISCUSSION : The results are consistent with androgens as active products of bovine placental steroidogenesis . The substantial up - regulation of AR expression during P21980 differentiation suggests that androgens may be related to this process .", "Targeting androgen receptor in estrogen receptor - negative breast cancer . Endocrine therapies for breast cancer that target the estrogen receptor ( ER ) are ineffective in the 25 % - 30 % of cases that are ER negative ( ER - ) . P10275 ( AR ) is expressed in 60 % - 70 % of breast tumors , independent of ER status . How androgens and AR regulate breast cancer growth remains largely unknown . We find that AR is enriched in ER - breast tumors that overexpress P04626 . Through analysis of the AR cistrome and androgen - regulated gene expression in ER -/ P04626 + breast cancers we find that AR mediates ligand - dependent activation of Wnt and P04626 signaling pathways through direct transcriptional induction of P56706 and P21860 . Specific targeting of AR , Wnt or P04626 signaling impairs androgen - stimulated tumor cell growth suggesting potential therapeutic approaches for ER -/ P04626 + breast cancers .", "Increased dihydrotestosterone receptor levels in high - stage renal adenocarcinoma . Primary renal adenocarcinoma tissue , metastatic deposits , and normal kidney parenchyma from 16 patients were assayed for sex hormone receptors by dextran - coated charcoal adsorption and sucrose gradient centrifugation techniques . DB02901 receptors ( P10275 ) were found in all renal carcinomatous tissue ( 20 / 20 ) and in 93 % ( 13 / 14 ) autologous normal kidneys analyzed . DB00624 receptors were found in 84 % ( 16 / 19 ) of tumors and 93 % ( 14 / 15 ) or normal kidneys analyzed . Estrogen receptors in small amounts ( ER ) were detected in only 5 % ( 1 / 19 ) of tumors and in 7 % ( 1 / 15 ) of normal kidneys . Progesterone receptors ( PR ) in low quantities were detected in 30 % ( 6 / 20 ) of renal tumors and in 40 % ( 6 / 15 ) of normal kidneys . P10275 levels in high - stage tumors ( DB00279 , DB00451 ) were significantly elevated over levels in autologous normal kidney , whereas in low - stage tumors localized to the kidney ( T1 and P24752 tumors ) P10275 levels were not significantly different from autologous normal kidney . The mean levels of P10275 in high - stage kidney tumors were significantly elevated over levels in low - stage tumors ( P less than 0 . 001 ) . P10275 estimation in renal neoplasms may help in biologic staging of renal adenocarcinoma and could define a group of patients in whom anti - androgen therapy may be worth a trial .", "The androgen receptor : a mediator of diverse responses . Androgens mediate a number of diverse responses through the androgen receptor , a 110 kD ligand - activated nuclear receptor . P10275 expression , which is found in a variety of tissues , changes throughout development , aging , and malignant transformation . The androgen receptor can be activated by two ligands , testosterone and dihydrotestosterone , which bind to the androgen receptor with different affinities . This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands . The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element . The ability to confer androgen specific actions by the androgen response element may depend on other cell - specific transcription factors and cis - acting DNA elements in close proximity to it . DB00624 and dihydrotestosterone appear to act upon an identical nuclear receptor . However , in certain instances , they mediate different physiologic responses . For example , dihydrotestosterone , but not testosterone , is capable of mediating full sexual development of the male external genitalia . In some cases , the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location . For example , in male pattern baldness , activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal - epithelial actions , whereas other hair follicles continue to proliferate . In other cases , altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation .", "Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( DB02901 ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the DB02901 level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .", "Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824 . P10275 plays a critical role in the development of primary as well as advanced hormone - refractory prostate cancer . Therefore , ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen - dependent prostate cancer but also for metastatic hormone - refractory prostate cancer , for which there is no effective treatment available . We report here that LAQ824 , a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials , effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations . LAQ824 seemed capable of depleting both the mutant and wild - type androgen receptors in either androgen - dependent and androgen - independent prostate cancer cells . Although LAQ824 may exert its effect through multiple mechanisms , several lines of evidence suggest that inactivation of the heat shock protein - 90 ( Hsp90 ) molecular chaperone is involved in LAQ824 - induced androgen receptor depletion . Besides androgen receptor , LAQ824 reduced the level of Hsp90 client proteins HER - 2 ( ErbB2 ) , Akt / P31749 , and P04049 in LNCaP cells . Another Hsp90 inhibitor , 17 - allyamino - 17 - demethoxygeldanamycin ( 17 - P29372 ) , also induced androgen receptor diminution . LAQ824 induced Hsp90 acetylation in LNCaP cells , which resulted in inhibition of its DB00171 - binding activity , dissociation of Hsp90 - androgen receptor complex , and proteasome - mediated degradation of androgen receptor . Consequently , LAQ824 blocked androgen - induced prostate - specific antigen production in LNCaP cells . LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells . These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer .", "Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK47___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .", "P10275 in human skin cytosol . Human skin , an accessible tissue , is an androgen target organ . We have measured the androgen - binding capacity of human skin cytosol using either 5 alpha [ 3H ] dihydrotestosterone ( [ 3H ] DB02901 ) or [ 3H ] methyltrienolone ( [ 3H ] R - 1881 ) as ligand . Samples were incubated for 20 h at 0 C , and dextran - coated charcoal was used to separate bound from free steroids . The androgen receptor has a high affinity for both ligands ( 0 . 23 +/- 0 . 04 nM for [ 3H ] DB02901 ; 0 . 32 +/- 0 . 16 nM for [ 3H ] R - 1881 ) . DB00624 , cyproterone acetate , and , to a lesser extent , estradiol also bind this protein . Progesterone displaces R - 1881 from its binding sites , whereas its 5 alpha - reduced metabolite somewhat inhibits DB02901 binding . The highest binding capacity is measured in cytosol of skin from external genitalia ( 129 . 14 +/- 58 . 0 fmol / g skin ; n = 34 ) ; it is lower in pubic skin ( 21 . 8 +/- 13 fmol / g skin ; n = 6 ) . There is no variation as a function of age or sex in genital skin ; the higher concentrations observed in the cytosol of pubic skin of women compared to that of men are probably related to lower levels of endogenous steroids . Whereas most patients with the complete form of the testicular feminization syndrome do not have detectable concentrations of androgen receptor , one patient with apparent complete clinical androgen insensitivity had a normal androgen - binding capacity . The parity of values in genital skin from men and women , the absence of variation with age , and the presence of a cytosolic androgen receptor in some androgen - insensitive patients suggest that the androgen receptor in human skin cytosol is not regulated by androgens .", "Gene expression in sexually dimorphic muscles in sheep . DB00624 is known to act differentially on skeletal muscle from different regions of the body . Two genes likely to mediate the testosterone effect are insulin - like growth factor I ( P05019 ) , an important growth regulator acting in an autocrine and paracrine way , and androgen receptor ( AR ) , because receptor density could account for differential muscle growth . Another muscle - specific gene that may play a role in differential muscle growth is myostatin , a member of the transforming growth factor - beta superfamily , shown to be a negative regulator of skeletal muscle mass . The objective of this study was to quantify and compare the steady state expression of these three genes in two different skeletal muscles in sheep . Eleven Dorset rams were slaughtered after reaching puberty and total RNA was extracted from samples of semitendinosus and splenius muscles . P05019 mRNA was measured using a competitive reverse - transcription - polymerase chain reaction . P10275 and myostatin mRNA were measured by a ribonuclease protection assay ( RPA ) with standard curves . The means ( attomoles / microg RNA ) for splenius and semitendinosus muscles were 1 . 39 and 1 . 02 ( SE = 0 . 14 ) , 4 . 05 and 2 . 96 ( SE = 0 . 24 ) , and 4 . 30 and 3 . 85 ( SE = 0 . 37 ) for P05019 , AR , and myostatin , respectively . The difference between the two muscles was significant for P05019 and AR mRNA levels with higher levels in the splenius but not significant for myostatin . Our results show that locally produced P05019 and the regulation of AR expression may be important for sexually dimorphic muscle growth patterns .", "P10275 in nuclei of rat testis . Testis nuclei of hypophysectomized rats selectively accumulate labeled testosterone and 5alpha - dihydrotestosterone following the injection of tritiated testosterone in vivo . DB00624 and 5alpha - dihydrotestosterone are bound to macromolecules in nuclei and can be extracted with 0 . 5 M DB00761 . Accumulation of protein bound radioactive androgens in nuclei of isolated seminiferous tubules is similar to that of whole testis . The relative amounts of testosterone and dihydrotestosterone in purified nuclei were similar to the relative amounts bound to cytoplasmic receptors , suggesting that cytoplasmic androgen - receptor complexes may be transported into the nuclei . Binding of labeled androgen is saturable and inhibited by prior injection of unlabeled testosterone or cyproterone acetate . Nuclear binding sites are destroyed by the proteolytic enzyme pronase , but not by DNase . Like the cytoplasmic androgen - receptor complexes in rat testis , nuclear androgen - protein complexes are heat labile and dissociate slowly at 0 degrees C . androgens fail to accumulate in testis nuclei of the Stanley - Gumbreck androgen insensitive rat , a species lacking cytoplasmic androgen receptors in testis and other androgen target tissues .", "P10275 - dependent activation of endothelial nitric oxide synthase in vascular endothelial cells : role of phosphatidylinositol 3 - kinase / akt pathway . The mechanisms of testosterone - induced vasodilatation are not fully understood . This study investigated the effect of testosterone on nitric oxide ( NO ) synthesis and its molecular mechanism using human aortic endothelial cells ( HAEC ) . DB00624 at physiological concentrations ( 1 - 100 nm ) induced a rapid ( 15 - 30 min ) increase in NO production , which was associated with phosphorylation and activation of endothelial NO synthase ( P29474 ) . Then , the involvement of the androgen receptor ( AR ) , which is abundantly expressed in HAEC , was examined . The effect of testosterone on P29474 activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA . In contrast , testosterone - induced P29474 phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERalpha small interference RNA . DB02901 , a nonaromatizable androgen , also stimulated P29474 phosphorylation . Next , the signaling cascade that leads to P29474 phosphorylation was explored . DB00624 stimulated rapid phosphorylation of Akt in a time - and dose - dependent manner , with maximal response at 15 - 60 min . The rapid phosphorylation of P29474 or NO production induced by testosterone was inhibited by Akt inhibitor SH - 5 or by phosphatidylinositol ( PI ) 3 - kinase inhibitor wortmannin . Co - immunoprecipitation assays revealed a testosterone - dependent interaction between AR and the p85alpha subunit of P19957 - kinase . In conclusion , testosterone rapidly induces NO production via AR - dependent activation of P29474 in HAEC . Activation of P19957 - kinase / Akt signaling and the direct interaction of AR with p85alpha are involved , at least in part , in P29474 phosphorylation .", "D - DB00128 implication in the modulation of frog brain sex steroid levels . There is evidence that D - aspartate ( D - DB00128 ) modulates sex hormone levels in frog testis by regulating the activity of P450 aromatase ( P450 aro ) , the key enzyme which converts DB00624 ( T ) in 17ß - Estradiol ( E2 ) . Here we report , for the first time , that there is a direct correlation among brain levels of D - DB00128 , P450 aro , E2 and Estradiol Receptor ( ERα ) in the male frogs during the reproductive as well as the post - reproductive phases of the breeding cycle , with highest levels being observed in the post - reproductive period . D - DB00128 i . p . administration to frogs ready for reproduction , induced an increase of brain P450 aro protein expression with concomitant enhancement of both E2 levels and ERα expression ; at the same time , brain T levels and P10275 expression decreased . In contrast , in the post - reproductive frogs , D - DB00128 treatment did not modify any of these parameters . Taken together , these results imply that the regulation of P450 aro expression by D - DB00128 could be an important step in the control of E2 levels in the frog brain .", "Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK68___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK68___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK68___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK68___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK68___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .", "Serum testosterone plays an important role in the metastatic ability of castration resistant prostate cancer . PURPOSE : Prostate cells are dependent on androgens for growth and proliferation . Androgen deprivation therapy is the recommended treatment for advanced / metastatic prostate cancer . Under this therapy , prostate cancer will inevitably progress to castration resistant prostate cancer ( CRPC ) . Despite putative castration resistance , testosterone might still play a crucial role in the progression of CRPC . The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings . METHODS : In vitro , the effect of testosterone and the non - aromatizable androgen methyltrienolone on migration , invasion and proliferation of a castration - resistant prostate cancer rat cell line ( Dunning R3327 - MATLyLu ) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67 . P10275 status was determined using Western blot . In vivo , Copenhagen rats were divided in four groups ( males , females , castrated males and females with testosterone suppletion ) and inoculated with MATLyLu cells . Tumor size was assessed daily . RESULTS : DB00624 increased cell migration and invasion in a concentration - dependent manner in vitro . DB00624 did not affect in vitro cell proliferation . No difference was shown between the effect of testosterone and methyltrienolone . In vivo , in groups with higher levels of circulating testosterone , more rats had ( micro ) metastases compared with groups with low levels of testosterone . No effect was observed on primary tumor size / growth . CONCLUSIONS : Despite assumed castration resistance , progression of prostate cancer is still influenced by androgens . Therefore , continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted .", "DB00624 stimulates proliferation and inhibits interleukin - 6 production of normal and hereditary gingival fibromatosis fibroblasts . Hereditary gingival fibromatosis ( P14210 ) is a rare oral condition characterized by a slow and progressive enlargement of the gingiva , involving both the maxilla and mandible . In vitro , P14210 fibroblasts demonstrate a proliferative index significantly higher than fibroblasts from normal gingiva ( NG ) . The objective of this study was to determine the effect of dihydrotestosterone on the proliferation of gingival fibroblasts derived from patients with P14210 ( n = 4 ) and from four healthy individuals . Additionally , we analyzed the effect of dihydrotestosterone on interleukin - 6 ( P05231 ) production and determined the expression levels of androgen receptors in NG and P14210 fibroblasts . Gingival fibroblasts from NG and P14210 were incubated with increasing concentrations of dihydrotestosterone with or without androgen blockers , and cultured for 24 h , and the proliferation index was determined by automated cell counter . P05231 production , in this system , was quantified using a \" capture \" enzyme - linked immunosorbent assay ( ELISA ) . Semi - quantitative reverse transcriptase - polymerase chain reaction ( RT - PCR ) was performed to measure the mRNA expression of androgen receptors . The results indicated that dihydrotestosterone simultaneously downregulates the production of P05231 and upregulates the cell proliferation . DB01216 and cyprosterone acetate , two anti - androgens , partially reversed these effects . P10275 mRNA expression was identified in both NG and P14210 fibroblasts ; however , the levels in NG were higher than those observed in P14210 . These results show that testosterone coordinates the proliferation and production of P05231 of normal and P14210 fibroblasts .", "___MASK36___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .", "Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .", "P01236 influence on cytosol and nuclear androgen receptors in the ventral , dorsal , and lateral lobes of the rat prostate . PRL augments testosterone - mediated growth of the prostate in a permissive manner . To elucidate the mechanism of this hormonal interaction , the present study examined the effect of PRL on cytosol and nuclear androgen receptors in the three prostate lobes . Adult male Sprague - Dawley rats were castrated , given 5 - mm Silastic implants of testosterone , and either grafted with two anterior pituitary glands under the kidney capsule or sham operated . Three weeks later , animals were killed , serum was collected for PRL and testosterone RIA , and the ventral , dorsal , and lateral prostate lobes were processed for either cytosol or nuclear androgen receptor quantitation . Pituitary grafts significantly elevated the serum PRL concentration and increased the weight and the content of protein and DNA of the lateral prostate lobe compared to control values . There was no effect on these parameters in the ventral or dorsal lobes . P10275 levels and apparent distributions were different in the ventral , dorsal , and lateral lobes of control animals . Unoccupied and total cytosolic androgen receptors in the three separate prostate lobes were not significantly affected by the presence of the grafts . However , an elevated PRL concentration was associated with an increase ( P less than 0 . 005 ) in nuclear androgen receptor content in the lateral lobe exclusively . The binding affinity was not altered by pituitary grafts in any of the lobes . These findings suggest that PRL promotes lateral prostatic growth by increasing nuclear androgen receptor levels in that tissue and , thus , optimizes its response to circulating testosterone .", "Differential role of beta - catenin in P15692 and histamine - induced P08253 production in microvascular endothelial cells . Increases in endothelial cell permeability and production of matrix - degrading enzymes are two early steps in the angiogenic process . Factors such as vascular endothelial growth factor ( P15692 ) and histamine induce the angiogenic process through alterations in both permeability and proteolysis . We hypothesized that beta - catenin acts as a positive regulator of P08253 and P50281 transcription following P15692 or histamine stimulation . Rat microvascular endothelial cells were exposed to P15692 or histamine overnight and P08253 protein production was assessed by gelatin zymography . Latent P08253 protein levels were increased following P15692 and histamine treatment as were P08253 mRNA transcript levels . Endothelial cells exposed to P15692 and histamine had an increased level of nuclear beta - catenin , which was sensitive to inhibition of the P19957 - kinase signaling pathway . Promoter assays indicated increased transcriptional activity of both P08253 and P50281 in endothelial cells co - transfected with luciferase reporter constructs and beta - catenin . Inhibition of beta - catenin signaling with inhibitor of catenin and T cell factor ( Q9NSA3 ) revealed that the P15692 - induced increase in P08253 mRNA is beta - catenin dependent . Interestingly , while P08253 mRNA levels increased in response to histamine H1 or H2 receptor activation , significantly larger increases were observed in cells co - treated with Q9NSA3 and histamine or the histamine receptor agonists , HTMT and dimaprit . While both P15692 and histamine increase nuclear beta - catenin and P08253 production , the role of beta - catenin in P08253 regulation differs between the two stimuli .", "P10275 is essential for sexual differentiation of responses to olfactory cues in mice . During sexual differentiation males and females are exposed to different levels of testosterone , which promotes sex differences in the adult brain and in behavior . DB00624 can act after aromatization or reduction via a number of steroid hormone receptors . Here we provide new evidence that the androgen receptor ( AR ) is essential for sexual differentiation in mice . We used mice carrying the testicular feminization ( Tfm ) mutation of the AR . Adult Tfm males , wild - type male and female littermates were gonadectomized and given subcutaneous estradiol implants . In all sexually dimorphic traits , Tfm males had responses equivalent to females and different from males . In simultaneous choice tests , males spent significantly more time investigating female - soiled bedding , whereas females and Tfm males preferred to investigate male - soiled bedding . Tfm males and females did not have a partner preference in tests with awake stimulus animals , whereas males showed a preference for females over males . Exposure to male - soiled , but not clean , bedding produced a significant increase in c - Fos - immunoreactive cells in the medial preoptic area and bed nucleus of the stria terminalis in Tfm males and females , no increase was noted in males . Masculine sexual behavior ( mounting and thrusting ) was not sexually dimorphic , and all groups displayed these behaviors . Our results support data collected in humans suggesting a role for the androgen receptor in sexual differentiation of social preferences and neural responses to pheromones .", "___MASK4___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK4___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .", "P10275 up - regulates insulin - like growth factor binding protein - 5 ( P24593 ) expression in a human prostate cancer xenograft . The insulin - like growth factor ( IGF ) binding proteins ( IGFBPs ) are important modulators of IGF action in many tissues including human prostate . IGFBPs and the androgen receptor ( AR ) are expressed in CWR22 , an androgen - dependent epithelial cell human CaP xenograft that retains biological characteristics of human CaPs , including regression following androgen withdrawal and recurrent growth of AR - containing cells in the absence of testicular androgens beginning several months after castration . Northern blot and in situ hybridization analyses demonstrated that P24593 is androgen - regulated in CWR22 . P24593 messenger RNA ( mRNA ) decreased by 90 % following castration of tumor - bearing mice compared with noncastrate androgen - stimulated mice . DB00624 treatment of CWR22 tumor - bearing mice 6 or 12 days after castration increased P24593 mRNA 10 - to 12 - fold . Levels of other IGFBP mRNAs did not change following androgen withdrawal and replacement . P24593 protein in tumor extracts bound 125I - labeled P05019 in ligand blot assays and the amounts of P24593 measured by immunoblotting paralleled the levels of P24593 mRNA . Androgen - induced expression of P24593 was at a maximum level within 24 h after testosterone replacement , whereas the major increase in cell proliferation as measured by Ki - 67 immunostaining occurred between 24 - 48 h . This time course suggested P24593 may be a mediator of androgen - induced growth of CWR22 . In tumors that recurred several months following castration , P24593 mRNA and protein increased to levels that approached those in androgen - stimulated CWR22 tumors from noncastrate mice . P24593 immunohistochemical staining of prostate tissue specimens from patients was stronger in androgen - dependent and androgen - independent CaP than in areas of intraepithelial neoplasia ( P63167 ) or benign prostatic hyperplasia ( BPH ) . P24593 mRNA in these specimens was localized predominantly to stromal cells and P24593 protein to epithelial cell membranes .", "P10275 signalling in peritubular myoid cells is essential for normal differentiation and function of adult Leydig cells . DB00624 synthesis depends on normal Leydig cell ( LC ) development , but the mechanisms controlling this development remain unclear . We recently demonstrated that androgen receptor ( AR ) ablation from a proportion of testicular peritubular myoid cells ( PTM - ARKO ) did not affect LC number , but resulted in compensated LC failure . The current study extends these investigations , demonstrating that PTM AR signalling is important for normal development , ultrastructure and function of adult LCs . Notably , mRNAs for LC markers [ e . g . steroidogenic factor 1 ( Nr5a1 ) , insulin - like growth factor ( Igf - 1 ) and insulin - like factor 3 ( Insl3 ) ] were significantly reduced in adult PTM - ARKOs , but not all LCs were similarly affected . Two LC sub - populations were identified , one apparently ' normal ' sub - population that expressed adult LC markers and steroidogenic enzymes as in controls , and another ' abnormal ' sub - population that had arrested development and only weakly expressed P51460 , luteinizing hormone receptor , and several steroidogenic enzymes . Furthermore , unlike ' normal ' LCs in PTM - ARKOs , the ' abnormal ' LCs did not involute as expected in response to exogenous testosterone . Differential function of these LC sub - populations is likely to mean that the ' normal ' LCs work harder to compensate for the ' abnormal ' LCs to maintain normal serum testosterone . These findings reveal new paracrine mechanisms underlying adult LC development , which can be further investigated using PTM - ARKOs .", "The androgen axis in recurrent prostate cancer . PURPOSE : Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen - independent . High levels of expression of androgen receptor and androgen receptor - regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence . EXPERIMENTAL DESIGN : Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied . P10275 expression was measured using monoclonal antibody and automated digital video image analysis . Tissue androgens were measured using radioimmunoassay . RESULTS : Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer ( mean optical density , 0 . 284 +/- SD 0 . 115 and percentage positive nuclei , 83 . 7 +/- 11 . 6 ) was similar to benign prostate ( mean optical density , 0 . 315 +/- 0 . 044 and percentage positive nuclei , 77 . 3 +/- 13 . 0 ) . Tissue levels of testosterone were similar in recurrent prostate cancer ( 2 . 78 +/- 2 . 34 pmol / g tissue ) and benign prostate ( 3 . 26 +/- 2 . 66 pmol / g tissue ) . Tissue levels of dihydrotestosterone , dehydroepiandrosterone , and androstenedione were lower ( Wilcoxon , P = 0 . 0000068 , 0 . 00093 , and 0 . 0089 , respectively ) in recurrent prostate cancer than in benign prostate , and mean dihydrotestosterone levels , although reduced , remained 1 . 45 nM . P10275 activation in recurrent prostate cancer was suggested by the androgen - regulated gene product , prostate - specific antigen , at 8 . 80 +/- 10 . 80 nmol / g tissue . CONCLUSIONS : DB00624 and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor . Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue .", "Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK76___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .", "Dissociated development of T cells mediating delayed - type hypersensitivity and protective T cells against Listeria monocytogenes and their functional difference in lymphokine production . P01730 + T cells mediating both delayed - type hypersensitivity ( DTH ) and acquired cellular resistance ( P10323 ) were generated in mice after immunization with viable Listeria monocytogenes . In contrast , P01730 + T cells from mice immunized with killed L . monocytogenes in complete Freund ' s adjuvant were capable of mediating only DTH but not P10323 . To determine the functional difference between T cells mediating DTH and T cells mediating P10323 , we examined two different populations of T cells for profiles of lymphokine production after stimulation with a specific antigen in vitro . The production of interleukin - 2 ( P60568 ) and P08700 but not P05112 was observed in both T cells mediating only DTH and those mediating DTH and P10323 . In this respect , both types of T cells could be categorized into the Q8IXH7 population , and they produced macrophage chemotactic factor equally well . However , the production of gamma interferon ( P01579 ) was observed only in T cells capable of mediating both DTH and P10323 . This result was confirmed not only by an enzyme immunoassay specific for murine P01579 but also by Northern ( RNA ) analysis for the detection of P01579 mRNA . These results suggested that the Q8IXH7 population may be subdivided further into two distinct subsets and that the ineffectiveness of the killed bacterial vaccine may be partly explained by the dissociated development of T cell function .", "DB00624 inhibits matrix metalloproteinase - 1 production in human endometrial stromal cells in vitro . P10275 ( AR ) is reported to be expressed in human uterine endometrium , but not much information is available on the role of androgens in human endometrium . The purpose of this study is to investigate the role of androgens in the regulation of matrix metalloproteinase ( MMP ) - 1 , which is one of the important MMPs for menstruation and embryo implantation in human endometrium . Human endometrial stromal cells ( HESCs ) were obtained from human endometrium by enzymatic dissociation method . Purified HESCs were incubated with 17beta - estradiol ( E2 ) , testosterone , or E2 + testosterone . Progestins ( natural progesterone or medroxyprogesterone acetate ) or vehicle ( dimethyl sulfoxide ) were also added to the media instead of testosterone . Furthermore , hydroxyflutamide ( FLU ), a specific AR antagonist , was also supplemented to cultured media . The amounts of P03956 in cultured media and in HESC lysates were examined by ELISA measurements and western blotting analysis respectively . The expression of ARmRNA in HESCs RNA was analyzed by RT - PCR . DB00624 significantly inhibited P03956 in both cultured media and cell lysates in a dose - dependent manner . Progestins also inhibited P03956 . Furthermore , FLU completely recovered the decrease of P03956 induced by testosterone . ARmRNA was detected in all HESCs RNA . The present study demonstrated that the secretion and production of P03956 in HESCs in vitro were inhibited by testosterone through androgen receptors in a manner similar to that seen for progesterone . These findings indicate that androgen may play an important role in morphological and functional changes of human endometrium .", "Q07869 - γ agonists , mainly 15d - PGJ ( 2 ) , reduce eosinophil recruitment following allergen challenge . We evaluate the immunomodulation of Peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) agonists 15d - PGJ ( 2 ) and rosiglitazone ( RGZ ) in a model of chronic eosinophilia . 15d - PGJ ( 2 ) and RGZ significantly reduce eosinophil migration into the peritoneal cavity and down - regulate the eosinopoiesis . The synthesis of P05113 was decreased after the treatment with 15d - PGJ ( 2 ) and RGZ corroborating with the eosinophil migration inhibition . However , IgE was decreased only after the administration of 15d - PGJ ( 2 ) in part due to B - cell inhibition . We also observed a decrease in the synthesis of O95760 , Q16552 and IL - 23 , suggesting that besides the modulation of Th2 pattern , there is a modulation via IL - 23 and Q16552 suggesting a role of these cytokines in the eosinophil recruitment . In fact Q16552 (-/-) mice failed to develop an eosinophilic response . Altogether , the results showed that Q07869 - γ agonists mainly 15d - PGJ ( 2 ) , have therapeutic efficacy in eosinophil - induced diseases with an alternative mechanism of control , via IL - 23 / Q16552 and O95760 .", "Activation of serotonin receptor - 2B rescues small - for - size liver graft failure in mice . The implantation of grafts below 30 % of the normal liver volume is associated with a high risk of failure known as small - for - size ( SFS ) syndrome . Strategies to rescue small grafts may have a dramatic impact on organ shortage . Serotonin is a potent growth factor for the liver . The goal of this study was to determine whether enhanced serotonin signaling could prevent the deleterious effects of SFS syndrome . We performed 30 % normal liver volume transplantations in wild - type C57 / BL6 and interleukin - 6 ( P05231 ) (-/-) mice . Some animals received α - methyl - 5 - HT ( DOI ) , an agonist of serotonin receptor - 2 ( P41595 ) . Endpoints included long - term survival , serum and hepatic markers of liver injury and regeneration , assessment of hepatic microcirculation by intravital fluorescence microscopy and scanning electron microscopy , and transcript levels of a variety of serotonin receptors , tumor necrosis factor α , and P05231 . All recipients of small grafts ( controls ) died within 2 - 4 days of transplantation , whereas half of those receiving DOI survived permanently . Control animals disclosed major liver injury , including diffuse microvesicular steatosis in hepatocytes , impairment of microcirculation , and a failure of regeneration , whereas these parameters were dramatically improved in animals subjected to DOI . Blockage of P41595 blunted the protective effects of DOI . Whereas P05231 levels were higher in DOI - treated animals , P05231 (-/-) mice were still protected by DOI , suggesting a protective pathway independent of P05231 . CONCLUSION : Serotonin through its action on receptor - 2B protects SFS liver grafts from injury and prevents microcirculation and regeneration . The mechanism of hepato - protection is independent of P05231 .", "P10275 - dependent transactivation of growth arrest - specific gene 6 mediates inhibitory effects of testosterone on vascular calcification . Recent epidemiological studies have found that androgen deficiency is associated with a higher incidence of cardiovascular disease in men . However , little is known about the mechanism underlying the cardioprotective effects of androgens . Here we show the inhibitory effects of testosterone on vascular calcification and a critical role of androgen receptor ( AR ) - dependent transactivation of growth arrest - specific gene 6 ( Gas6 ) , a key regulator of inorganic phosphate ( P ( i ) ) - induced calcification of vascular smooth muscle cells ( VSMC ) . DB00624 and nonaromatizable androgen dihydrotestosterone inhibited P ( i )- induced calcification of human aortic VSMC in a concentration - dependent manner . Androgen inhibited P ( i )- induced VSMC apoptosis , an essential process for VSMC calcification . The effects on VSMC calcification were mediated by restoration of P ( i )- induced down - regulation of Gas6 expression and a subsequent reduction of Akt phosphorylation . These effects of androgen were blocked by an AR antagonist , flutamide , but not by an estrogen receptor antagonist , DB00947 . We then explored the mechanistic role of the AR in Gas6 expression and found an abundant expression of AR predominantly in the nucleus of VSMC and two consensus ARE sequences in the Gas6 promoter region . DB02901 stimulated Gas6 promoter activity , and this effect was abrogated by flutamide and by AR siRNA . Site - specific mutation revealed that the proximal ARE was essential for androgen - dependent transactivation of Gas6 . Furthermore , chromatin immunoprecipitation assays demonstrated ligand - dependent binding of the AR to the proximal ARE of Gas6 . These results indicate that AR signaling directly regulates Gas6 transcription , which leads to inhibition of vascular calcification , and provides a mechanistic insight into the cardioprotective action of androgens .", "17 ___MASK71___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .", "P05112 enhances prostate - specific antigen expression by activation of the androgen receptor and Akt pathway . P10275 ( AR ) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgen - responsive elements ( AREs ) on the target genes . Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen - independent prostate cancer . The levels of interleukin - 4 ( P05112 ) are significantly elevated in sera of patients with hormone refractory prostate cancer . The potential role of P05112 on the activation of AR was investigated in prostate cancer cells . P05112 enhances AR - mediated prostate - specific antigen ( PSA ) expression and ARE - containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells . The AR can also be sensitized by P05112 and activated by significantly lower levels of androgen ( 10 pM of R1881 ) in prostate cancer cells . P05112 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells . Blocking of the Akt pathway by an Akt - specific inhibitor LY294002 abrogates P05112 - induced PSA expression and AR signaling . These results demonstrate that P05112 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells . Understanding P05112 - induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen - independent progression of prostate cancer cells .", "Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK22___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK22___ is also being investigated as part of triplet drug regimens . ___MASK22___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .", "DB00624 modulation of dendritic spines of somatosensory cortical pyramidal neurons . Brain structures and functions are increasingly recognized to be directly affected by gonadal hormones , which classically determine reproductive functions and sexual phenotypes . In this regard , we found recently that ovariectomy trimmed the dendritic spines of female rat primary somatosensory cortical neurons and estradiol supplement reversed it . Here , we investigated whether in the male androgen also has a cortical modulatory effect . The dendritic arbors and spines of rat somatosensory cortical pyramidal neurons were studied following intracellular dye injection and three - dimensional reconstruction . Dendritic spines , but not length , of the layers III and V pyramidal neurons were found reduced at 2 weeks and rebounded slightly at 4 weeks and further at 8 and 24 weeks following castration , which , however , remained significantly fewer than those of the intact animals . Two weeks of osmotic pump - delivered testosterone treatment to animals castrated for 4 weeks replenished serum testosterone and reversed the densities of dendritic spines on these neurons to control animal levels . P10275 appears to mediate this effect as its antagonist flutamide reduced the dendritic spines of normal adult rats while causing a mild feedback surge of serum testosterone . On the other hand , blocking the conversion of testosterone to estrogen with the aromatase inhibitor anastrozole failed to alter the dendritic spine densities in male adult rats . In conclusion , these results support our hypothesis that testosterone acts directly on the androgen receptor in males to modulate the dendritic spines of somatosensory cortical output neurons .", "Androgen receptors , serum androgen levels and survival of breast cancer patients . Steroid receptor levels and serum androgen levels were determined in 61 breast cancer patients and 34 patients with non - malignant breast lesions . DB00624 and dehydroepiandrosterone - sulfate did not and androstenedione did show a difference between the two groups . Androgen levels had no influence on survival rates . P10275 ( AR ) levels correlated with progesterone receptor levels , but not with estrogen receptor levels or with tumor stage . Patients with positive AR findings had a better survival rate ; this was independent of tumor stage . AR findings may therefore be a prognostic index in breast cancer patients ." ]

[ "___MASK22___", "___MASK23___", "___MASK28___", "___MASK36___", "___MASK47___", "___MASK4___", "___MASK68___", "___MASK71___", "___MASK76___" ]

[ "Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK87___ ( ___MASK87___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK87___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK87___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .", "___MASK30___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK30___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK30___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .", "P00533 dimerization status determines skin toxicity to HER - kinase targeted therapies . Skin toxicity , a common drug - related adverse event observed in cancer patients treated with epidermal growth factor receptor ( P00533 ) - directed therapies is rarely seen with therapies targeting P04626 . This study reports the significance of the P00533 and P04626 dimerization status in skin with regard to these dermatologic side effects . We demonstrate the differential effect of HER - directed therapies on the ligand driven activation status of P00533 , P04626 and MAPK in normal human epidermal keratinocytes . P00533 - directed therapies , such as gefitinib and cetuximab , inhibited ligand - induced activation of P00533 and MAPK in human keratinocytes . DB06366 , an antibody interfering with functional P04626 heterodimerization , failed to block ligand - induced HER signaling in primary keratinocytes . Using a novel proximity - based dimerization assay ( eTagtrade mark ) we show that P00533 homodimers are the predominant HER dimer pair in normal primary kertinocytes and in normal skin tissue from 16 patients with solid malignancies . The presence of [ p ] P00533 and [ p ] MAPK , but the absence of [ p ] P04626 , demonstrates productive signaling via P00533 but not P04626 in human skin . These data illustrate the importance of the P00533 dimerization partner in human skin and suggests that inhibition of P00533 homodimer signaling rather than P00533 / P04626 heterodimer signaling maybe the key molecular event determining dermatologic toxicity discrepancies observed between P00533 - targeted versus P04626 - targeted therapies .", "Use of pertuzumab for the treatment of P04626 - positive metastatic breast cancer . INTRODUCTION : Targeting the human epidermal growth factor receptor ( HER ) family of tyrosine kinase receptors has proven to be effective as a therapeutic strategy for HER type 2 ( P04626 ) - positive breast cancer . Since resistance to trastuzumab occurs relatively frequently , particularly in the metastatic setting , novel anti - P04626 targeted therapies with complementary and / or synergistic mechanisms of action have been under development . DB06366 , a P04626 - targeted monoclonal antibody that prevents P04626 dimerisation , is the first of a class of promising targeted agents for the treatment of P04626 - positive breast cancer . METHODS : A review of the biomedical literature published prior to February 2013 was conducted in English using PubMed . ClinicalTrials . gov was searched for appropriate clinical trials . The search terms used included breast neoplasm , pertuzumab , dimerisation , and P04626 - positive . Abstracts of studies presented at the ASCO and ESMO Annual Meetings , and San Antonio Breast Cancer Symposium were also included . RESULTS : DB06366 represents a novel anti - P04626 targeted therapy for P04626 - positive breast cancers . In this article , we describe the mechanism of action of pertuzumab , as well as its drug development process and preclinical testing results . Based on the results of ancillary studies , dual inhibition using pertuzumab and trastuzumab was shown to be effective for the management of P04626 - positive metastatic breast cancers pre - treated with trastuzumab - based therapy . For the first - line setting , the combination of both pertuzumab and trastuzumab with docetaxel ( CLEOPATRA trial ; clinical evaluation of pertuzumab and trastuzumab ) has changed the paradigm of patient management . CONCLUSION : DB06366 provided a more comprehensive inhibition of P04626 - driven signalling pathways . When administered together with trastuzumab , pertuzumab represent a significant advancement for the treatment of P04626 - positive metastatic breast cancer patients .", "Combined effects of C225 and 125 - iodine seed radiation on colorectal cancer cells . BACKGROUND : To characterize the effect of combined treatment of the anti - epidermal growth factor receptor ( P00533 ) monoclonal antibody C225 and 125 - iodine ( 125I ) seed radiation in human colorectal cancer . METHODS : We treated LS180 cells with 125I continuous low dose rate radiation in the presence and absence of 100 nM C225 . The clonogenic capacity , cellular proliferation , cell cycle distribution , apoptosis , and molecular pathways of the cells following the treatments were analyzed in vitro . RESULTS : The sensitizer enhancement ratio of C225 was approximately 1 . 4 . Treatment with C225 and radiation alone produced significant inhibition of cell growth , but combination therapy produced greater inhibition than either treatment administered alone . C225 increased the radiation - induced apoptosis and the fraction of γ - P16104 foci positive cells at 48 h after treatment . The Akt phosphorylation level was lower in the cells receiving the combination treatment than in the cells treated with radiation or C225 alone . CONCLUSIONS : These findings indicate that C225 sensitizes LS180 cells to 125I seed radiation . Growth inhibition is mediated by inducing apoptosis and not cell cycle arrest . Additionally , we confirmed that C225 impairs DNA repair by reducing the cellular level of the P78527 and P12956 proteins . Furthermore , the inhibition of Akt signaling activation may be responsible for the C225 - mediated radiosensitization .", "DB06366 in combination with trastuzumab and docetaxel for P04626 - positive metastatic breast cancer . Overexpression of P04626 - found in approximately 15 - 20 % of all breast cancers - is a negative prognostic factor . Although trastuzumab significantly improves the prognosis of P04626 - positive breast cancer , half of the patients with metastatic breast cancer experience disease progression within 1 year . DB06366 is a novel P04626 - targeted humanized monoclonal antibody that binds to the dimerization domain of P04626 and acts synergically with trastuzumab in inhibiting tumor progression . The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression - free survival and overall survival without increasing severe adverse events . Conclusively , pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with P04626 - positive metastatic breast cancer . Furthermore , various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present . Thus , pertuzumab has been becoming important for the treatment of patients with P04626 - positive metastatic breast cancer .", "DB06366 and its accelerated approval : evolving treatment paradigms and new challenges in the management of P04626 - positive breast cancer . The addition of trastuzumab , a monoclonal antibody to human epidermal growth factor receptor 2 ( P04626 ) , to standard chemotherapy in patients with P04626 - positive breast cancer has resulted in major improvements in breast cancer outcomes , including improved survival , in both the adjuvant and metastatic settings . However , some patients experience disease relapse despite adjuvant trastuzumab - containing therapy , and resistance to trastuzumab develops in the majority of patients in the metastatic setting . An understanding of the molecular mechanisms underlying trastuzumab resistance has aided the development of novel P04626 - targeted therapies . In June 2012 , the P04626 dimerization inhibitor pertuzumab was approved by the US Food and Drug Administration ( FDA ) for use with chemotherapy and trastuzumab in the first - line treatment of metastatic P04626 - positive breast cancer . In September 2013 , accelerated approval was granted for use of pertuzumab in the neoadjuvant setting , representing a landmark decision by the FDA . This article discusses the development of pertuzumab to date , with a particular focus on the accelerated approval decision . We highlight the need to identify reliable biomarkers of sensitivity and resistance to P04626 - targeted therapy , which would make possible the individualization of treatment for patients with P04626 - positive breast cancer .", "Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .", "Hypoxic / normoxic preconditioning increases endothelial differentiation potential of human bone marrow CD133 + cells . CD133 + cells are hemangioblasts that have capacity to generate into both hematopoietic and endothelial cells ( ECs ) . Hypoxia / normoxia has shown to be the regulator of the balance between stemness and differentiation . In this study we performed Agilent ' s whole human genome oligo microarray analysis and examined the differentiation potential of the bone - marrow - derived CD133 + cells after hypoxic / normoxic preconditioning of CD133 + cells . Results showed that there was no significant increase in erythroid colony forming unit ( CFU - E ) and CFU - granulocyte , erythrocyte , monocyte , and megakaryocyte formation with cells treated under hypoxia / normoxia . However , a significant increment of EC forming unit at 24 h ( 143 . 2 +/- 8 . 0 % ) compared to 0 h ( 100 +/- 11 . 4 % ) was observed in CFU - EC analysis . Reverse transcription - polymerase chain reaction and immunostaining analysis showed that the differentiated cells diminished hematopoietic stem cell surface markers and acquired the gene markers and functional phenotype of ECs . The transcriptome profile revealed a cluster of 232 downregulated and 498 upregulated genes in cells treated for 24 h under hypoxia . The upregulated genes include angiogenic genes , angiogenic growth factor genes , angiogenic cytokine and chemokine genes , as well as angiogenic - positive regulatory genes , including Q14512 , PDGFB , Q16663 , P48061 , P80162 , P05231 , P21246 , O14944 , P04626 , O95136 , P11487 , Q92913 , Q99988 , P05412 , L1CAM , Q02297 , P08138 , and PDGFB . On the other hand , angiogenesis inhibitors and related genes , including P29459 , P98177 , Q9NY15 , and P16035 , are downregulated . Taken together , hypoxic / normoxic preconditioning may lead to the differentiation of CD133 + cells toward endothelial lineage , which may improve the current clinical trial studies .", "Targeting of T lymphocytes to Neu / P04626 - expressing cells using chimeric single chain Fv receptors . Cell surface molecules essential for the transformed phenotype or growth of malignant cells are attractive targets for anticancer immunotherapy . Antibodies specific to Neu / P04626 , a human adenocarcinoma - associated growth factor receptor , were demonstrated to have tumor - inhibitory capacity . Yet , the inefficient accessibility of antibodies to solid tumors limits their clinical use . To redirect effector lymphocytes to adenocarcinomas , we constructed and functionally expressed in T cells chimeric single chain receptor genes incorporating both the Ag - binding domain of anti - Neu / P04626 antibodies and the zeta - signal - transducing subunit of the TCR / CD3 complex or the gamma - signal - transducing subunit of the Ig Fc receptor complex . Surface expression of the anti - Neu / P04626 chimeric genes in cytotoxic T cell hybridomas endowed them with specific Neu / P04626 recognition enabling their activation for P60568 production and lysis of transformed cells overexpressing Neu / P04626 . These chimeric genes hold promise for the immunotherapy of cancer .", "A phase IIa dose - finding and safety study of first - line pertuzumab in combination with trastuzumab , capecitabine and cisplatin in patients with P04626 - positive advanced gastric cancer . BACKGROUND : DB06366 plus trastuzumab provides a more comprehensive blockade of P04626 signalling than trastuzumab alone . Therefore , we conducted a phase IIa study of the pharmacokinetics and safety of pertuzumab plus trastuzumab and chemotherapy in advanced gastric cancer ( aGC ) . METHODS : Patients received pertuzumab 840 mg for cycle 1 and 420 mg q3w for cycles 2 - 6 ( Arm A ) or pertuzumab 840 mg q3w for six cycles ( Arm B ) . DB00072 , cisplatin and capecitabine were also given for six cycles , then trastuzumab q3w until disease progression or unmanageable toxicity . The co - primary endpoints were day 43 pertuzumab serum trough concentration ( Cmin ) and safety . RESULTS : Thirty patients were randomised . Mean pertuzumab Cmin at day 43 was 40 . 0 μg ml (- 1 ) ( s . d . : 17 . 3 ) in Arm A and 62 . 7 μg ml (- 1 ) ( 29 . 1 ) in Arm B . Mean day 43 Cmin in Arm A was ~ 37 % lower than that seen in metastatic breast cancer . The safety profiles were similar between arms and treatment was well tolerated . Partial responses were achieved by 86 % and 55 % of patients in Arms A and B , respectively . CONCLUSIONS : On the basis of the pharmacokinetic and safety data , the 840 mg q3w pertuzumab dose has been selected for a phase III study of pertuzumab , trastuzumab and chemotherapy in P04626 - positive aGC .", "DB06366 : new hope for patients with P04626 - positive breast cancer . BACKGROUND : Human epidermal growth factor receptor 2 ( P04626 ) overexpression is detected in approximately 15 % to 20 % of all breast cancers ( BCs ) . A revolutionary change in the prognosis of this subgroup of patients has occurred since trastuzumab therapy was introduced into daily clinical practice . However , because trastuzumab resistance is common , new molecules with complementary and / or synergistic mechanisms of action have been developed . DB06366 is a new anti - P04626 humanized monoclonal antibody that prevents the formation of P04626 dimers . MATERIAL AND METHODS : A computer - based literature search was carried out using PubMed ( keywords : breast neoplasm , dimerization , HER - 2 , pertuzumab ) ; data reported at international meetings are included . RESULTS : This paper describes pertuzumab ' s mechanism of action , safety , and role in P04626 - positive BCs . It also explores the role of pertuzumab as a single agent or combined with trastuzumab by reviewing data from preclinical research to ongoing clinical trials . Recently published trials , particularly the CLEOPATRA study , highlight the efficacy , tolerability , and increase in disease - free survival associated with this novel agent when combined with trastuzumab . CONCLUSION : The pertuzumab and trastuzumab anti - P04626 dual blockade is likely to represent a substantial advance for patients with P04626 - positive BCs and a new milestone on the way to personalized medicine .", "Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .", "Emerging strategies for the dual inhibition of P04626 - positive breast cancer . PURPOSE OF REVIEW : To review the recently published trials to help us refine and optimize the use of approved P04626 - targeted agents ( trastuzumab and lapatinib ) and highlight future combination strategies for the treatment of P04626 - positive breast cancer . RECENT FINDINGS : DB06366 , which prevents the dimerization of P04626 / P21860 , and trastuzumab emtansine ( DB05773 ) , a novel antibody drug conjugate ( trastuzumab joined via a stable linker to a derivative of the potent cytotoxic agent maytansine ) , have both demonstrated promising clinical activity in P04626 - positive breast cancer . Dual anti - P04626 regimens combining trastuzumab with lapatinib or pertuzumab show remarkable synergy and improved outcomes in patients previously thought to have refractory disease . In the neoadjuvant setting , dual anti - P04626 blockade and chemotherapy have almost doubled the rates of pathologic complete response compared to single anti - P04626 therapy . A better understanding of the mechanisms of resistance has led to the development of rational combination therapies cotargeting the PI3K and vascular endothelial growth factor signaling pathways . SUMMARY : New therapeutic options such as pertuzumab or DB05773 will yield clinically meaningful improvements for patients with P04626 - positive breast cancer . Given the high prevalence of intrinsic and acquired resistance to single - agent regimens , the treatment paradigm is shifting toward a dual anti - P04626 therapeutic approach .", "P35354 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients . In breast cancer , the prognostic impact of P35354 expression varies widely between studies . We examined the prognostic value of P35354 expression in a large cohort of breast cancer patients treated with primary surgery between 1985 and 1994 and explained the variable results of P35354 expression found in the literature . A tissue microarray was constructed of available tumour material , and ER , PgR , P04626 , Ki67 and P35354 were examined by immunohistochemistry . Median follow - up was 19 years . Fifty - five percent ( n = 369 / 677 ) of patients received no systemic treatment . P35354 was scored using a weighted histoscore . Analysis of P35354 expression in two groups based on the median ( 148 ; below vs . above ) showed an increased hazard ratio ( HR ) of 1 . 35 ( 95 % CI 1 . 05 - 1 . 75 , P = 0 . 021 ) for disease - free survival ( DFS ) and of 1 . 39 ( 95 % CI 1 . 03 - 1 . 82 , P = 0 . 016 ) for overall survival ( OS ) . However , P35354 did not remain independent in multivariate analysis . In patients with hormone receptor positive tumours , P35354 expression had a negative influence on outcome ( low vs . high : DFS : HR 1 . 37 , 95 % CI 1 . 07 - 1 . 76 , P = 0 . 013 ) . This effect disappeared when endocrine therapy was administered ( low vs . high : DFS : HR 0 . 93 , 95 % CI 0 . 51 - 1 . 70 , P = 0 . 811 ) while it remained statistically significant when endocrine therapy was omitted ( low vs . high : DFS : HR 1 . 48 , 95 % CI 1 . 12 - 1 . 94 , P = 0 . 005 ) . Our results show that P35354 plays a role in hormonal pathways . Our results can explain the results found in previously published studies .", "Recent advances in novel targeted therapies for P04626 - positive breast cancer . The monoclonal antibody trastuzumab has improved the outcomes of patients with breast cancer that overexpresses the human epidermal growth factor receptor 2 ( P04626 ) . However , despite this advancement , many tumors develop resistance and novel approaches are needed . Recently , a greater understanding of cellular biology has translated into the development of novel anti - P04626 agents with varying mechanisms of action . The small molecule tyrosine kinase inhibitor lapatinib has demonstrated activity in P04626 - positive metastatic breast cancer ( MBC ) and in the preoperative setting . DB06366 is a monoclonal antibody with a distinct binding site from trastuzumab , which inhibits receptor dimerization . In recent studies , the addition of pertuzumab to combination therapy has led to improvements in progression - free survival in patients with P04626 - positive MBC and higher response rates in the preoperative setting . An alternative approach is the use of novel antibody - drug conjugates such as trastuzumab - emtansine , which recently demonstrated activity in MBC . Neratinib , a pan - HER tyrosine kinase inhibitor , which irreversibly inhibits P00533 and P04626 , also has proven activity in MBC . A range of compounds is being developed to attempt to overcome trastuzumab resistance by targeting heat shock protein 90 , a molecular chaperone required for the stabilization of cellular proteins . Furthermore , agents are being developed to inhibit the mammalian target of rapamycin , a downstream component of the P60484 / PI3K pathway , which has been implicated in trastuzumab resistance . Finally , there are emerging data indicating that combinations of anti - P04626 agents may circumvent resistance mechanisms and improve patient outcomes . In this review , recent data on these emerging agents and novel combinations for P04626 - positive breast cancer are discussed .", "Enhanced antitumor activity of trastuzumab emtansine ( DB05773 ) in combination with pertuzumab in a P04626 - positive gastric cancer model . Human epidermal growth factor receptor 2 ( P04626 ) - targeted therapy by trastuzumab has become increasingly important for treating P04626 - positive cancers , and trastuzumab emtansine ( DB05773 ) is expected to serve as an effective alternative to trastuzumab . DB06366 , a P04626 dimerization inhibitor , showed prolonged progression - free survival when used with trastuzumab for P04626 - positive breast cancer . In this study , we investigated the effect of combining DB05773 and pertuzumab on xenografted gastric tumors . DB05773 as a single agent showed significant antitumor activity in all the three P04626 - high expression tumor models tested ( NCI - N87 , P35240 and 4 - 1ST ) but was ineffective against two P04626 - low expression tumors ( SNU - 16 and MKN - 28 ) . Using the DB05773 - sensitive NCI - N87 model , the combination efficacy of DB05773 and pertuzumab was elucidated . The combination induced significant tumor regression , whereas DB05773 or pertuzumab alone did not . In cultured NCI - N87 cells stimulated with epidermal growth factor ( P01133 ) or heregulin - α , concomitant treatment of DB05773 and pertuzumab significantly inhibited proliferation and increased caspase 3 / 7 activity compared to either agent alone . Only the combination significantly inhibited the phosphorylation of P00533 or P21860 , and its downstream factor AKT . Suppressed P21860 phosphorylation by the combination was also seen in the NCI - N87 xenografted tumors . Compared to single agent treatments , the combination treatment significantly enhanced antibody - dependent cellular cytotoxicity ( ADCC ) against NCI - N87 cells . These findings suggest that DB05773 in combination with pertuzumab shows significant antitumor activity by increasing AKT signal inhibition and ADCC in P04626 - positive gastric cancers .", "[ DB06366 . Dual strategy for the first - line treatment of metastatic P04626 - positive breast cancer ] .", "The expanding role of pertuzumab in the treatment of P04626 - positive breast cancer . Breast cancer tumors that demonstrate gene amplification or overexpression of human epidermal growth factor receptor 2 ( P04626 ) are classified as P04626 - positive . They account for approximately 15 % of all breast cancers and represent an adverse prognostic factor . Over the past years , many new therapies have become available for the treatment of breast cancer . Particularly , the treatment of patients with P04626 - positive breast cancer has developed with the arrival of anti - P04626 targeted therapies that have been proven to increase survival in both the metastatic and early - stage settings of the disease . DB00072 , a monoclonal antibody targeting P04626 , significantly improves survival in P04626 - positive breast cancer . Nevertheless , it is still a challenge to evolve anti - P04626 therapies , as the disease may progress . DB06366 inhibits P04626 by binding to a different P04626 epitope than trastuzumab and represents a complementary mechanism of action to trastuzumab . The efficacy and safety of pertuzumab in combination with trastuzumab with or without chemotherapy have been demonstrated in both advanced and early stages of P04626 - positive breast cancer . Herein , we review the available data on the use of pertuzumab for the treatment of patients with P04626 - positive breast cancer .", "A phase Ib , dose - finding study of erlotinib in combination with a fixed dose of pertuzumab in patients with advanced non - small - cell lung cancer . BACKGROUND : DB06366 , a dimerization inhibitor of human epidermal growth factor receptor 2 ( P04626 ) , has demonstrated pharmacodynamic activity , with stable disease in non - small - cell lung cancer . Combining erlotinib and pertuzumab may enhance antitumor activity . This study aimed to establish the recommended dosing of the erlotinib and pertuzumab combination ; assess safety , preliminary efficacy , and pharmacokinetics ; and analyze biomarkers . PATIENTS AND METHODS : Fifteen patients with stage IIIb / IV non - small - cell lung cancer who failed chemotherapy were recruited . The patients received erlotinib ( days - 8 to - 1 ) , then combination therapy ( 21 - day cycles for 6 cycles ) . DB06366 was given intravenous at 840 mg , then 420 mg once every three weeks , with erlotinib given daily ( 100 or 150 mg ) . RESULTS : No dose - limiting toxicities were observed . Adverse events were generally grade 1 / 2 and manageable . The objective response rate was 20 % ( 3 / 15 patients ; 2 responders had mutant P00533 , 1 responder had wild - type P00533 ) , median overall progression - free survival was 9 . 3 weeks . High P00533 , P04626 , and P21860 messenger RNA expression correlated with increased progression - free survival . Combination therapy did not affect erlotinib ' s pharmacokinetics ; however , pertuzumab mean exposures ( maximum concentration , 231 mg / L ; area under the concentration - time curve from 0 to 21 days , 1780 mg * d / L ) were slightly higher than in previous studies . CONCLUSIONS : Combination therapy was well tolerated in patients with good performance status , with encouraging efficacy . A loading dose of pertuzumab 840 mg followed by 420 mg once every three weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination .", "Capture and identification of proteins that bind to a GGA - rich sequence from the P04626 gene promoter region . The P04626 gene ( P04626 / neu ) is overexpressed in many human breast cancers . It is an important therapeutic target and its product protein is a key biomarker for breast cancer . A 28 - bp GGA repeat sequence ( Pu28 - mer ) in the nuclease hypersensitive site of the P04626 promoter region may play an important role in the regulation of P04626 transcription , possibly involving the formation of a G - quadruplex . In order to investigate this possibility , an affinity MALDI - MS approach was used for in vitro protein capture from nuclear extracts from cultured MCF - 7 and BT - 474 cancer cells at Pu28 - mer and control oligonucleotide - modified surfaces . Captured proteins from MCF - 7 cells were analyzed by LC - MS / MS . Based on these results , Western blot was then used to interrogate captured proteins from both MCF - 7 and the Her - 2 / neu - positive BT - 474 cells . Results support the formation of a G - quadruplex by Pu28 - mer , indicated by circular dichroism spectroscopy , that selectively captures transcription factors including P12956 , P13010 , Q00577 , nucleolin , and P61978 . Chromatin immunoprecipitation confirmed binding of P12956 , P13010 , Q00577 , and nucleolin to P04626 promoter in the live BT - 474 cells . These findings may lead to a better understanding of the role of non - duplex DNA structures in gene regulation and provide a more complete picture of the regulation of ErbB2 expression in breast cancer . The results also provide a blueprint for development of \" genome - inspired \" aptamers based on the Pu28 - mer sequence for in vitro and in vivo detection of proteins related to regulation of P04626 gene expression and breast cancer .", "Linear and conformational B cell epitope prediction of the HER 2 O95905 - subdomain III by in silico methods . Human epidermal growth factor receptor 2 ( P04626 ) is a member of the epidermal growth factor receptor family of receptor tyrosine kinases that play important roles in all processes of cell development . Their overexpression is related to many cancers , including examples in the breast , ovaries and stomach . Anticancer therapies targeting the P04626 receptor have shown promise , and monoclonal antibodies against subdomains II and IV of the P04626 extra - cellular domain ( O95905 ) , DB06366 and Herceptin , are currently used in treatments for some types of breast cancers . Since anti P04626 antibodies targeting distinct epitopes have different biological effects on cancer cells ; in this research linear and conformational B cell epitopes of P04626 O95905 , subdomain III , were identified by bioinformatics analyses using a combination of linear B cell epitope prediction web servers such as ABCpred , BCPREDs , Bepired , Bcepred and Elliprro . Then , Discotope , CBtope and SUPERFICIAL software tools were employed for conformational B cell epitope prediction . In contrast to previously reported epitopes of P04626 O95905 we predicted conformational B cell epitopes P1C : 378 - 393 ( PESFDGDPASNTAPLQ ) and P2C : 500 - 510 ( PEDECVGEGLA ) by the integrated strategy and and P4 : PESFDGD - X - TAPLQ ; Q15084 : PESFDGDP X TAPLQ ; P6 : ESFDGDP X NTAPLQP ; Q0GE19 : PESFDGDP - X - NTAPLQ ; P8 : ESFDG - XX - TAPLQPEQL and P9 : ESFDGDP - X - NTAPLQP by SUPERFICIAL software . These epitopes could be further used as peptide antigens to actively immune mice for development of new monoclonal antibodies and peptide cancer vaccines that target different epitopes or structural domains of P04626 O95905 .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK94___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "DB06366 in Combination with DB00072 and Chemotherapy in the Treatment of P04626 - Positive Metastatic Breast Cancer : Safety , Efficacy , and Progression Free Survival . Tyrosine kinase inhibitors have revolutionized the oncology community and were pioneered by the use in P04626 - targeted therapies . Improved outcomes were seen with the advent of trastuzumab , leading investigators to develop newer agents to target the P04626 pathway such as the novel monoclonal antibody pertuzumab . In this paper , we describe the attributes of pertuzumab including : mechanism of action , pharmacokinetics and metabolism , safety / cardiotoxicity , drug interactions , efficacy , and role in P04626 - positive breast cancer management . Newly reviewed here versus previously published reviews on pertuzumab oriented therapy are data of pertuzumab monotherapy as it is used in combination with other anti - P04626 agents derived from preclinical research and ongoing clinical trials . MATERIALS AND METHODS : A computer based literature search was carried out using PubMed data reported at international meetings ( ASCO ) up to September 2013 were included .", "DB06366 : development beyond breast cancer . DB06366 ( Perjeta ® ) represents the first monoclonal antibody in a new class of agents known as dimerization inhibitors . DB06366 was recently approved for the treatment of Human Epidermal Receptor 2 ( P04626 ) - positive breast cancer in the metastatic and neo - adjuvant setting . This approval for first - line therapy for metastatic breast cancer was based on the results of a large randomized multicenter phase III trial showing a significant improvement in overall survival when pertuzumab was combined with trastuzumab and docetaxel in P04626 - positive metastatic breast cancer . In the neoadjuvant setting , dual P04626 blockade by trastuzumab and pertuzumab improved the complete pathological response rate . However , pertuzumab development was not confined to breast cancer and in the present article , we focus on pertuzumab data for solid tumors other than breast cancer , and review the biological rationale for its use , the published pre - clinical and clinical evidence , as well ongoing trials .", "Anti - P04626 cancer therapy and cardiotoxicity . A significant milestone in the treatment of breast cancer is the identification of the P04626 receptor as a drug target for cancer therapies . DB00072 ( Herceptin ) , a monoclonal antibody that blocks the P04626 receptor , is among the first of such drugs approved by the US Food and Drug Administration for targeted cancer therapy . Clinical studies have shown that DB00072 significantly improves the overall survival of breast cancer patients . However , an unforeseen significant side - effect of cardiotoxicity manifested as left ventricular dysfunction and heart failure . Concurrent studies have demonstrated the essential role of the P04626 receptor in cardiac development and maintaining the physiological function of an adult heart . The P04626 receptor , therefore , has become a critical link between the oncology and cardiology fields . In addition to DB00072 , new drugs targeting the P04626 receptor , such as DB01259 , DB06366 and DB08916 , are either approved or being evaluated in clinical trials for cancer therapy . With the concern of cardiotoxicity caused by P04626 inhibition , it becomes clear that new therapeutic strategies for preventing such cardiac side effects need to be developed . It is the intent of this paper to review the potential cardiac impact of anti - P04626 cancer therapy .", "A phase I study of the safety and pharmacokinetics of the combination of pertuzumab ( rhuMab 2C4 ) and capecitabine in patients with advanced solid tumors . PURPOSE : To study the safety , pharmacokinetics , and recommended dose of the combination of pertuzumab , a humanized monoclonal antibody P04626 - dimerization inhibitor , and capecitabine in patients with advanced malignancies . EXPERIMENTAL DESIGN : Patients that had progressed to standard treatment were treated with pertuzumab at a fixed dose of 1 , 050 mg given i . v . on day 1 plus capecitabine at doses of 825 - 1 , 000 - 1 , 250 mg / m ( 2 ) , twice daily orally on days 1 to 14 of each 21 - day treatment cycle , in three sequential cohorts . The pharmacokinetics of capecitabine and pertuzumab were studied . Patients received a single dose of capecitabine in a pretreatment phase ( day - 7 ) followed by serum sampling for capecitabine and its metabolites . RESULTS : Nineteen patients were accrued and 18 were assessable . The combination of capecitabine and pertuzumab was well tolerated at all dose levels and no dose - limiting toxicities were observed . The most frequent adverse event was asthenia , which was grade 3 in two patients . One asymptomatic pulmonary embolism occurred . No other grade 3 or 4 adverse events or cardiac or left ventricular ejection fraction events were reported . There was no apparent change in the pharmacokinetics of capecitabine and its metabolites when combined with pertuzumab . The pharmacokinetics of pertuzumab was apparently not modified when administered with capecitabine . Disease stabilization was observed in 11 patients . CONCLUSIONS : DB06366 and capecitabine were well tolerated at all dose levels . Escalation beyond the highest dose level tested was not planned , as this included the recommended doses of monotherapy for both drugs . In conclusion , this combination is ready for phase II testing .", "P12931 - family kinases are activated in non - small cell lung cancer and promote the survival of epidermal growth factor receptor - dependent cell lines . The role of Src - family kinases ( SFKs ) in non - small cell lung cancer ( NSCLC ) has not been fully defined . Here we addressed this question by examining SFK phosphorylation in NSCLC biopsy samples and using genetic and pharmacological approaches to inhibit SFK expression and activity in cultured NSCLC cells . Immunohistochemical analysis of NSCLC biopsy samples using a Tyr416 phosphorylation - specific , pan - SFK antibody revealed staining in 123 ( 33 % ) of 370 tumors . Because c - Src is known to be both an upstream activator and downstream mediator of epidermal growth factor receptor ( P00533 ) , we next investigated SFK phosphorylation in a panel of NSCLC cell lines , including ones that depend on P00533 for survival . The P00533 - dependent NSCLC cell lines HCC827 and H3255 had increased phosphorylation of SFKs , and treatment of these cells with an SFK inhibitor ( P50391 or ___MASK95___ ) induced apoptosis . P50391 decreased phosphorylation of P00533 , ErbB2 , and ErbB3 and strikingly enhanced apoptosis by gefitinib , an P00533 inhibitor . HCC827 cells transfected with c - Src short hairpin RNA exhibited diminished phosphorylation of P00533 and ErbB2 and decreased sensitivity to apoptosis by P50391 or gefitinib . We conclude that SFKs are activated in NSCLC biopsy samples , promote the survival of P00533 - dependent NSCLC cells , and should be investigated as therapeutic targets in NSCLC patients .", "DB06366 monotherapy after trastuzumab - based treatment and subsequent reintroduction of trastuzumab : activity and tolerability in patients with advanced human epidermal growth factor receptor 2 - positive breast cancer . PURPOSE : The combination of pertuzumab and trastuzumab resulted in a clinical benefit rate ( P16152 ) of 50 % in patients with human epidermal growth factor receptor 2 ( P04626 ) - positive breast cancer whose disease progressed during prior trastuzumab - based therapy . To define whether this previously observed encouraging activity was a result of the combination of pertuzumab and trastuzumab or of pertuzumab alone , we recruited a third cohort of patients who received pertuzumab without trastuzumab . We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on pertuzumab monotherapy . PATIENTS AND METHODS : Twenty - nine patients with P04626 - positive breast cancer whose disease progressed during prior trastuzumab - based therapy received pertuzumab ( 840 mg loading dose , then 420 mg every 3 weeks ) until progressive disease or unacceptable toxicity . Seventeen patients with disease progression continued to receive pertuzumab ( at the same dose ) , with the addition of trastuzumab ( 4 mg / kg loading dose and then 2 mg / kg weekly or 8 mg / kg loading dose and then 6 mg / kg every 3 weeks ) . RESULTS : All 29 patients enrolled for pertuzumab monotherapy experienced disease progression . The objective response rate ( ORR ) and P16152 were 3 . 4 % and 10 . 3 % , respectively , during pertuzumab monotherapy . With the addition of trastuzumab , the ORR and P16152 were 17 . 6 % and 41 . 2 % , respectively . Progression - free survival was longer with combination therapy than pertuzumab monotherapy ( 17 . 4 v 7 . 1 weeks , respectively ) . Treatment was well tolerated with minimal cardiac dysfunction . CONCLUSION : Although pertuzumab has some activity in patients with P04626 - positive breast cancer that progressed during therapy with trastuzumab , the combination of pertuzumab and trastuzumab seems to be more active than monotherapy .", "DB06366 : a new targeted therapy for P04626 - positive metastatic breast cancer . DB00072 , a humanized monoclonal antibody , has become an important targeted therapy for patients with all stages of human epidermal growth factor receptor - 2 ( P04626 ) - positive breast cancer . However , primary and acquired resistance to trastuzumab remains a significant problem . DB06366 , a humanized monoclonal antibody that binds to a domain of the P04626 receptor separate from trastuzumab , may have the potential to overcome trastuzumab resistance . Clinical trials have shown that pertuzumab can be effectively combined with other biologic therapy or chemotherapy in patients with metastatic P04626 - positive breast cancer . DB06366 is relatively well tolerated with minimal increases in hematologic and cardiac toxicity observed when added to trastuzumab and / or docetaxel . In addition to becoming the standard of care in combination with docetaxel and trastuzumab in patients with newly diagnosed P04626 - positive metastatic breast cancer , clinical trials continue to evaluate pertuzumab in combination with other targeted therapy , chemotherapy , and in patients with early stage breast cancer . These trials will help to further determine the role of pertuzumab in the treatment of P04626 - positive breast cancer .", "DB06366 and erlotinib in patients with relapsed non - small cell lung cancer : a phase II study using 18F - DB09150 positron emission tomography / computed tomography imaging . BACKGROUND : Combination blockade of human epidermal growth factor receptor ( HER ) family signaling may confer enhanced antitumor activity than single - agent blockade . We performed a single - arm study of pertuzumab , a monoclonal antibody that inhibits P04626 dimerization , and erlotinib in relapsed non - small cell lung cancer ( NSCLC ) . METHODS : Patients received pertuzumab ( 840 - mg loading dose and 420 - mg maintenance intravenously every 3 weeks ) and erlotinib ( 150 - mg or 100 - mg dose orally , daily ) . The primary endpoint was response rate ( RR ) by 18F - DB09150 positron emission tomography ( DB09150 - PET ) at day 56 in all patients and those with P00533 wild - type tumors . RESULTS : Of 41 patients , 28 ( 68 . 3 % ) experienced treatment - related grade ≥ 3 adverse events , including pneumatosis intestinalis ( 3 patients ) , resulting in early cessation of enrollment . Tissue samples from 32 patients showed mutated P00533 status in 9 of 41 ( 22 % ) and wild - type P00533 in 23 of 41 ( 56 % ) . The DB09150 - PET RR for patients with assessments at day 56 was 19 . 5 % in all patients ( n = 41 ) and 8 . 7 % in patients with wild - type P00533 NSCLC ( n = 23 ) . Investigator - assessed computed tomography RR at day 56 was 12 . 2 % . CONCLUSION : DB09150 - PET suggests that pertuzumab plus erlotinib is an active combination , but combination therapy was poorly tolerated , which limits its clinical applicability . More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles .", "Time - resolved fluorescence resonance energy transfer ( TR - FRET ) to analyze the disruption of P00533 / P04626 dimers : a new method to evaluate the efficiency of targeted therapy using monoclonal antibodies . In oncology , simultaneous inhibition of epidermal growth factor receptor ( P00533 ) and P04626 by monoclonal antibodies ( mAbs ) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood . Here , we describe a time - resolved fluorescence resonance energy transfer ( TR - FRET ) method to quantify P00533 / P04626 heterodimers on cell surface to shed some light on the mechanism of such therapies . First , we tested this antibody - based TR - FRET assay in NIH / 3T3 cell lines that express P00533 and / or P04626 and in various tumor cell lines . Then , we used the antibody - based TR - FRET assay to evaluate in vitro the effect of different targeted therapies on P00533 / P04626 heterodimers in the ovarian carcinoma cell line SKOV - 3 . A simultaneous incubation with Cetuximab ( anti - P00533 ) and DB00072 ( anti - P04626 ) disturbed P00533 / P04626 heterodimers resulting in a 72 % reduction . Cetuximab , DB00072 or DB06366 ( anti - P04626 ) alone induced a 48 , 44 , or 24 % reduction , respectively . In contrast , the tyrosine kinase inhibitors Erlotinib and DB01259 had very little effect on P00533 / P04626 dimers concentration . In vivo , the combination of Cetuximab and DB00072 showed a better therapeutic effect ( median survival and percentage of tumor - free mice ) than the single mAbs . These results suggest a correlation between the extent of the mAb - induced P00533 / P04626 heterodimer reduction and the efficacy of such mAbs in targeted therapies . In conclusion , quantifying P00533 / P04626 heterodimers using our antibody - based TR - FRET assay may represent a useful method to predict the efficacy and explain the mechanisms of action of therapeutic mAbs , in addition to other commonly used techniques that focus on antibody - dependent cellular cytotoxicity , phosphorylation , and cell proliferation .", "YAP modifies cancer cell sensitivity to P00533 and survivin inhibitors and is negatively regulated by the non - receptor type protein tyrosine phosphatase 14 . The Yes - associated protein ( YAP ) is a transcriptional factor involved in tissue development and tumorigenesis . Although YAP has been recognized as a key element of the Hippo signaling pathway , the mechanisms that regulate YAP activities remain to be fully characterized . In this study , we demonstrate that the non - receptor type protein tyrosine phosphatase 14 ( Q15678 ) functions as a negative regulator of YAP . We show that YAP forms a protein complex with Q15678 through the WW domains of YAP and the PPXY motifs of Q15678 . In addition , Q15678 inhibits YAP - mediated transcriptional activities . Knockdown of YAP sensitizes cancer cells to various anti - cancer agents , such as cisplatin , the P00533 tyrosine kinase inhibitor erlotinib and the small - molecule antagonist of survivin , P28222 . YAP - targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects .", "[ Efficacy and Safety of DB06366 for P04626 - Positive Metastatic Breast Cancer ] . The CLEOPATRA trial showed a significant improvement in the progression - free survival ( PFS ) and overall survival of patients with P04626 - positive first - line metastatic breast cancer ( MBC ) who were treated with pertuzumab ( O15534 ) , trastuzumab ( TRA ) , and docetaxel ( DTX ) , compared to those treated with placebo , TRA , and DTX . O15534 was approved in 2013 for treating P04626 - positive MBC in Japan . Herein , we present the retrospective review of data from 10 P04626 - positive MBC patients who received O15534 in our hospital between September 2013 and August 2014 . T he median age was 52 years ( range , 45 - 66 years ) , and 7 patients were positive for ER . Six patients had not received any previous chemotherapy for their metastatic disease , while the others had received comparatively heavy pretreatment doses of chemotherapy . Our patients received the O15534 , TRA , and DTX regimen , although 2 patients were treated without DTX . Four patients experienced a partial response , 6 patients experienced stable disease ( SD ) , and 3 patients experienced SD for ≥ 6 months . The response rate was 40 % , and the clinical benefit rate was 70 % . The median PFS was 7 . 3 months ( range , 2 . 5 - 11 . 5 months ) . Grade 3 neutropenia and allergic reactions were observed in 1 and 2 patients , respectively ; no Grade 4 adverse events were observed , and thus , the regimen was well tolerated . Further clinical research seems to be warranted for developing new treatment strategies involving O15534 for P04626 - positive MBC .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "Dual P04626 blockade in the neoadjuvant and adjuvant treatment of P04626 - positive breast cancer . Human epidermal growth factor receptor 2 ( P04626 ) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15 % - 20 % of breast tumors and has been associated with poor prognosis . Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer . However , resistance to trastuzumab may pose a major problem in the effective treatment of P04626 - positive breast cancer . Dual P04626 blockade , using agents that work in a complimentary fashion to trastuzumab , has more recently been explored to evade resistance in both the preoperative ( neoadjuvant ) and adjuvant settings . Increased effectiveness of dual anti - P04626 agents over single blockade has been recently reported in clinical studies . DB06366 in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of P04626 - positive breast cancer . Various biomarkers have also been investigated to identify subsets of patients with P04626 - positive tumors who would likely respond best to these targeted therapy combinations . In this article , available trial data regarding efficacy and toxicity of treatment with combination P04626 agents in the neoadjuvant and adjuvant setting have been reviewed , and relevant correlative biomarker data from these trials have been discussed .", "DB06366 in breast cancer : a systematic review . DB06366 is a monoclonal antibody that represents the first among a new class of agents known as human epidermal growth factor receptor ( HER ) dimerization inhibitors . This is the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta - Analyses guidelines to synthesize all available data of pertuzumab in breast cancer . The search strategy retrieved 11 studies that evaluated pertuzumab . One study was conducted in the neoadjuvant setting ( 417 patients ) , whereas all the others dealt with patients with recurrent , metastatic , or refractory disease ( 1023 patients ) . Six studies were conducted in P04626 (+) breast cancer population ( 1354 patients ) , whereas 5 studies ( 86 patients ) were conducted in P04626 (-) ( or unknown P04626 status ) disease . DB06366 is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with P04626 (+) metastatic breast cancer who have not received prior anti - P04626 therapy or chemotherapy for metastatic disease . This approval has been based on data from a phase III Clinical Evaluation of DB06366 and DB00072 ( CLEOPATRA ) study . The antitumor activity with the significant reduction in the risk of progression or death , as reflected upon the increase of 6 . 1 months in median progression - free survival , indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with P04626 (+) . Moreover , pertuzumab seems to have a putative role in the management of patients with P04626 who are resistant to trastuzumab . The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future .", "DB06366 in human epidermal growth - factor receptor 2 - positive breast cancer : clinical and economic considerations . In the absence of specific therapy , the 15 % - 20 % of breast cancers demonstrating human epidermal growth - factor receptor 2 ( P04626 ) protein overexpression and / or gene amplification are characterized by a more aggressive phenotype and poorer prognosis compared to their P04626 - negative counterparts . DB00072 ( Herceptin ) , the first anti - P04626 - targeted therapy , has been associated with improved survival outcomes in P04626 - positive breast cancer . However , many patients with early stage disease continue to relapse , and metastatic disease remains incurable . In order to further improve these outcomes , several novel P04626 - targeted agents have recently been developed . DB06366 ( Perjeta ) , a monoclonal antibody against the P04626 dimerization domain , has also been associated with improved patient outcomes in clinical trials , and has recently been approved in combination with chemotherapy and trastuzumab for neoadjuvant therapy of early stage , P04626 - positive breast cancer and first - line treatment of metastatic disease . This review briefly summarizes pertuzumab ' s clinical development as well as the published evidence supporting its use , and highlights some of the currently unanswered questions that will influence pertuzumab ' s incorporation into clinical practice .", "Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK36___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .", "DB06366 protects the achilles ' heel of trastuzumab -- emtansine . DB00072 emtansine ( DB05773 ) represents a significant advancement in the treatment of P04626 (+) breast cancers . Its clinical efficacy however will be limited by the development of therapeutic resistance . In this report , the P21860 ligand neuregulin is shown to mediate DB05773 resistance , which was overcome by administration of pertuzumab , a steric inhibitor of P04626 dimerization .", "Absence of pharmacokinetic drug - drug interaction of pertuzumab with trastuzumab and docetaxel . DB06366 is a novel antihuman epidermal growth factor receptor 2 ( P04626 ) humanized monoclonal antibody . Combined with trastuzumab plus docetaxel , pertuzumab improved progression - free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial ( NCT00567190 ) in first - line P04626 - positive metastatic breast cancer . Thirty - seven patients participated in a pharmacokinetic ( PK ) / corrected QT interval substudy of CLEOPATRA , which evaluated potential PK drug - drug interaction ( DB00900 ) . PK parameters were calculated using noncompartmental methods , and DB00900 analyses were carried out . In the presence of trastuzumab and docetaxel , the mean pertuzumab Cmin and Cmax in cycle 3 were 63 . 6 and 183 µg / ml , respectively . The pertuzumab concentrations observed were consistent with simulations from a validated population PK model , indicating that trastuzumab and docetaxel did not alter pertuzumab PK . Comparison of geometric least - squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel . In conclusion , no PK DB00900 was observed when pertuzumab , trastuzumab , and docetaxel were combined for the treatment of P04626 - positive metastatic breast cancer .", "Antibody therapy for breast cancer . Targeted therapies against tumor biological properties are an essential part of individualized therapy concepts in breast cancer . Next to risk - adapted strategies using conventional chemo - and / or endocrine therapies , antibody therapy has become an additional option . The humanized monoclonal antibody trastuzumab ( Herceptin ) is the first novel targeted therapy approved for routine clinical application in advanced breast cancer . Patients with P04626 / neu protein overexpression as assessed by immunohistochemistry ( IHC ) and / or gene amplification as assessed by fluorescence in - situ hybridization ( Q5TCZ1 ) in their tumors respond well to palliative trastuzumab therapy , either as single agent or in combination with chemotherapy . New combinations with endocrine therapy are currently being evaluated in clinical trials . DB00072 therapy is generally well - tolerated . So far , considerable cardiotoxicity was seen only in combination with doxorubicin . Thus , extensive cardiomonitoring is now performed in trials assessing further chemotherapeutic partners . Clinical trials looking at early trastuzumab therapy in the adjuvant ( e . g . O75616 , BOND 006 ) or neoadjuvant ( e . g . TECHNO ) setting are still open for recruitment in Germany . Since only about those 25 % of breast cancers which are P04626 / neu - positive are eligible for trastuzumab , novel targeted therapeutics for the remaining P04626 / neu - negative tumors are needed . Another therapeutic antibody , 2C4 ( DB06366 , DB06366 ) , is currently under clinical evaluation . It binds to a different epitope on P04626 / neu than trastuzumab and inhibits heterodimerization with other HER receptors . Phase I data showed that 2C4 is well tolerated and clinically active .", "P04626 Dimerization Inhibitor DB06366 - Mode of Action and Clinical Data in Breast Cancer . The humanized monoclonal antibody pertuzumab prevents the dimerization of P04626 with other HER receptors , in particular the pairing of the most potent signaling heterodimer P04626 / P21860 , thus providing a potent strategy for dual P04626 inhibition . It binds to the extracellular domain of P04626 at a different epitope than trastuzumab . DB06366 and trastuzumab act in a complementary fashion and provide a more complete blockade of P04626 - mediated signal transduction than either agent alone . Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and / or cytotoxic agents , and implied an improved clinical efficacy of the combination of pertuzumab and trastuzumab in early and advanced P04626 - positive breast cancer . Results of the pivotal phase III study CLEOPATRA in patients with P04626 - positive metastatic breast cancer demonstrated that the addition of pertuzumab to first - line combination therapy with docetaxel and trastuzumab significantly prolonged progression - free and overall survival without increasing cardiac toxicity . Currently , the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early P04626 - positive breast cancer . Dual P04626 inhibition with the P04626 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in P04626 - positive first - line metastatic breast cancer treatment .", "Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .", "Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .", "Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non - small - cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 / neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 / RARα for all - trans - retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .", "Attenuated P08908 receptor signaling in brains of suicide victims : involvement of adenylyl cyclase , phosphatidylinositol 3 - kinase , Akt and mitogen - activated protein kinase . Positron emission tomography studies in major depression show reduced serotonin ( 5 - HT ) 1A receptor antagonist - binding potentials in many brain regions including occipital cortex . The functional meaning of this observation in terms of signal transduction is unknown . We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of P08908 receptor activation . The diagnosis was established by means of psychological autopsy using Diagnostic and Statistical Manual of Mental Disorders ( DSM ) III - R criteria . Measurements of [ 35S ] GTPgammaS binding to Galphai / o in the occipital cortex of suicide victims and matched controls revealed a blunted response in suicide subjects and a decrease in the coupling of P08908 receptor to adenylyl cyclase . No significant group differences were detected in the expression levels of Galphai / o , Galphaq / 11 or Galphas proteins , or in the activity of DB02527 - dependent protein kinase A . Studies of a parallel transduction pathway downstream from P08908 receptor activation demonstrated a decrease in the activity of phosphatidylinositol 3 - kinase and its downstream effector Akt , as well as an increase in P60484 ( phosphatase and tensin homolog deleted on chromosome 10 ) , the phosphatase that hydrolyzes phosphatidylinositol 3 , 4 , 5 - triphosphate . Finally , the activation of extracellular signal - regulated kinases 1 and 2 was attenuated in suicide victims . These data suggest that the alterations in agonist - stimulated P08908 receptor activation in depressed suicide victims are also manifest downstream from the associated G protein , affecting the activity of second messengers in two P08908 receptor transduction pathways that may have implications for cell survival .", "Discovery and structure - activity relationship of ( 1R ) - 8 - chloro - 2 , 3 , 4 , 5 - tetrahydro - 1 - methyl - 1H - 3 - benzazepine ( ___MASK11___ ) , a selective serotonin P28335 receptor agonist for the treatment of obesity . The synthesis and SAR of a novel 3 - benzazepine series of P28335 agonists is described . Compound 7d ( lorcaserin , APD356 ) was identified as one of the more potent and selective compounds in vitro ( pEC50 values in functional assays measuring [( 3 ) H ] phosphoinositol turnover : P28335 = 8 . 1 ; 5 - Q13049 = 6 . 8 ; P41595 = 6 . 1 ) and was potent in an acute in vivo rat food intake model upon oral administration ( ED50 at 6 h = 18 mg / kg ) . ___MASK11___ was further characterized in a single - dose pharmacokinetic study in rat ( t1 / 2 = 3 . 7 h ; F = 86 % ) and a 28 - day model of weight gain in growing Sprague - Dawley rat ( 8 . 5 % decrease in weight gain observed at 36 mg / kg b . i . d . ) . ___MASK11___ was selected for further evaluation in clinical trials for the treatment of obesity .", "Influence of mammographic density on the diagnostic accuracy of tumor size assessment and association with breast cancer tumor characteristics . PURPOSE : The accuracy of breast cancer staging involves the estimation of the tumor size for the initial decision - making in the treatment . We investigated the accuracy of tumor size estimation and the association between tumor characteristics and breast density ( BD ) . MATERIALS AND METHODS : A total of 434 women with a primary diagnosis of breast cancer were included in this prospective study at a specialist breast unit . Estimated tumor characteristics included tumor size , nodal status , estrogen / progesterone receptor status , Ki - 67 , P04626 / neu , vascular invasion . Radiomorphological data included tumor size as assessed by mammography , breast ultrasonography , and clinical examination , and American College of Radiology ( P10323 ) categories for BD . RESULTS : BD did not have a significant impact on the assessment of tumor size using breast ultrasound ( deviation from P10323 categories 1 - 4 : 0 . 55 - 0 . 68 cm ; P = 0 . 331 ) . The deviation in mammography was significantly different dependent on BD ( 0 . 42 - 0 . 9 cm ; P < 0 . 001 ) . The clinical examination was not affected by BD . Age and tumor size were the only parameters associated with a denser breast in the multivariate analysis . Older women were less likely to have dense breasts ( odds ratio 0 . 157 for women aged > or = 70 years ) , and patients with larger tumors were less likely to have dense breasts ( adjusted OR 0 . 36 for tumors > 2 cm ) . CONCLUSION : Breast ultrasonography is more accurate than mammography for assessing tumor size in breasts with a higher BD . The difference in tumor size assessment needs to be taken into consideration in the design of clinical trials and treatment decisions .", "___MASK96___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK96___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK21___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .", "P04626 signaling pathway activation and response of breast cancer cells to P04626 - targeting agents is dependent strongly on the 3D microenvironment . Development of effective and durable breast cancer treatment strategies requires a mechanistic understanding of the influence of the microenvironment on response . Previous work has shown that cellular signaling pathways and cell morphology are dramatically influenced by three - dimensional ( 3D ) cultures as opposed to traditional two - dimensional ( 2D ) monolayers . Here , we compared 2D and 3D culture models to determine the impact of 3D architecture and extracellular matrix ( Q13201 ) on P04626 signaling and on the response of P04626 - amplified breast cancer cell lines to the P04626 - targeting agents DB00072 , DB06366 and DB01259 . We show that the response of the P04626 - amplified AU565 , SKBR3 and HCC1569 cells to these anti - P04626 agents was highly dependent on whether the cells were cultured in 2D monolayer or 3D laminin - rich Q13201 gels . Inhibition of beta1 integrin , a major cell - Q13201 receptor subunit , significantly increased the sensitivity of the P04626 - amplified breast cancer cell lines to the humanized monoclonal antibodies DB00072 and DB06366 when grown in a 3D environment . Finally , in the absence of inhibitors , 3D cultures had substantial impact on P04626 downstream signaling and induced a switch between PI3K - AKT - and DB01367 - MAPK - pathway activation in all cell lines studied , including cells lacking P04626 amplification and overexpression . Our data provide direct evidence that breast cancer cells are able to rapidly adapt to different environments and signaling cues by activating alternative pathways that regulate proliferation and cell survival , events that may play a significant role in the acquisition of resistance to targeted therapies .", "[ ___MASK68___ sodium ( Photofrin - II ) ] . ___MASK68___ sodium ( ___MASK68___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK68___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .", "Synergism between bosutinib ( ___MASK95___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL ." ]

[ "___MASK11___", "___MASK21___", "___MASK30___", "___MASK36___", "___MASK68___", "___MASK87___", "___MASK94___", "___MASK95___", "___MASK96___" ]

[ "Adipose tissue tumor necrosis factor and interleukin - 6 expression in human obesity and insulin resistance . Adipose tissue expresses tumor necrosis factor ( P01375 ) and interleukin ( IL ) - 6 , which may cause obesity - related insulin resistance . We measured P01375 and P05231 expression in the adipose tissue of 50 lean and obese subjects without diabetes . P01308 sensitivity ( S ( I ) ) was determined by an intravenous glucose tolerance test with minimal - model analysis . When lean [ body mass index ( BMI ) < 25 kg / m ( 2 ) ] and obese ( BMI 30 - 40 kg / m ( 2 ) ) subjects were compared , there was a 7 . 5 - fold increase in P01375 secretion ( P < 0 . 05 ) from adipose tissue , and the P01375 secretion was inversely related to S ( I ) ( r = - 0 . 42 , P < 0 . 02 ) . P05231 was abundantly expressed by adipose tissue . In contrast to P01375 , plasma ( rather than adipose ) P05231 demonstrated the strongest relationship with obesity and insulin resistance . Plasma P05231 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S ( I ) ( r = - 0 . 71 , P < 0 . 001 ) . To separate the effects of BMI from S ( I ) , subjects who were discordant for S ( I ) were matched for BMI , age , and gender . By use of this approach , subjects with low S ( I ) demonstrated a 3 . 0 - fold increased level of P01375 secretion from adipose tissue and a 2 . 3 - fold higher plasma P05231 level ( P < 0 . 05 ) compared with matched subjects with a high S ( I ) . Plasma P05231 was significantly associated with plasma nonesterified fatty acid levels ( r = 0 . 49 , P < 0 . 002 ) . Thus the local expression of P01375 and plasma P05231 are higher in subjects with obesity - related insulin resistance .", "UMD ( Universal mutation database ) : a generic software to build and analyze locus - specific databases . The human genome is thought to contain about 80 , 000 genes and presently only 3 , 000 are known to be implicated in genetic diseases . In the near future , the entire sequence of the human genome will be available and the development of new methods for point mutation detection will lead to a huge increase in the identification of genes and their mutations associated with genetic diseases as well as cancers , which is growing in frequency in industrial states . The collection of these mutations will be critical for researchers and clinicians to establish genotype / phenotype correlations . Other fields such as molecular epidemiology will also be developed using these new data . Consequently , the future lies not in simple repositories of locus - specific mutations but in dynamic databases linked to various computerized tools for their analysis and that can be directly queried on - line . To meet this goal , we devised a generic software called UMD ( Universal Mutation Database ) . It was developed as a generic software to create locus - specific databases ( LSDBs ) with the 4 ( th ) Dimension ( R ) package from ACI . This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data . Thanks to the flexible structure of the UMD software , it has been successfully adapted to nine genes either involved in cancer ( P25054 , P04637 , P06400 , O00255 , Q09428 , P40337 , and P19544 ) or in genetic diseases ( P35555 and P01130 ) . Four new LSDBs are under construction ( P49748 , P11310 , KIR6 , and P29400 ) . Finally , the data can be transferred to core databases .", "DB00731 and mitiglinide , but not sulfonylureas , induce insulin secretion through a mechanism mediated by calcium release from endoplasmic reticulum . DB00731 and mitiglinide ( glinides ) are characterized as rapid - onset and short - acting insulinotropic agents . Although both compounds do not have a sulfonylurea structure , it has been postulated that insulin secretion is preceded by their binding to Kir6 . 2 / Q09428 complex , and a mechanism of insulin secretion of glinides has been accounted for by this pathway . However , we hypothesized the involvement of additional mechanisms of insulin secretion enhanced by glinides , and we analyzed the pattern of time course of insulin secretion from MIN6 cells with the existence of agents that have specific pharmacologic actions . Dose - dependent effects of tolbutamide , glibenclamide , nateglinide , and mitiglinide were observed . P01308 secretion induced by 3 microM tolbutamide and 1 nM glibenclamide was completely inhibited by 10 microM diazoxide and 3 microM verapamil , although the latter half - component of insulin secretion profile induced by 3 microM nateglinide or 30 nM mitiglinide remained with the existence of those agents . Glinides enhanced insulin secretion even in Ca2 +- depleted medium , and its pattern of secretion was same as the pattern with existence of verapamil . The latter half was suppressed by 1 microM dantrolene , and concomitant addition of verapamil and dantrolene completely suppressed the entire pattern of insulin secretion enhanced by nateglinide . Thus , we conclude that glinide action is demonstrated through two pathways , dependently and independently , from the pathway through K ( DB00171 ) channels . We also demonstrated that the latter pathway involves the intracellular calcium release from endoplasmic reticulum via ryanodine receptor activation .", "Bayesian modelling of multivariate quantitative traits using seemingly unrelated regressions . We investigate a Bayesian approach to modelling the statistical association between markers at multiple loci and multivariate quantitative traits . In particular , we describe the use of Bayesian Seemingly Unrelated Regressions ( Q09428 ) whereby genotypes at the different loci are allowed to have non - simultaneous effects on the phenotypes considered with residuals from each regression assumed correlated . We present results from simulations showing that , under rather general conditions that are likely to hold in real situations , the Bayesian Q09428 approach has increased probability of selecting the true model compared to univariate analyses . Finally , we apply our methods to data from subjects genotyped for 12 SNPs in the apolipoprotein E ( P02649 ) gene . Phenotypes relate to response to treatment with atorvastatin and include changes in total cholesterol , low - density lipoprotein cholesterol , and triglycerides . Missing genotype data are naturally accommodated in our Bayesian framework by imputing them using a nested haplotype phasing algorithm .", "Characterization of the inhibitory effects of erythromycin and clarithromycin on the Q12809 potassium channel . Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans , however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current ( IKr ) encoded by Q12809 ( the human ether - a - go - go - related gene ) at drug concentrations , temperature and ionic conditions mimicking those occurring in human subjects . DB01345 currents in P29320 293 cells stably transfected with Q12809 were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the Q12809 encoded potassium current in a concentration dependent manner with an IC50 of 38 . 9 +/- 1 . 2 microM and Hill Slope factor of 0 . 4 +/- 0 . 1 . ___MASK15___ produced a similar concentration - dependent block with an IC50 of 45 . 7 +/- 1 . 1 microM and Hill Slope factor of 1 . 0 +/- 0 . 1 . Erythromycin ( 25 - 250 microM ) and clarithromycin ( 5 or 25 microM ) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the Q12809 potassium current at clinically relevant concentrations .", "[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK44___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .", "DB00731 is Effective for Diabetes Mellitus with Reactive Hypoglycemia in a Child with a Compound Heterozygous Q09428 Mutation . Q09428 encodes the sulfonylurea receptor 1 ( Q09428 ) subunits of the beta - cell DB00171 - sensitive potassium ( K - DB00171 ) channel playing a critical role in the regulation of insulin secretion , and inactivating mutations in Q09428 cause congenital hyperinsulinism . Recently , Q09428 inactivating mutations were reported to be involved in the development of diabetes mellitus later in life . We report a girl who was born macrosomic with transient hypoglycemia and thereafter developed diabetes mellitus accompanied by severe reactive hypoglycemia at the age of 11 yr . An OGTT ( oral glucose tolerance test ) revealed hyperglycemia due to poor early insulin response and subsequent hypoglycemia due to delayed prolonged insulin secretion . Hypoglycemia was improved by the combination of nateglinide , which stimulates early insulin secretion , and an alpha - glucosidase inhibitor , voglibose . Sequencing of the Q09428 identified a compound heterozygous mutation ( R1420H / F591fs604X ) , suggesting that this mutation may alter regulation of insulin secretion with advancing age , leading to diabetes mellitus with reactive hypoglycemia from hyperinsulinism . Therefore , long - term follow - up and periodic OGTTs are important for early detection of insulin dysregulation in congenital hyperinsulinism patients carrying the Q09428 mutation , even though hypoglycemia resolves spontaneously during infancy . Furthermore , nateglinide may be useful therapeutically in the treatment of not only diabetes mellitus but also reactive hypoglycemia .", "Pharmacogenomic analysis of DB00171 - sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A . OBJECTIVES : The common DB00171 - sensitive potassium ( KATP ) channel variants E23K and S1369A , found in the Q14654 and Q09428 genes , respectively , form a haplotype that is associated with an increased risk for type 2 diabetes . Our previous studies showed that KATP channel inhibition by the A - site sulfonylurea gliclazide was increased in the Q9C075 / A1369 haplotype . Therefore , we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure - activity relationships in KATP channels containing either the E23 / S1369 nonrisk or Q9C075 / A1369 risk haplotypes . RESEARCH DESIGN AND METHODS : The patch - clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23 / S1369 or the Q9C075 / A1369 haplotype . RESULTS : KATP channels containing the Q9C075 / A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide , chlorpropamide , and glimepiride ( IC50 values for Q9C075 / A1369 vs . E23 / S1369 = 1 . 15 vs . 0 . 71 μmol / l ; 4 . 19 vs . 3 . 04 μmol / l ; 4 . 38 vs . 2 . 41 nmol / l , respectively ) . In contrast , KATP channels containing the Q9C075 / A1369 haplotype were significantly more sensitive to inhibition by mitiglinide ( IC50 = 9 . 73 vs . 28 . 19 nmol / l for Q9C075 / A1369 vs . E23 / S1369 ) and gliclazide . DB00731 , glipizide , and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype . CONCLUSION : Our results demonstrate that the ring - fused pyrrole moiety in several A - site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the Q9C075 / A1369 risk haplotype . It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes .", "Comparison of the micro - and macro - vascular effects of glimepiride and gliclazide in metformin - treated patients with Type 2 diabetes : a double - blind , crossover study . AIMS : To compare the metabolic and vascular effects of two sulphonylureas ( SU ) , gliclazide ( specific for the pancreatic [ Q09428 ] receptor ) and glimepiride ( a nonspecific agent that also binds to vascular and cardiac [ SUR2 ] receptors ) , during chronic administration in metformin - treated patients with Type 2 diabetes ( T2DM ) . METHODS : A randomized , double - blind , crossover study of gliclazide 80 mg P55957 and glimepiride 2 mg OD , each for 4 weeks as add - on therapy to metformin , with a 4 - week washout period . Patients attended four study mornings after first dose and 4 weeks ' SU treatment for measurements of arterial distensibility ( Ax ) , pressor responsiveness to i . v . angiotensin II ( ANGII ) , and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine ( ACh ) and sodium nitroprusside ( SNP ) . RESULTS : Glycaemic responses were similar ( e . g . serum fructosamine was 315 vs 329 micro mol l - 1 after 4 weeks ) , and there was no change in augmentation index during treatment with either SU ( 9 . 1 vs 9 . 8 mmHg after 4 weeks [ 95 % confidence interval - 8 . 1 , 10 . 5 ] ) . Similarly , there were no differences between treatments in pressor responsiveness ( e . g . PD10 [ dose of agonist required to increase mean BP by 10 mmHg ] for ANGII was 1 . 37 vs 1 . 68 ng kg - 1 min - 1 [ - 4 . 3 , 6 . 9 ] ) or cutaneous microvascular vasodilator responses ( peak ACh response 68 +/- 36 vs 63 +/- 34 perfusion units [ - 82 . 7 , 79 . 1 ] ) . CONCLUSIONS : There is no evidence that Q09428 - specific and nonspecific SUs have differential effects on arterial distensibility , endothelial function or vasodilator mechanisms in metformin - treated patients with T2DM .", "The effects of mitiglinide ( KAD - 1229 ) , a new anti - diabetic drug , on DB00171 - sensitive K + channels and insulin secretion : comparison with the sulfonylureas and nateglinide . DB01252 ( KAD - 1229 ) , a new anti - diabetic drug , is thought to stimulate insulin secretion by closing the DB00171 - sensitive K + ( K ( DB00171 ) ) channels in pancreatic beta - cells . However , its selectivity for the various K ( DB00171 ) channels is not known . In this study , we examined the effects of mitiglinide on various cloned K ( DB00171 ) channels ( Kir6 . 2 / Q09428 , Kir6 . 2 / SUR2A , and Kir6 . 2 / SUR2B ) reconstituted in COS - 1 cells , and compared them to another meglitinide - related compound , nateglinide . Patch - clamp analysis using inside - out recording configuration showed that mitiglinide inhibits the Kir6 . 2 / Q09428 channel currents in a dose - dependent manner ( IC50 value , 100 nM ) but does not significantly inhibit either Kir6 . 2 / SUR2A or Kir6 . 2 / SUR2B channel currents even at high doses ( more than 10 microM ) . DB00731 inhibits Kir6 . 2 / Q09428 and Kir6 . 2 / SUR2B channels at 100 nM , and inhibits Kir6 . 2 / SUR2A channels at high concentrations ( 1 microM ) . Binding experiments on mitiglinide , nateglinide , and repaglinide to Q09428 expressed in COS - 1 cells revealed that they inhibit the binding of [ 3H ] glibenclamide to Q09428 ( IC50 values : mitiglinide , 280 nM ; nateglinide , 8 microM ; repaglinide , 1 . 6 microM ) , suggesting that they all share a glibenclamide binding site . The insulin responses to glucose , mitiglinide , tolbutamide , and glibenclamide in MIN6 cells after chronic mitiglinide , nateglinide , or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment . These results indicate that , similar to the sulfonylureas , mitiglinide is highly specific to the Kir6 . 2 / Q09428 complex , i . e . , the pancreatic beta - cell K ( DB00171 ) channel , and suggest that mitiglinide may be a clinically useful anti - diabetic drug .", "Identification of insulin - stimulated phosphorylation sites on calmodulin . P01308 enhances calmodulin phosphorylation in vivo . To determine the insulin - sensitive phosphorylation sites , phosphocalmodulin was immunoprecipitated from Chinese hamster ovary cells expressing human insulin receptors ( CHO / IR ) . P62158 was constitutively phosphorylated on serine , threonine , and tyrosine residues , and insulin enhanced phosphate incorporation on serine and tyrosine residues . Phosphocalmodulin immunoprecipitated from control and insulin - treated CHO / IR cells , and calmodulin phosphorylated in vitro by the insulin receptor kinase and casein kinase II were resolved by two - dimensional phosphopeptide mapping . Several common phosphopeptides were detected . The phosphopeptides from the in vitro maps were eluted and phosphoamino acid analysis , manual sequencing , strong cation exchange chromatography , and additional proteolysis were performed . This strategy demonstrated that DB00135 - 99 and DB00135 - 138 were phosphorylated in vitro by the insulin receptor kinase and DB00156 - 79 , DB00133 - 81 , DB00133 - 101 and DB00156 - 117 were phosphorylated by casein kinase II . In vivo phosphorylation sites were identified by comigration of phosphopeptides on two - dimensional maps with phosphopeptides derived from calmodulin phosphorylated in vitro and by phosphoamino acid analysis . This approach revealed that DB00135 - 99 and DB00135 - 138 of calmodulin were phosphorylated in CHO / IR cells in response to insulin . Additional sites remain to be identified . The identification of the insulin - stimulated in vivo tyrosine phosphorylation sites should facilitate the elucidation of the physiological role of phosphocal - modulin .", "Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK32___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .", "Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .", "Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK38___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK38___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .", "Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .", "Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .", "___MASK99___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK99___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .", "P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK44___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK44___ is in clinical development as an orally active agent .", "[ Moclobemide ( ___MASK34___ ) , the first P21397 - inhibitor : really something new ? ] .", "DB00731 , a D - phenylalanine derivative lacking either a sulfonylurea or benzamido moiety , specifically inhibits pancreatic beta - cell - type K ( DB00171 ) channels . A novel antidiabetic agent , nateglinide , is a D - phenylalanine derivative lacking either a sulfonylurea or benzamido moiety . We examined with the patch - clamp method the effect of nateglinide on recombinant DB00171 - sensitive K (+) ( K ( DB00171 ) ) channels expressed in human embryonic kidney 293T cells transfected with a Kir6 . 2 subunit and either of a sulfonylurea receptor ( Q09428 ) 1 , SUR2A , and SUR2B . In inside - out patches , nateglinide reversibly inhibited the spontaneous openings of all three types of Q09428 / Kir6 . 2 channels . DB00731 inhibited Q09428 / Kir6 . 2 channels with high and low affinities ( K ( i ) = 75 nM and 114 microM ) but SUR2A / Kir6 . 2 and SUR2B / Kir6 . 2 channels only with low affinity ( K ( i ) = 105 and 111 microM , respectively ) . DB00731 inhibited the K ( DB00171 ) current mediated by Kir6 . 2 lacking C - terminal 26 amino acids only with low affinity ( K ( i ) = 290 microM ) in the absence of Q09428 . Replacement of serine at position 1237 of Q09428 to tyrosine [ Q09428 ( S1237Y ) ] specifically abolished the high - affinity inhibition of Q09428 / Kir6 . 2 channels by nateglinide . MgADP or MgUDP ( 100 microM ) augmented the inhibitory effect of nateglinide on Q09428 / Kir6 . 2 but not Q09428 ( S1237Y )/ Kir6 . 2 or SUR2A / Kir6 . 2 channels . This augmenting effect of MgADP was also observed with the Q09428 / Kir6 . 2 ( K185Q ) channel , which was not inhibited by MgADP , but not with the Q09428 ( K1384A )/ Kir6 . 2 channel , which was not activated by MgADP . These results indicate that therapeutic concentrations of nateglinide ( approximately 10 microM ) may selectively inhibit pancreatic type Q09428 / Kir6 . 2 channels through Q09428 , especially when the channel is activated by intracellular MgADP , even though the agent does not contain either a sulfonylurea or benzamido moiety .", "P01308 - induced Q86X55 upregulation facilitates hepatocyte proliferation . Previously , we reported that Q86X55 undergoes ubiquitination - dependent degradation in renal podocytes . It was also reported that Q86X55 is necessary for fasting - induced hepatic gluconeogenesis . Based on these reports , we hypothesized that treatment with insulin , a hormone typically present under the ' fed ' condition , would inhibit gluconeogenesis via Q86X55 degradation . HepG2 cells , AML - 12 cells , and rat primary hepatocytes were treated with insulin to confirm Q86X55 downregulation . Surprisingly , insulin treatment increased Q86X55 expression in all cell types examined . Furthermore , treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells . To elucidate the role of insulin - induced Q86X55 upregulation , the HA - Q86X55 plasmid was transfected into HepG2 cells . Q86X55 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling . Moreover , Q86X55 knockdown did not influence insulin sensitivity . P01308 is known to facilitate hepatic proliferation . Like insulin , Q86X55 overexpression increased P24941 and P11802 expression . In addition , Q86X55 knockdown reduced the number of insulin - induced G2 / M phase cells . Moreover , GFP - Q86X55 overexpression increased the number of G2 / M phase cells . Based on these results , we concluded that insulin - induced Q86X55 upregulation facilitates hepatocyte proliferation . These observations indicate that Q86X55 plays an important role in liver pathophysiology .", "Suppression of dendritic cell maturation by Trichinella spiralis excretory / secretory products . Evidence from experimental studies indicates that during chronic infections with certain helminth species a regulatory network is induced that can down - modulate not only parasite - induced inflammation but also reduce other immunopathologies such as allergies and autoimmune diseases . The mechanisms however , and the molecules involved in this immunomodulation are unknown . Here , we focus on the effect of Trichinella spiralis excretory / secretory antigens ( TspES ) on the innate immune response by studying the effect of TspES on DC maturation in vitro . Bone marrow - derived DC from BALB / c mice were incubated with TspES either alone or in combination with LPS derived from two different bacteria . As indicators of DC maturation , the cytokine production ( IL - 1alpha , P05231 , P22301 , IL - 12p70 and P01375 ) and the expression of various surface molecules ( MHC - II , P25942 , P33681 and P42081 ) were measured . Results indicate that while TspES alone did not change the expression of the different surface molecules or the cytokine production , it completely inhibited DC maturation induced by Escherichia coli LPS ( E . coli LPS ) . In contrast , DC maturation induced by LPS from another bacterium , Neisseria meningitidis , was not affected by TspES . These results were confirmed using O00206 / Q9Y6Y9 / P08571 transfected P29320 293 cells . In conclusion , T . spiralis ES antigens lead to suppression of DC maturation but this effect depends on the type of LPS used to activate these cells .", "Anticytokine treatment prevents the increase in the activity of DB00171 - ubiquitin - and Ca ( 2 +)- dependent proteolytic systems in the muscle of tumour - bearing rats . The ascites hepatoma Yoshida AH - 130 induces loss of body weight and tissue waste . Tumour necrosis factor alpha ( P01375 ) plays a pivotal role in the pathogenesis of muscle wasting in this model system , but other cytokines , such as interleukin - 6 , may be involved . In order to verify whether a combined anticytokine treatment may synergistically counteract muscle protein degradation , tumour bearing rats were treated with pentoxyfilline ( PTX , an inhibitor of P01375 synthesis ) , or with suramin ( Q09428 , an antiprotozoal drug blocking the peripheral action of several cytokines including P05231 and P01375 ) , or both the drugs , and the effects on muscle proteolytic systems were assessed . Muscle protein loss in the AH - 130 - bearing rats was associated with increased activity of both the DB00171 - ubiquitin - and the calpain - dependent proteolytic pathways ( 246 % and 230 % of controls , respectively ) . Both PTX and Q09428 , either alone or in combination , prevented the depletion of muscle mass and significantly reduced the activity of muscle proteolytic systems . In particular , treatment with Q09428 , either alone or with PTX , induced a decrease in enzymatic activities to values similar to those of controls . The results obtained in the present paper demonstrate that : ( i ) muscle depletion in this model is indeed associated with increased proteasome - and calpain - dependent proteolysis , as previously suggested by increased mRNA expression of molecules pertaining to both pathways ; ( ii ) anticytokine treatments effectively reduce muscle protein loss by down - regulating the activity of at least two major proteolitic systems ; ( iii ) Q09428 is more effective than PTX in reducing the activity of proteolytic systems , possibly because of its multiple anticytokine action .", "___MASK46___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK46___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .", "The potential role of PD0332991 ( ___MASK46___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK46___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .", "DB06756 modulates age - related NF - kappaB by thiol - enhancing action . Depletion of glutathione levels and perturbations in redox status are considered to play a crucial role in aging and chronic inflammatory processes through the activation of redox sensitive transcription factors , including nuclear factor - kappaB ( NF - kappaB ) . In the current study , we assessed the regulatory action of dietary betaine in the suppression of NF - kappaB by comparing kidney tissue from old , betaine - supplemented rats or non - betaine - supplemented rats ( age 21 months ) and 7 month - old rats . In addition , cultured P29320 293T cells were utilized for the molecular assessment of betaine ' s restorative ability of redox status when treating cells with potent glutathione ( DB00143 ) - depleting agents . Results showed that in old rats a short - term feeding ( 10 d ) with betaine attenuated the age - related decrease in thiol levels , increase in reactive species and TNFalpha expression via NF - kappaB activation , compared to the young controls . These findings were verified in the cell - cultured system . Further investigations found that redox imbalance due to thiol depletion caused increased NF - kappaB activation , and cyclooxygenase ( P36551 ) - 2 and TNFalpha levels , both of which were suppressed by betaine treatment . Based on both in vivo and in vitro data , we concluded that betaine exerts its efficacy by maintaining thiol status in the regulation of P35354 and TNFalpha via NF - kappaB activation during aging .", "Aging and age - related diseases -- from endocrine therapy to target therapy . Aging represents an important health issue not only for the individual , but also for society in general . Burdens associated with aging are expanding as longevity increases . This has led to an enhanced focus on issues related to aging and age - related diseases . Until recently , anti - aging endocrine - therapy has been largely limited to hormone - replacement therapy ( HRT ) that is associated with multiple side effects , including an increased risk of cancer . This has greatly limited the application of HRT in anti - aging therapy . Recently , the focus of anti - aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks . In this regard , the P01286 - GH - DB01277 / P01308 , TOR - P23443 , NAD (+)- Sirtuin , P04637 , Q9UEF7 and P02649 pathways have been linked to processes associated with age - related diseases , including cancer , cardiovascular disease , diabetes , osteoporosis , and neurodegenerative diseases , all of which directly influence health in aging , and represent key targets in anti - aging therapy .", "[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK15___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .", "Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK58___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .", "The zinc - finger protein Q9P0J7 is overexpressed during pancreatic cancer development and downregulation of Q9P0J7 inhibits pancreatic cancer development in mice . Q9P0J7 1 ( Q9P0J7 ) was found upregulated in a differential screen in the metaplastic epithelium in the pancreas of transforming growth factor ( TGF ) - alpha transgenic mice . Expression analysis indicated broad overexpression in human cancer tissues . Therefore , we investigated the hypothesis that Q9P0J7 promotes metaplastic changes and tumor development . Q9P0J7 represents an evolutionarily highly conserved protein with a 95 % identity between human and zebrafish . Q9P0J7 is expressed during embryonic development and in the majority of adult tissues investigated . Upregulation of nuclear Q9P0J7 expression is evident in preneoplastic lesions and in several epithelial malignancies , such as pancreatic cancer in mice and humans . In cell culture and in the chicken chorioallantoic membrane model , Q9P0J7 enhances proliferation , migration and invasion of P29320 - 293 and Panc1 cells . In crossbreeding experiments , Q9P0J7 - knockdown gene trap mice showed a reduced number and size of premalignant lesions and absence of pancreatic cancer formation in TGF - alpha transgenic mice . This effect is related to the decreased expression of P55008 to S cell - cycle regulators such as cyclin D and cyclin - dependent kinase ( CDK ) 4 . Our data support the hypothesis that Q9P0J7 mediates pro - oncogenic functions in vitro and in vivo and downregulation of Q9P0J7 results in the inhibition of pancreatic cancer formation in mice . These effects are mediated through downregulation of cell - cycle control genes such as cyclin D and P11802 .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "Pancreatic beta - cell K ( DB00171 ) channel activity and membrane - binding studies with nateglinide : A comparison with sulfonylureas and repaglinide . DB00731 ( A - 4166 ) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes . The aim of this study was to determine whether nateglinide ' s interaction at the K ( DB00171 ) channel / sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models . Binding studies were carried out with membranes prepared from Q99578 - m5F cells and P29320 - 293 cells expressing recombinant human sulfonylurea receptor 1 ( Q09428 ) . The relative order for displacement of [( 3 ) H ] glibenclamide in competitive binding experiments with Q99578 - m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L - nateglinide > tolbutamide . The results with P29320 - 293 / recombinant human Q09428 cells were similar with the exception that glipizide was more potent than repaglinide . Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [( 3 ) H ] glibenclamide , consistent with both compounds competitively binding to the glibenclamide - binding site on Q09428 . Finally , the inability to measure [( 3 ) H ] nateglinide binding suggests that nateglinide dissociates rapidly from Q09428 . Direct interaction of nateglinide with K ( DB00171 ) channels in rat pancreatic beta - cells was investigated with the patch - clamp method . The relative potency for inhibition of the K ( DB00171 ) channel was repaglinide > glibenclamide > nateglinide . Kinetics of the inhibitory effect on K ( DB00171 ) current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide . The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide . These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K ( DB00171 ) channel .", "Targeting of plasmid DNA - lipoplexes to cells with molecules anchored via a metal chelator lipid . BACKGROUND : The ability to deliver plasmid DNA ( pDNA ) to specific cells in vivo is crucial for achieving efficient targeted transfection with nonviral vectors . We previously used stealth liposomes containing the chelator lipid 3 ( nitrilotriacetic acid ) - ditetradecylamine ( NTA ( 3 )- DTDA ) to target delivery of antigen and cytokines to immune cells in vivo . In the present study , we utilized liposomes containing NTA ( 3 )- DTDA and the ionizable aminolipid 1 , 2 - dioleoyl - 3 - dimethyl - ammonium - propane ( DODAP ) to incorporate pDNA into complexes for targeting to cells . METHODS : Liposomes containing DODAP , NTA ( 3 )- DTDA and helper lipids were acidified ( pH 5 . 5 ) and mixed with pDNA to form complexes . These lipoplexes were neutralized and engrafted with DB00117 - tagged molecules for targeting to extracellular receptors . Targeted transfection efficiency was assessed using the enhanced green fluorescent protein reporter gene . RESULTS : Initial transfections of P29320 - 293 cells using a DB00117 - tagged peptide ( P24752 ) related to the DB00125 - rich motif of HIV - 1 TAT protein resulted in a low transfection efficiency ( < 2 . 5 % ) . Optimization of the lipid formulation and use of an endosome - destabilizing peptide and inhibitor of DNase II , increased transfection approximately 20 - fold . These lipoplexes are approximately 250 nm in diameter , and transfection efficiencies were : approximately 50 % for P29320 - 293 cells targeted with lipoplexes containing pEGFP - N1 and engrafted with P24752 , and 30 - 40 % for HepG2 cells targeted with lipoplexes engrafted with a peptide specific for the P15692 receptor Flt - 1 . CONCLUSIONS : The results show that DODAP - containing lipoplexes incorporating NTA ( 3 )- DTDA enable the engraftment of targeting molecules and the effective targeting of pDNA to cells in serum - containing media , resulting in efficient transgene expression . The strategy may provide a convenient approach for targeting pDNA to cells in vivo in therapeutic applications .", "Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .", "beta - Arrestin - 2 interaction and internalization of the human P47900 receptor are dependent on C - terminal phosphorylation sites . The nucleotide receptor P2Y ( 1 ) regulates a variety of physiological processes and is involved in platelet aggregation . Using human P2Y ( 1 )- receptors C - terminally fused with a fluorescent protein , we studied the role of potential receptor phosphorylation sites in receptor internalization and beta - arrestin - 2 translocation by means of confocal microscopy . Three receptor constructs were generated that lacked potential phosphorylation sites in the third intracellular loop , the proximal C terminus , or the distal C terminus . The corresponding receptor constructs were expressed in human embryonic kidney ( P29320 ) - 293 cells and stimulated with 100 muM ADP . Rapid receptor internalization was observed for the wild - type receptor and from those constructs mutated in the third intracellular loop and the proximal C terminus . However , the construct lacking phosphorylation sites at the distal C terminus did not show receptor internalization upon stimulation . The microscopic data were validated by HA - tagged receptor constructs using a cell surface enzyme - linked immunosorbent assay . P2Y ( 1 )- receptor stimulated beta - arrestin - 2 - yellow fluorescent protein ( YFP ) translocation followed the same pattern as receptor internalization . Hence , no beta - arrestin - 2 - YFP translocation was observed when the distal C - terminal phosphorylation sites were mutated . Individual mutations indicate that residues Ser352 and Thr358 are essential for receptor internalization and beta - arrestin - 2 - YFP translocation . In contrast , protein kinase C ( PKC ) - mediated receptor desensitization was not affected by mutation of potential phosphorylation sites in the distal C terminus but was prevented by mutation of potential phosphorylation sites in the proximal C terminus . P2Y ( 1 )- receptor internalization in P29320 - 293 cells was not blocked by inhibitors of PKC and calmodulin - dependent protein kinase . Thus , we conclude that P2Y ( 1 )- receptor desensitization and internalization are mediated by different phosphorylation sites and kinases .", "Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK14___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK14___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK14___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK14___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK14___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK14___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK14___ .", "Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .", "Q99717 regulates Akt2 expression and insulin - induced glucose uptake in Q9BTT4 myotubes . P01308 - induced glucose uptake by skeletal muscle results from Akt2 activation and is severely impaired during insulin resistance . Recently , we and others have demonstrated that Q9UK05 improves glucose homeostasis in diabetic and non - diabetic rodents . However , the mechanism by which Q9UK05 modulates insulin action remains unknown . Here we demonstrate that Q99717 , a transcription factor activated by Q9UK05 , and Akt2 , are upregulated in differentiated Q9BTT4 myotubes . Q99717 , rather than Q15797 / 8 , is downregulated \" in vivo \" and \" in vitro \" by dexamethasone . Q99717 knockdown decreased Akt2 expression and serine phosphorylation and insulin - induced glucose uptake , and increased the expression of the lipid phosphatase Ship2 . Additionally , binding of Q99717 to Akt2 gene is decreased in dexamethasone - treated rats and increased in Q9BTT4 myotubes compared to myoblasts . The present study indicates that Q99717 regulates glucose uptake in skeletal muscle by controlling Akt2 expression and phosphorylation . These finding reveals Q99717 as a potential target for the therapeutic of type 2 diabetes .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "First analysis of the relation between P33261 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel : the ONSET / OFFSET and RESPOND genotype studies . BACKGROUND : The influence of cytochrome P450 ( CYP ) 2C19 genotype on platelet function in patients treated with ticagrelor versus clopidogrel is unknown . METHODS AND RESULTS : P33261 ( * 1 , * 2 , * 3 , * 4 , * 5 , * 6 , * 7 , * 8 , * 17 ) genotyping was performed in patients with coronary artery disease treated with ticagrelor ( 180 - mg load , 90 mg P55957 ) ( n = 92 ) or clopidogrel ( 600 - mg load , 75 mg / d ) ( n = 82 ) . All patients received 75 to 100 mg / d aspirin . Platelet function was measured by aggregometry , VerifyNow Q9H244 assay , and vasodilator - stimulated phosphoprotein - phosphorylation assay at predose , 8 hours postloading , and maintenance . In each treatment group , patients were categorized according to 2C19 genotype carrier status ( loss - of - function , gain - of - function ) and metabolizer status . Kruskal - Wallis test was used to compare platelet function among these categories for each treatment , and Wilcoxon rank sum test was used to compare platelet function between the clopidogrel and ticagrelor groups for each category . There was no statistically significant influence of genotype on platelet function during aspirin therapy alone . ___MASK44___ exhibited lower platelet reactivity than clopidogrel by all assays irrespective of 2C19 genotype or metabolizer status ( P < 0 . 01 ) . Loss - of - function carriers had greater platelet reactivity during clopidogrel therapy . The influence of genotype on platelet reactivity was greatest during clopidogrel maintenance and best demonstrated by the VerifyNow Q9H244 assay . CONCLUSIONS : This report is the first to demonstrate the superior pharmacodynamic effect of ticagrelor compared with clopidogrel irrespective of P33261 genotype . Whereas P33261 genotype influenced the antiplatelet effect of clopidogrel , there was no effect of P33261 genotype during ticagrelor therapy .", "Synthesis of new thiazolo [ 4 , 5 - d ] pyrimidines as DB01285 releasing factor modulators . P06850 ( CRF ) is a neurohormone that plays a crucial role in integrating the body ' s overall response to stress . It appears necessary and sufficient for the organism to mount functional , physiological and endocrine responses to stressors . CRF is released in response to various triggers such as chronic stress . The role of CRF and its involvement in these neurological disorders suggest that new drugs that can target the CRF function or bind to its receptors may represent a new development of neuropsychiatric medicines to treat various stress - related disorders including depression , anxiety and addictive disorders . Based on pharmacophore of the CRF1 receptor antagonists , a new series of thiazolo [ 4 , 5 - d ] pyrimidines were synthesized as P06850 ( CRF ) receptor modulators and the prepared compounds carry groups shown to produce optimum binding affinity to CRF receptors . Twenty two compounds were evaluated for their CRF1 receptor binding affinity in P29320 293 cell lines and two compounds 5o and 5s showed approximately 25 % binding affinity to CRF1 receptors . Selected compounds ( 5c and 5f ) were also evaluated for their effect on expression of genes associated with depression and anxiety disorders such as CRF1 , P16220 , P21397 , P31645 , P01303 , DatSLC6a3 , and P09172 and significant upregulation of CRF1 mRNA has been observed with compound 5c .", "Suppressed Ca2 +/ P62158 / CaMKII - dependent K ( DB00171 ) channel activity in primary afferent neurons mediates hyperalgesia after axotomy . Painful axotomy decreases K ( DB00171 ) channel current ( IK ( DB00171 ) ) in primary afferent neurons . Because cytosolic Ca ( 2 +) signaling is depressed in injured dorsal root ganglia ( Q86YR7 ) neurons , we investigated whether Ca ( 2 +)- calmodulin ( P62158 ) - Ca ( 2 +)/ P62158 - dependent kinase II ( CaMKII ) regulates IK ( DB00171 ) in large Q86YR7 neurons . Immunohistochemistry identified the presence of K ( DB00171 ) channel subunits Q09428 , SUR2 , and Kir6 . 2 but not Kir6 . 1 , and pCaMKII in neurofilament 200 - positive Q86YR7 somata . Single - channel recordings from cell - attached patches revealed that basal and evoked IK ( DB00171 ) by ionomycin , a Ca ( 2 +) ionophore , is activated by CaMKII . In axotomized neurons from rats made hyperalgesic by spinal nerve ligation ( Q16658 ) , basal K ( DB00171 ) channel activity was decreased , and sensitivity to ionomycin was abolished . Basal and Ca ( 2 +)- evoked K ( DB00171 ) channel activity correlated inversely with the degree of hyperalgesia induced by Q16658 in the rats from which the neurons were isolated . Inhibition of IK ( DB00171 ) by glybenclamide , a selective K ( DB00171 ) channel inhibitor , depolarized resting membrane potential ( O94763 ) recorded in perforated whole - cell patches and enhanced neurotransmitter release measured by amperometry . The selective K ( DB00171 ) channel opener diazoxide hyperpolarized the O94763 and attenuated neurotransmitter release . Axotomized neurons from rats made hyperalgesic by Q16658 lost sensitivity to the myristoylated form of autocamtide - 2 - related inhibitory peptide ( AIPm ) , a pseudosubstrate blocker of CaMKII , whereas axotomized neurons from Q16658 animals that failed to develop hyperalgesia showed normal IK ( DB00171 ) inhibition by AIPm . AIPm also depolarized O94763 in control neurons via K ( DB00171 ) channel inhibition . Unitary current conductance and sensitivity of K ( DB00171 ) channels to cytosolic DB00171 and ligands were preserved even after painful nerve injury , thus providing opportunities for selective therapeutic targeting against neuropathic pain .", "P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .", "Differential interactions of nateglinide and repaglinide on the human beta - cell sulphonylurea receptor 1 . DB00912 and nateglinide represent a new class of insulin secretagogues , structurally unrelated to sulphonylureas , that were developed for the treatment of type 2 diabetes . The inhibitory effect of these drugs was investigated on recombinant wild - type and mutant Kir6 . 2 / Q09428 channels expressed in HEK293 cells . DB00731 and repaglinide dose - dependently inhibited whole - cell Kir6 . 2 / Q09428 currents with half - maximal inhibitory concentration ( IC ( 50 ) ) values of 800 and 21 nmol / l , respectively . Mutation of serine 1237 in Q09428 to tyrosine ( S1237Y ) abolished tolbutamide and nateglinide block , suggesting that these drugs share a common point of interaction on the Q09428 subunit of the DB00171 - sensitive K (+) channel . In contrast , repaglinide inhibition was unaffected by the S1237Y mutation ( IC ( 50 ) = 23 nmol / l ) . Radioligand binding studies revealed a single high - affinity binding site for [( 3 ) H ] repaglinide on membranes prepared from HEK293 cells expressing wild - type ( equilibrium dissociation constant [ K ( D ) ] = 0 . 40 nmol / l ) or mutant ( K ( D ) = 0 . 31 nmol / l ) Kir6 . 2 / Q09428 channels . DB00731 and tolbutamide displaced [( 3 ) H ] repaglinide binding to wild - type channels with IC ( 50 ) values of 0 . 7 and 26 micro mol / l , respectively , but produced < 10 % displacement of [( 3 ) H ] repaglinide bound to mutant channels . This is consistent with the idea that binding of nateglinide and tolbutamide , but not repaglinide , is abolished by the Q09428 [ S1237Y ] mutation and that the binding site for repaglinide is not identical to that of nateglinde / tolbutamide . These results are discussed in terms of a conformational analysis of the drug molecules ." ]

[ "___MASK14___", "___MASK15___", "___MASK32___", "___MASK34___", "___MASK38___", "___MASK44___", "___MASK46___", "___MASK58___", "___MASK99___" ]

[ "Human T - cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF - kappaB . Adult T - cell leukemia ( ATL ) is a highly aggressive T - cell malignancy caused by human T - cell leukemia virus type 1 ( HTLV - 1 ) . The activation of NF - kappaB by Tax has been reported to play a crucial role in HTLV - 1 - induced transformation . The HTLV - 1 bZIP factor ( P02008 ) , which is encoded by an mRNA of the opposite polarity of the viral genomic RNA , is involved in both T cell proliferation and suppression of Tax - mediated viral gene transcription , suggesting that P02008 cooperates closely with Tax . In the present study , we observed that P02008 specifically suppressed NF - kappaB - driven transcription mediated by p65 ( the classical pathway ) without inhibiting the alternative NF - kappaB signaling pathway . In an immunoprecipitation assay , P02008 bound to p65 and diminished the DNA binding capacity of p65 . In addition , P02008 induced p65 degradation through increasing the expression of the Q96JY6 gene , which encodes a ubiquitin E3 ligase for p65 . Finally , P02008 actually repressed the transcription of some classical NF - kappaB target genes , such as P10145 , P01589 , Q15306 , P19320 , and P15692 . Selective suppression of the classical NF - kappaB pathway by P02008 renders the alternative NF - kappaB pathway predominant after activation of NF - kappaB by Tax or other stimuli , which might be critical for oncogenesis .", "___MASK66___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .", "Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK32___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK32___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK32___ .", "Simulations of symptomatic treatments for Alzheimer ' s disease : computational analysis of pathology and mechanisms of drug action . INTRODUCTION : A substantial number of therapeutic drugs for Alzheimer ' s disease ( AD ) have failed in late - stage trials , highlighting the translational disconnect with pathology - based animal models . METHODS : To bridge the gap between preclinical animal models and clinical outcomes , we implemented a conductance - based computational model of cortical circuitry to simulate working memory as a measure for cognitive function . The model was initially calibrated using preclinical data on receptor pharmacology of catecholamine and cholinergic neurotransmitters . The pathology of AD was subsequently implemented as synaptic and neuronal loss and a decrease in cholinergic tone . The model was further calibrated with clinical Alzheimer ' s Disease Assessment Scale - cognitive subscale ( ADAS - Cog ) results on acetylcholinesterase inhibitors and P50406 antagonists to improve the model ' s prediction of clinical outcomes . RESULTS : As an independent validation , we reproduced clinical data for apolipoprotein E ( P02649 ) genotypes showing that the ApoE4 genotype reduces the network performance much more in mild cognitive impairment conditions than at later stages of AD pathology . We then demonstrated the differential effect of memantine , an N - Methyl - D - aspartic acid ( DB01221 ) subunit selective weak inhibitor , in early and late AD pathology , and show that inhibition of the DB01221 receptor Q14957 / O15399 subunits located on inhibitory interneurons compensates for the greater excitatory decline observed with pathology . CONCLUSIONS : This quantitative systems pharmacology approach is shown to be complementary to traditional animal models , with the potential to assess potential off - target effects , the consequences of pharmacologically active human metabolites , the effect of comedications , and the impact of a small number of well described genotypes .", "___MASK57___ binding to human and rat dopamine and 5 - HT receptors . ___MASK57___ ( ___MASK57___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK57___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK57___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK57___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .", "DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .", "The influence of non - HLA gene polymorphisms and interactions on disease risk in a Western Australian multiple sclerosis cohort . Non - Human Leukocyte Antigen ( HLA ) genes have concomitant , although modest , effects on multiple sclerosis ( MS ) susceptibility ; however findings have varied in different populations . Here we present the results of an association study of 16 single nucleotide polymorphisms ( SNPs ) in 10 non - HLA genes ( P16871 , P01589 , CLEC - 16A , P29597 , P19256 , Q13568 , P40763 , P16410 , P02649 , P05362 ) in a Western Australian cohort of 350 MS patients and 498 population control subjects . Our results indicate that in this population , SNPs in P16871 , P29597 , Q13568 and P02649 have modifying effects on MS susceptibility . We also found evidence of interactive protective effects between polymorphisms in the P16871 / P19256 , CLEC - 16A / P16410 , and P29597 / Q13568 genes , which in some instances are restricted within HLA - or gender - defined groups .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .", "Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK49___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK49___ peptide content within the pituitary , and plasma ___MASK49___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK49___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK49___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK49___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .", "Efficacy and mechanism - of - action of a novel superagonist interleukin - 15 : interleukin - 15 receptor αSu / Fc fusion complex in syngeneic murine models of multiple myeloma . ALT - 803 , a complex of an interleukin ( IL ) - 15 superagonist mutant and a dimeric P40933 receptor αSu / Fc fusion protein , was found to exhibit significantly stronger in vivo biologic activity on NK and T cells than P40933 . In this study , we show that a single dose of ALT - 803 , but not P40933 alone , eliminated well - established 5T33P and MOPC - 315P myeloma cells in the bone marrow of tumor - bearing mice . ALT - 803 treatment also significantly prolonged survival of myeloma - bearing mice and provided resistance to rechallenge with the same tumor cells through a CD8 (+) T - cell - dependent mechanism . ALT - 803 treatment stimulated CD8 (+) T cells to secrete large amounts of IFN - γ and promoted rapid expansion of CD8 (+) P16070 ( high ) memory T cells in vivo . These memory CD8 (+) T cells exhibited ALT - 803 - mediated upregulation of P26718 ( P26718 ) but not P18621 ( Q15116 ) or CD25 ( P01589 ) on their cell surfaces . ALT - 803 - activated CD8 (+) memory T cells also exhibited nonspecific cytotoxicity against myeloma and other tumor cells in vitro , whereas IFN - γ had no direct effect on myeloma cell growth . ALT - 803 lost its antimyeloma activity in tumor - bearing IFN - γ knockout mice but retained the ability to promote CD8 (+) P16070 ( high ) memory T - cell proliferation , indicating that ALT - 803 - mediated stimulation of CD8 (+) P16070 ( high ) memory T cells is IFN - γ - independent . Thus , besides well - known P40933 biologic functions in host immunity , this study shows that P40933 - based ALT - 803 could activate CD8 (+) P16070 ( high ) memory T cells to acquire a unique innate - like phenotype and secrete IFN - γ for nonspecific tumor cell killing . This unique immunomodulatory property of ALT - 803 strongly supports its clinical development as a novel immunotherapeutic agent against cancer and viral infections .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK24___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "Lactobacillus acidophilus L - 92 Cells Activate Expression of Immunomodulatory Genes in THP - 1 Cells . To understand the immunomodulatory effects of Lactobacillus acidophilus L - 92 cells suggested from our previous study of in vivo anti - allergy and anti - virus effects , host immune responses in macrophage - like THP - 1 cells after 4 h ( the early phase ) and 24 h ( the late phase ) of cocultivation with L - 92 cells were investigated by transcriptome analysis . In the early phase of L - 92 treatment , various transcription regulator genes , such as , NFkB1 , NFkB2 , P05412 , P31629 and Q01201 , and genes encoding chemokines and cytokines , such as P13236 , O14625 , P10147 and P01375 , were upregulated . Two transmembrane receptor genes , Q9NYK1 and P05362 , were also upregulated in the early phase of treatment . In contrast , many transmembrane receptor genes , such as P16871 , P33681 , Q9HC73 , P42081 , P06127 , HLA - DQA1 , P01589 , Q13261 and P15509 , and some cytokine genes , including P05231 , Q9NPF7 and O00626 , were significantly upregulated in the late phase after L - 92 exposure . Some genes encoding cytokines , such as P01583 , P01584 and P10145 , and the enzyme P14902 were upregulated at both the early and the late phases of treatment . These results suggest that probiotic L - 92 might promote Th1 and regulatory T - cell responses by activation of the MAPK signaling pathway , followed by the NOD - like receptor signaling pathway in THP - 1 cells .", "Non - HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients . Autoimmune Polyglandular Syndrome Type II ( APSII ) is characterized by the co - occurrence of clinical insufficiency of at least two endocrine glands . Although , HLA determinants of APSII predisposition have been identified , little attention has been paid to non - HLA genes . Here , we used SNP genotyping in a Sequenom platform and genetic association tests to study a cohort of 60 APSII Tunisian patients presenting highly frequent co - occurrence of Autoimmune Thyroid Disease ( AITD ) and Type 1 Diabetes ( T1D ) and lower frequency of Addison ' s disease ( AD ) . We tested the high a priori possibility that well - established non - HLA autoimmunity loci were involved in APSII and confirmed five association signals to APSII , namely : ( 1 ) two T1D - associated SNPs , in P16410 and P01589 , suggest their involvement in T1D pathogenesis in this cohort ; ( 2 ) two SNPs in Q14765 and P40933 not previously associated to endocrinopathies , are possibly involved in co - occurrence of organ autoimmunity in APSII , and ; ( 3 ) one SNP in P01375 alpha showed association to APSII irrespective of AD . While this work was performed in a relatively small cohort , these results support the notion that the non - HLA genetic component of APSII include genetic factors specific of particular autoimmune manifestations as well as genetic factors that promote the co - occurrence of multiple autoimmune endocrinopathies .", "Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK99___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .", "Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK87___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .", "Improving prediction of type 1 diabetes by testing non - HLA genetic variants in addition to HLA markers . OBJECTIVE : The purpose of this study was to explore whether non - human leukocyte antigen ( non - HLA ) genetic markers can improve type 1 diabetes ( T1D ) prediction in a prospective cohort with high - risk HLA - DR , DQ genotypes . METHODS : The Diabetes Autoimmunity Study in the Young ( DAISY ) follows prospectively for the development of T1D and islet autoimmunity ( IA ) children at increased genetic risk . A total of 1709 non - Hispanic White DAISY participants have been genotyped for 27 non - HLA single nucleotide polymorphisms ( SNPs ) and one microsatellite . RESULTS : In multivariate analyses adjusting for family history and HLA - Q93038 / 4 genotype , Q9Y2R2 ( rs2476601 ) and two P57075 ( rs11203203 and rs9976767 ) SNPs were associated with development of IA [ hazard ratio ( HR )= 1 . 87 , 1 . 55 , and 1 . 54 , respectively , all p ≤ 0 . 003 ] , while Q8NEA6 and P01589 showed borderline association with development of IA . P01308 , P57075 , and Q9BYX4 were significantly associated with progression from IA to diabetes ( HR = 1 . 65 , 1 . 44 , and 1 . 47 , respectively , all p ≤ 0 . 04 ) , while Q9Y2R2 and IL27 showed borderline association with progression from IA to diabetes . In survival analysis , 45 % of general population DAISY children with Q9Y2R2 rs2476601 TT or HLA - Q93038 / 4 and P57075 rs11203203 AA developed diabetes by age 15 , compared with 3 % of children with all other genotypes ( p < 0 . 0001 ) . Addition of non - HLA markers to HLA - Q93038 / 4 , DQ8 did not improve diabetes prediction in first - degree relatives . CONCLUSION : Addition of Q9Y2R2 and P57075 SNPs to HLA - DR , DQ genotyping can improve T1D risk prediction .", "aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK6___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .", "DB00074 induction in patients receiving tacrolimus - based immunosuppressive regimens . PURPOSE : The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine - based immunosuppression . However , its clinical utility in patients receiving tacrolimus - based immunosuppressive regimens is still uncertain . METHODS : We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants . Of them , 134 received basiliximab and tacrolimus ( TAC - P01589 ) , 100 received basiliximab and delayed tacrolimus ( dTAC - P01589 ) , and 132 patients received tacrolimus without basiliximab ( TAC - No ) . The endpoints were the incidence of acute rejection , graft function , and patient and graft survivals at 1 year . RESULTS : The incidence of acute rejection was higher in dTAC - P01589 compared to TAC - IL - 2RA and TAC - No Groups ( 33 vs . 14 . 9 vs . 14 . 3 % , p < 0 . 001 ) . Inferior creatinine clearance was observed in dTAC - P01589 Group compared to TAC - P01589 and TAC - No Groups at months 1 ( 41 . 6 vs . 49 . 9 vs . 44 . 8 mL / min , p = 0 . 004 ) , 3 ( 49 . 8 vs . 57 . 2 vs . 53 . 5 mL / min , p = 0 . 017 ) , and 6 ( 53 . 1 vs . 61 . 8 vs . 57 . 0 mL / min , p = 0 . 001 ) . Patients who received basiliximab ( TAC - P01589 and dTAC - P01589 Groups ) had lower incidence of posttransplant diabetes ( 24 vs . 18 vs . 39 . 3 % , p = 0 . 009 ) . Patient and graft survivals were similar among the groups . CONCLUSIONS : In low immunological risk kidney transplant recipients receiving tacrolimus , the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction .", "DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "___MASK86___ ( RAD001 ) : an P42345 inhibitor for the treatment of metastatic renal cell carcinoma . The recent introduction of drugs that inhibit angiogenesis or the P42345 has provided new options for the treatment of metastatic renal cell carcinoma , a disease which often has a poor prognosis . Chemotherapy and cytokine therapy are largely ineffective . The 5 - year survival rate is under 10 % . ___MASK86___ , an immunosuppressive drug widely used for the prevention of allograft rejection and an P42345 inhibitor , is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma . It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors ( sunitinib , sorafenib or both ) , which interfere with signaling pathways , such as the P15692 pathway . Clinical efficacy results ( progression - free survival ) for everolimus are promising and the safety profile is good .", "Peripheral blood gene expression as a novel genomic biomarker in complicated sarcoidosis . Sarcoidosis , a systemic granulomatous syndrome invariably affecting the lung , typically spontaneously remits but in ~ 20 % of cases progresses with severe lung dysfunction or cardiac and neurologic involvement ( complicated sarcoidosis ) . Unfortunately , current biomarkers fail to distinguish patients with remitting ( uncomplicated ) sarcoidosis from other fibrotic lung disorders , and fail to identify individuals at risk for complicated sarcoidosis . We utilized genome - wide peripheral blood gene expression analysis to identify a 20 - gene sarcoidosis biomarker signature distinguishing sarcoidosis ( n = 39 ) from healthy controls ( n = 35 , 86 % classification accuracy ) and which served as a molecular signature for complicated sarcoidosis ( n = 17 ) . As aberrancies in T cell receptor ( TCR ) signaling , JAK - P35610 ( JS ) signaling , and cytokine - cytokine receptor ( CCR ) signaling are implicated in sarcoidosis pathogenesis , a 31 - gene signature comprised of T cell signaling pathway genes associated with sarcoidosis ( TCR / JS / CCR ) was compared to the unbiased 20 - gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis . Additional validation strategies included significant association of single nucleotide polymorphisms ( SNPs ) in signature genes with sarcoidosis susceptibility and severity ( unbiased signature genes - P49238 , P62942 , Q13253 , Q8IXT5 , SENS3 , Q9NRE2 ; T cell / JAK - P35610 pathway genes such as Q9Y243 , Q13191 , Q12959 , P01579 , P01589 , P16871 , Q08881 , P05412 , Q9UDY8 , Q13469 , P19174 , Q7Z699 ) . In summary , this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis ." ]

[ "___MASK24___", "___MASK32___", "___MASK49___", "___MASK57___", "___MASK66___", "___MASK6___", "___MASK86___", "___MASK87___", "___MASK99___" ]

[ "Expression of Th2 - skewed pathology mediators in monocyte - derived type 2 of dendritic cells ( DC2 ) . The information conveyed from dendritic cells ( DCs ) to naïve P01730 (+) T cells has crucial influence on their differentiation toward effector T cells . In an effort to identify DC - derived molecules directly contributing to T cell differentiation , we searched for molecules distinctively expressed between two DC subtypes , which were differentiated from peripheral monocytes by cultivation with GM - P04141 ( for Q9NPG8 ) or P08700 ( for DC2 ) in the presence of P05112 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells , respectively . As the first step to address this issue , we subtracted Q9NPG8 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2 , whose products are known to reside in other than the nucleus . Intriguingly , many of them were molecules involved in Th2 - skewed disease pathologies , such as P02751 , P38570 , Q14956 , Q03405 , P25089 , Q8NHJ6 , P05121 , P16050 , P24557 , P19878 , P10147 , P18510 , P09486 , and Q9NY15 , suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations . We also found that expressions of Q02318 , O14495 , Q8WXG1 , and O15438 were up - regulated in DC2 , implying their significant function in Th2 - deviated states . The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC - derived key molecules for T cell differentiation .", "Possible involvement of O15111 2 and O14733 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand . Recent studies have revealed the essential role of the receptor activator of nuclear factor kappaB ( NF - kappaB ) ligand ( O14788 ) in osteoclast differentiation and activation . Adenovirus vector could efficiently transduce genes into RAW264 . 7 cells , which differentiate into osteoclast - like multinucleated cells in the presence of O14788 . The role of NF - kappaB and c - jun N - terminal kinase ( JNK ) activation in O14788 - induced osteoclast differentiation was investigated using an adenovirus vector carrying the dominant negative 1kappaB kinase 2 gene ( AxIKK2DN ) or dominant negative O14733 gene ( AxMKK7DN ) . IKK2DN and MKK7DN overexpression in RAW cells specifically suppressed the NF - kappaB activation and JNK activation in response to O14788 , respectively , without affecting other signaling pathways . Either inhibition of NF - kappaB or JNK pathways dose - dependently inhibited osteoclast formation induced by O14788 . These results suggest that both NF - kappaB and JNK activation are independently required for osteoclast differentiation .", "Dual endothelin receptor antagonism prevents remodeling of resistance arteries in diabetes . Vascular remodeling , characterized by extracellular matrix deposition and increased media - to - lumen ( M / L ) ratio , contributes to the development of microvascular complications in diabetes . We have previously shown in type 2 diabetic Goto - Kakizaki ( GK ) rats that selective P25101 receptor blockade prevents medial thickening of mesenteric arteries via regulation of matrix metalloproteases ( MMP ) , whereas selective ETB receptor blockade augments this thickening . The goal of this study was to determine the effect of combined P25101 and ETB receptor blockade on resistance vessel remodeling . Vessel structure , MMP activity , and extracellular matrix proteins were assessed in control Wistar and diabetic GK rats treated with vehicle or ___MASK37___ ( 100 mg / kg per day ) for 4 weeks ( n = 7 - 9 per group ) . ___MASK37___ completely prevented the increase in M / L ratio and P08253 activity in diabetes but paradoxically increased M / L ratio and MMP activation in control animals . Collagenase ( P45452 ) activity and protein levels were significantly decreased in diabetes . Accordingly , collagen deposition was augmented in GK rats . Dual ET receptor antagonism improved enzyme activity and normalized P45452 levels in diabetic animals but blunted P45452 activity in control animals . In summary , current findings suggest that diabetes - mediated remodeling of resistance arteries is prevented by dual blockade of P25101 and ETB receptors and that the relative role of ET receptors in the regulation of vascular structure differs in the control and disease states .", "Effects of 25 - hydroxyvitamin D3 and 1 , 25 - dihydroxyvitamin D3 on cytokine production by human decidual cells . The active form of vitamin D , 1 , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 [ OH ]( 2 ) D ( 3 ) ) is a potent immunomodulatory seco - steroid . We have demonstrated that several components of vitamin D metabolism and signaling are strongly expressed in human uterine decidua from first trimester pregnancies , suggesting that locally produced 1 , 25 ( OH )( 2 ) D ( 3 ) may exert immunosuppressive effects during early stages of gestation . To investigate this further , we used primary cultures of human decidual cells from first and third trimester pregnancies to demonstrate expression and activity of the enzyme that catalyzes synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) , 1alpha - hydroxylase ( O15528 ) . Synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) was higher in first trimester decidual cells ( 41 +/- 11 . 8 fmoles / h / mg protein ) than in third trimester cells ( 8 +/- 4 . 4 fmoles / h / mg protein ; P < 0 . 05 ) . Purification of decidual cells followed by quantitative RT - PCR analysis showed that O15528 was expressed by both CD10 (+ VE ) stromal - enriched and CD10 (- VE ) stromal - depleted cells , with higher levels of mRNA in first trimester pregnancies . Expression of O15528 correlated with O00206 and P14902 . Functional responses to 1 , 25 ( OH )( 2 ) D ( 3 ) were studied using CD56 (+ VE ) natural killer ( NK ) cells isolated from first trimester decidua . Decidual NK cells treated with 1 , 25 ( OH )( 2 ) D ( 3 ) or precursor 25 - hydroxyvitamin D ( 3 ) ( 25OHD ( 3 ) ) for 28 h showed decreased synthesis of cytokines , such as granulocyte - macrophage colony stimulating factor 2 ( P04141 ) , tumor necrosis factor , and interleukin 6 , but increased expression of mRNA for the antimicrobial peptide cathelicidin antimicrobial peptide . These data indicate that human decidual cells are able to synthesize active 1 , 25 ( OH )( 2 ) D ( 3 ) , particularly in early gestation , and this may act in an autocrine / paracrine fashion to regulate both acquired and innate immune responses at the fetal - maternal interface .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "Differential ligand - dependent interactions between the AF - 2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and O15164 . Using a yeast two - hybrid system we report the isolation of a novel mouse protein , mSUG1 , that interacts with retinoic acid receptor alpha ( RAR alpha ) both in yeast cells and in vitro in a ligand - and AF - 2 activating domain ( AF - 2 AD ) - dependent manner and show that it is a structural and functional homologue of the essential yeast protein P62195 . mSUG1 also efficiently interacts with other nuclear receptors , including oestrogen ( ER ) , thyroid hormone ( TR ) , DB00169 ( P11473 ) and retinoid X ( RXR ) receptors . By comparing the interaction properties of these receptors with mSUG1 and O15164 , we demonstrate that : ( i ) RXR alpha efficiently interacts with O15164 , but not with mSUG1 , whereas TR alpha interacts much more efficiently with mSUG1 than with O15164 , and RAR alpha , P11473 and ER efficiently interact with mSUG1 and O15164 ; ( ii ) the amphipathic alpha - helix core of the AF - 2 AD is differentially involved in interactions of RAR alpha with mSUG1 and O15164 ; ( iii ) the AF - 2 AD cores of RAR alpha and ER are similarly involved in their interaction with O15164 , but not with mSUG1 . Thus , the interaction interfaces between the different receptors and either mSUG1 or O15164 may vary depending on the nature of the receptor and the putative mediator of its AF - 2 function . We discuss the possibility that mSUG1 and O15164 may mediate the transcriptional activity of the AF - 2 of nuclear receptors through different mechanisms .", "P10275 mutations identified in prostate cancer and androgen insensitivity syndrome display aberrant Q9UBK9 coactivator function . The transcriptional activity of the androgen receptor ( AR ) is modulated by interactions with coregulatory molecules . It has been proposed that aberrant interactions between AR and its coregulators may contribute to diseases related to AR activity , such as prostate cancer and androgen insensitivity syndrome ( AIS ) ; however , evidence linking abnormal receptor - cofactor interactions to disease is scant . Q9UBK9 is a recently identified AR N - terminal coactivator that is associated with AR - mediated growth inhibition . Here we analyze a number of naturally occurring AR mutations identified in prostate cancer and AIS for their ability to affect AR response to Q9UBK9 . Although the vast majority of AR mutations appeared capable of increased activation in response to Q9UBK9 , an AR mutation identified in prostate cancer ( AR P340L ) and AIS ( AR P36957 ) show reduced transcriptional responses to Q9UBK9 , whereas their response to the P52701 class of coactivators was not diminished . Relative to the wild - type receptor , less Q9UBK9 protein associated with the AR P36957 substitution , consistent with reduced transcriptional response . Surprisingly , more Q9UBK9 associated with AR P340L , despite the fact that the mutation decreased transcriptional activation in response to Q9UBK9 . Our findings suggest that aberrant AR - coactivator association interferes with normal Q9UBK9 coactivator function , resulting in suppression of AR activity , and may contribute to the pathogenesis of diseases related to alterations in AR activity , such as prostate cancer and AIS .", "1α , 25 - Dihydroxyvitamin D3 - liganded vitamin D receptor increases expression and transport activity of P - glycoprotein in isolated rat brain capillaries and human and rat brain microvessel endothelial cells . Induction of the multidrug resistance protein 1 ( P08183 ) / P - glycoprotein ( P - gp ) by the vitamin D receptor ( P11473 ) was investigated in isolated rat brain capillaries and rat ( RBE4 ) and human ( hCMEC / D3 ) brain microvessel endothelial cell lines . Incubation of isolated rat brain capillaries with 10 nM of the P11473 ligand , 1α , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] for 4 h increased P - gp protein expression fourfold . Incubation with 1 , 25 ( OH )( 2 ) D ( 3 ) for 4 or 24 h increased P - gp transport activity ( specific luminal accumulation of NBD - Q13216 , the fluorescent P - gp substrate ) by 25 - 30 % . In RBE4 cells , Mdr1b mRNA was induced in a concentration - dependent manner by exposure to 1 , 25 ( OH )( 2 ) D ( 3 ) . Concomitantly , P - gp protein expression increased 2 . 5 - fold and was accompanied by a 20 - 35 % reduction in cellular accumulation of the P - gp substrates , rhodamine 6G ( DB03825 ) , and HiLyte Fluor 488 - labeled human amyloid beta 1 - 42 ( hAβ ( 42 ) ) . In hCMEC / D3 cells , a 3 day exposure to 100 nM 1 , 25 ( OH )( 2 ) D ( 3 ) increased P08183 mRNA expression ( 40 % ) and P - gp protein ( threefold ) ; cellular accumulation of DB03825 and hAβ ( 42 ) was reduced by 30 % . Thus , P11473 activation up - regulates Mdr1 / P08183 and P - gp protein in isolated rat brain capillaries and rodent and human brain microvascular endothelia , implicating a role for P11473 in increasing the brain clearance of P - gp substrates , including hAβ ( 42 ) , a plaque - forming precursor in Alzheimer ' s disease .", "Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK85___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .", "[ Current Topics on Vitamin D . Evolution of animals and vitamin D ] . DB00169 is already found in the early evolution of life , but essentially as inactive products of the photochemical reaction of 7 - dehydrocholesterol . The full vitamin D endocrine system characterized by the specific vitamin D transport protein ( DBP ) , specific vitamin D - metabolizing CYP P450 enzymes , active vitamin D metabolites , 1α , 25 ( OH ) 2D3 , specific vitamin D nuclear receptor ( P11473 ) , and fibroblast growth factor 23 ( Q9GZV9 ) became essential for maintaining calcium and bone homeostasis in terrestrial animals cope with the challenging of higher gravity and calcium - poor environment . The present review describes the story about the evolution of animals and vitamin D .", "Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .", "Changes in circulating biomarkers during a single hemodialysis session . The hemodialysis ( HD ) procedure induces an inflammatory response potentially contributing to cardiovascular disease . Here we investigated the acute impact of HD on circulating biomarkers . Circulating biomarkers ( small solutes , middle molecular - sized peptides , and proteins ) related to inflammation , oxidative stress , and vascular calcification ( VC ) were measured before and after a single session of HD in 45 clinically stable patients . Concentrations were corrected for ultrafiltration - induced hemoconcentration . Among vascular calcification - related biomarkers , osteoprotegerin and fetuin - A remained unchanged while fibroblast growth factor - 23 ( Q9GZV9 ) decreased by - 19 % . Changes of Q9GZV9 and changes of phosphate correlated ( ρ = 0 . 61 , P < 0 . 001 ) . While P02741 did not change , interleukin - 6 ( P05231 ) increased by 14 % and pentraxin 3 ( PTX3 ) increased by 45 % . P05231 and PTX3 appear to be valid biomarkers of the intradialytic inflammatory response . VC - related markers were in general not affected by the single HD session ; however , the observed correlation between acute changes of Q9GZV9 and phosphate during HD warrants further studies .", "Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases . The 26S proteasome is a eukaryotic DB00171 - dependent protease functioning as a protein death machine . It is a large multisubunit complex , consisting of a catalytic 20S proteasome and two regulatory modules , named PA700 . The PA700 complex is composed of multiple subunits of 25 - 110 kDa , which are classified into two subgroups , a subgroup of at least 6 ATPases that consitute a unique multi - gene family encoding homologous polypeptides conserved during evolution and a subgroup of approximately 15 non - ATPase subunits , most of which are structurally unrelated to each other . In the present study , we report the chromosomal localization and immunological properties of six members of the human 26S proteasomal ATPase family . By use of the fluorescence in situ hybridization method , the S4 ( P62191 ) , P35998 ( P35998 ) , P17980 ( P17980 ) , P43686 ( P43686 ) , P29466 ( P62195 ) , and Q8NFH3 ( P62333 ) genes were mapped to human chromosomes 19p13 . 3 , 7q22 . 1 - q22 . 3 , 11p11 . 2 , 19q13 . 11 - q13 . 13 , 17q23 . 1 - q23 . 3 , and 12q15 , respectively , indicating that the genes for multiple ATPases of the 26S proteasome are located on different chromosomes . Immunoblot analysis revealed that all these ATPases were associated with the purified 26S proteasome and that some of them showed striking heterogeneity in their electrical charges .", "[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK62___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .", "DB00091 up - regulates Krüppel - like factor - 4 ( O43474 ) in vascular smooth muscle cells and drives phenotypic modulation in vivo . DB00091 A ( Q13216 , calcineurin inhibitor ) has been shown to block both vascular smooth muscle cell ( VSMC ) proliferation in cell culture and vessel neointimal formation following injury in vivo . The purpose of this study was to determine molecular and pathological effects of Q13216 on VSMCs . Using real - time reverse transcription - polymerase chain reaction , Western blot analysis , and immunofluorescence microscopy , we show that Q13216 up - regulated the expression of Krüppel - like factor - 4 ( O43474 ) in VSMCs . O43474 plays a key role in regulating VSMC phenotypic modulation . O43474 antagonizes proliferation , facilitates migration , and down - regulates VSMC differentiation marker gene expression . We show that the VSMC differentiation marker genes smooth muscle alpha - actin ( P62736 ) , transgelin ( Q01995 ) , smoothelin ( P53814 ) , and myocardin ( Q8IZQ8 ) are all down - regulated by Q13216 in VSMC monoculture , whereas cyclin - dependent kinase inhibitor - 1A ( P38936 ) and matrix metalloproteinase - 3 ( P08254 ) are up - regulated . Q13216 did not affect the abundance of the VSMC microRNA ( MIR ) markers MIR143 and MIR145 . Administration of Q13216 to rat carotid artery in vivo resulted in acute and transient suppression of P62736 , Q01995 , P53814 , Q8IZQ8 , and smooth muscle myosin heavy chain ( P35749 ) mRNA levels . The tumor suppressor genes O43474 , p53 , and P38936 , however , were up - regulated , as well as P08254 , P14780 , and collagen - VIII . Q13216 - treated arteries showed remarkable remodeling , including breakdown of the internal elastic lamina and reorientation of VSMCs , as well as increased O43474 immunostaining in VSMCs and endothelial cells . Altogether , these data show that cyclosporin up - regulates O43474 expression and promotes phenotypic modulation of VSMCs .", "Phosphorylation at serine 208 of the 1alpha , 25 - dihydroxy P11473 modulates the interaction with transcriptional coactivators . Upon ligand binding the 1alpha , 25 - dihydroxy P11473 ( P11473 ) undergoes a conformational change that allows interaction with coactivator proteins including P52701 / P12931 family members and the multimeric DRIP complex through the Q15648 subunit . Casein kinase II ( CKII ) phosphorylates P11473 both in vitro and in vivo at serine 208 within the hinge domain . This phosphorylation does not affect the ability of P11473 to bind DNA , but increases its ability to transactivate target promoters . Here , we have analyzed whether phosphorylation of P11473 by CKII modulates the ability of P11473 to interact with coactivators in vitro . We find that both mutation of serine 208 to aspartic acid ( VDRS208D ) or phosphorylation of P11473 by CKII enhance the interaction of P11473 with Q15648 in the presence of 1alpha , 25 - dihydroxy DB00169 . We also find that the mutation VDRS208D neither affects the ability of this protein to bind DNA nor to interact with Q15788 and RXRalpha . Together , our results indicate that phosphorylation of P11473 at serine 208 contributes to modulate the affinity of P11473 for the DRIP complex and therefore may have a role in vivo regulating P11473 - mediated transcriptional enhancement .", "Druggable oncogene fusions in invasive mucinous lung adenocarcinoma . PURPOSE : To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma ( IMA ) of the lung , a malignant type of lung adenocarcinoma in which P01116 mutations frequently occur . EXPERIMENTAL DESIGN : From an IMA cohort of 90 cases , consisting of 56 cases ( 62 % ) with P01116 mutations and 34 cases without ( 38 % ) , we conducted whole - transcriptome sequencing of 32 IMAs , including 27 cases without P01116 mutations . We used the sequencing data to identify gene fusions , and then performed functional analyses of the fusion gene products . RESULTS : We identified oncogenic fusions that occurred mutually exclusively with P01116 mutations : P04233 - Q02297 , P08195 - Q02297 , P15311 - Q15303 , O15164 - P15056 , and Q9P260 - P07949 . Q02297 fusions were present in 17 . 6 % ( 6 / 34 ) of P01116 - negative IMAs . The P04233 - Q02297 fusion activated P04626 : P21860 signaling , whereas the P15311 - Q15303 and O15164 - P15056 fusions constitutively activated the Q15303 and P15056 kinases , respectively . Signaling pathway activation and fusion - induced anchorage - independent growth / tumorigenicity of NIH3T3 cells expressing these fusions were suppressed by tyrosine kinase inhibitors approved for clinical use . CONCLUSIONS : Oncogenic fusions act as driver mutations in IMAs without P01116 mutations , and thus represent promising therapeutic targets for the treatment of such IMAs .", "DB00169 derivatives with adamantane or lactone ring side chains are cell type - selective vitamin D receptor modulators . The vitamin D receptor ( P11473 ) mediates the biological actions of 1 , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] , the active form of vitamin D , which regulates calcium homeostasis , immunity , cellular differentiation , and other physiological processes . We investigated the effects of three 1 , 25 ( OH )( 2 ) D ( 3 ) derivatives on P11473 function . AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position . These vitamin D derivatives bind to P11473 but do not stabilize an active cofactor conformation . In a P11473 transfection assay , AD47 and LAC67b act as partial agonists and all three compounds inhibit P11473 activation by 1 , 25 ( OH )( 2 ) D ( 3 ) . The derivatives enhanced the heterodimerization of P11473 with the retinoid X receptor , an effect unrelated to agonist / antagonist activity . AD47 and LAC67b weakly induced recruitment of the Q15788 cofactor to P11473 , and all three derivatives inhibited the recruitment of P52701 family cofactors to P11473 induced by 1 , 25 ( OH )( 2 ) D ( 3 ) . It is noteworthy that AD47 induced Q15648 recruitment as effectively as 1 , 25 ( OH )( 2 ) D ( 3 ) , whereas LAC67a and LAC67b were not effective . We examined the expression of endogenous P11473 target genes and the nuclear protein levels of P11473 and cofactors in several cell lines , including cells derived from intestine , bone , and monocytes , and found that the vitamin D ( 3 ) derivatives act as cell type - selective P11473 modulators . The data indicate that side chain modification is useful in the development of P11473 antagonists and tissue - selective modulators . Further elucidation of the molecular mechanisms of action of selective P11473 modulators will be essential for their clinical application .", "[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK21___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .", "Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK61___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .", "P10275 - mediated regulation of the anti - atherogenic enzyme Q02318 involves the JNK / c - jun pathway . Q02318 , an enzyme with several important roles in cholesterol homeostasis and vitamin D₃ metabolism , has been ascribed anti - atherogenic properties . This study addresses an important problem regarding how this enzyme , involved in cholesterol metabolism in the liver and peripheral tissues , is regulated . Our results identify the human Q02318 gene as a new target for the JNK / c - jun pathway . Initial experiments showed that an inhibitor of c - Jun N - terminal kinase ( JNK ) downregulated basal Q02318 promoter activity whereas overexpression of JNK slightly enhanced promoter activity . P10275 ( AR ) - mediated upregulation of mRNA levels and endogenous enzyme activity was recently reported . In the present study , the AR antagonist nilutamide blocked the androgen induction of Q02318 . The present data revealed that inhibition of the JNK / c - jun pathway abolishes the AR - mediated effect on Q02318 transcription and enzyme activity , whereas overexpression of JNK markedly increased androgenic upregulation of Q02318 . In conclusion , the current results indicate involvement of the JNK / c - jun pathway in AR - mediated upregulation of human Q02318 . The link to JNK signaling is interesting since inflammatory processes may upregulate Q02318 to clear cholesterol from peripheral tissues .", "Apoptosis induction by 1alpha , 25 - dihydroxyvitamin D3 in prostate cancer . Calcitriol [ 1alpha , 25 - dihydroxyvitamin D3 ] is the natural ligand of the vitamin D receptor ( P11473 ) . Using cultured prostate cancer ( PC ) cell lines , LN - CaP and ALVA - 31 , we studied the effects of 1alpha , 25 ( OH ) 2 - DB00169 ( VD3 ) on expression of several apoptosis - regulating proteins including : ( a ) Bcl - 2 family proteins ( Bcl - 2 , Bcl - X ( L ) , Mcl - 1 , Bax , and Bak ) ; ( b ) the heat shock protein 70 - binding protein BAG1L ; and ( c ) IAP family proteins ( P98170 , cIAP1 , and cIAP2 ) . VD3 induced decreases in levels of antiapoptotic proteins Bcl - 2 , Bcl - X ( L ) , and Mcl - 1 , BAG1L , P98170 , cIAP1 , and cIAP2 ( without altering proapoptotic Bax and Bak ) in association with increases in apoptosis . In contrast to P11473 - expressing LN - CaP and ALVA - 31 cells , P11473 - deficient prostate cancer line Du - 145 demonstrated no changes in apoptosis protein expression after treatment with VD3 . In sensitive PC cell lines , VD3 activates downstream effector protease , caspase - 3 , and upstream initiator protease caspase - 9 , the apical protease in the mitochondrial ( \" intrinsic \" ) pathway for apoptosis , but not caspase - 8 , an initiator caspase linked to an alternative ( \" extrinsic \" ) apoptosis pathway triggered by cytokine receptors . VD3 induced declines in antiapoptotic proteins and also stimulated cytochrome c release from mitochondria by a caspase - independent mechanism . Moreover , apoptosis induction by VD3 was suppressed by overexpressing Bcl - 2 , a known blocker of cytochrome c release , whereas the caspase - 8 suppressor CrmA afforded little protection . Thus , VD3 is capable of inhibiting expression of multiple antiapoptotic proteins in P11473 - expressing prostate cancer cells , leading to activation of the mitochondrial pathway for apoptosis .", "Natriuretic and vasoactive hormones and glomerular hyperfiltration in hyperglycaemic type 2 diabetic patients : effect of insulin treatment . Evidence that an increase in plasma atrial natriuretic peptide ( P01160 ) concentrations mediates , at least in part , glomerular hyperfiltration in diabetic rats prompted us to study the relationship between P01160 and renal haemodynamics in hyperfiltering type 2 diabetic patients in association with other hormones implicated in the control of glomerular filtration rate ( Q92565 ) ( catecholamines , vasopressin , renin ) and in sodium tubular transport ( aldosterone , ouabain - displacing factor , O14788 ) . Since hyperglycaemia is also associated to hyperfiltration , diabetic patients who presented with secondary drug failure were studied both in hyperglycaemic and in normoglycaemic condition . For this purpose , 11 normotensive non - macroproteinuric hyperfiltering patients with type 2 diabetes were treated with an 8 - day continuous insulin infusion ( days 0 - 7 ) . Dehydration was prevented or corrected and natriuresis was on day 0 above 100 mmol / day . The following parameters were determined on days 0 and 7 : Q92565 and renal plasma flow ( RPF ) by 99mTc - DTPA and 131I - hippuran clearances ; the extracellular volume , assimilated to the DTPA diffusion volume ; urinary O14788 by receptor - binding assay and urinary as well as plasma catecholamines by HPLC after extraction on alumin . Plasma P01160 and antidiuretic hormone ( DB00067 ) were measured by radioimmunoassay after extraction on phenyl - silylsilica ( P01160 ) and with ether ( DB00067 ) . Unextracted plasma was used for radioimmunological measurement of plasma renin activity and aldosterone . When correcting hyperglycaemia to normoglycaemia Q92565 decreased from high to normal mean value ( 138 +/- 27 and 115 +/- 6 ml / min , p < 0 . 001 ) , RPF followed the same trend , and the DTPA diffusion volume did not change . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK62___ and Tissue P00747 Activator in Occluded Arteries .", "DB00169 : a transcriptional modulator of the interferon - gamma gene . 1Alpha , 25 - dihydroxyvitamin D3 [ 1 , 25 -( OH ) 2D3 ] exerts several effects on the immune system , by regulating lymphocyte proliferation , differentiation of monocytes and secretion of cytokines as P60568 , granulocyte - macrophage colony - stimulating factor and P01579 in T cells . Here , we analyze the effect of 1 , 25 -( OH ) 2D3 on P01579 gene transcription . Transient transfection assays in Jurkat T cells indicate that activation of the P01579 promoter is down - regulated by 1 , 25 -( OH ) 2D3 . This effect is enhanced by retinoid X receptor ( RXR ) , and a functional vitamin D3 receptor ( P11473 ) DNA - binding domain in necessary for repression . We delineated two important promoter regions mainly involved in this modulation . The first of these is situated at the level of a promoter - silencer previously characterized and binds the heterodimer P11473 - RXR in electrophoretic mobility shift assay . Residual negative regulation was also detected at the level of the promoter fragment - 108 to + 64 bp from the transcription start site and , surprisingly , the activity of the P01579 enhancer from - 108 to - 36 bp in the context of a heterologous promoter was not affected by 1 , 25 -( OH ) 2D3 . Moreover , binding activity for P11473 - RXR has been detected in the P01579 minimal promoter , suggesting a possible mechanism of interference with transcription initiation / progression . The overall data indicate that direct modulation of the P01579 promoter activity is one of the possible mechanisms involved in the repressive effect of 1 , 25 -( OH ) 2D3 on P01579 gene expression .", "DB00169 supports osteoclastogenesis via functional vitamin D response element of human O14788 gene promoter . Receptor activator of NF - kappaB ligand ( O14788 ) has been identified as requisite for osteoclastogenesis . To elucidate the molecular mechanism that conducts its catabolic action on bone , the effect of 1alpha , 25 dihydroxyvitamin D ( 3 ) ( 1alpha , 25 ( OH )( 2 ) D ( 3 ) ) on osteoclastogenesis and O14788 mRNA expression was examined by coculture , RT - PCR and nuclear run - on studies . By accelerating the transcription rate of the O14788 gene in SaOS2 osteoblastic cells , 1alpha , 25 ( OH )( 2 ) D ( 3 ) enhanced in vitro osteoclast formation from peripheral monocytes . Cloning and characterization of the 5 '- flanking region of the human O14788 gene revealed that the basic promoter comprises inverted TATA - and CAAT - boxes flanked by Q13950 binding sites . Both electrophoresis mobility shift assay ( EMSA ) and transfection studies demonstrated that 1alpha , 25 ( OH )( 2 ) D ( 3 ) activated human O14788 promoter through vitamin D responsive elements ( VDRE ) located at - 1584 /- 1570 by binding P11473 and RXRalpha heterodimers in a ligand - dependent manner . The results provide direct evidence that 1alpha , 25 ( OH )( 2 ) D ( 3 ) augments osteoclastogenesis by transactivating the human O14788 gene in osteoblastic cells through VDRE .", "Human papilloma virus 16 E6 RNA interference enhances cisplatin and death receptor - mediated apoptosis in human cervical carcinoma cells . In cervical cancer , the p53 and retinoblastoma ( P06400 ) tumor suppressor pathways are disrupted by the human papilloma virus ( HPV ) E6 and E7 oncoproteins , because E6 targets p53 and E7 targets P06400 for rapid proteasome - mediated degradation . We have investigated whether E6 suppression with small interfering RNA ( siRNA ) restores p53 functionality and sensitizes the HPV16 - positive cervical cancer cell line SiHa to apoptosis by cisplatin , irradiation , recombinant human tumor necrosis factor - related apoptosis - inducing ligand ( rhTRAIL ) , or agonistic anti - Fas antibody . E6 siRNA resulted in decreased E6 mRNA levels and enhanced p53 and P38936 expression , demonstrating the restoration of p53 functionality in SiHa cells , without inducing high levels of apoptosis ( < 10 % ) . Cell surface expression of the proapoptotic death receptors ( DRs ) DR4 , DR5 , and Fas was not affected by E6 suppression . E6 suppression conferred susceptibility to cisplatin - induced apoptosis but not to irradiation - , rhTRAIL - , or anti - Fas antibody - induced apoptosis . Combining cisplatin with rhTRAIL or anti - Fas antibody induced even higher apoptosis levels in E6 - suppressed cells . At the molecular level , cisplatin treatment resulted in elevated p53 levels , enhanced caspase - 3 activation , and reduced P38936 levels in E6 - suppressed cells . DB00515 in combination with death receptor ligands enhanced caspase - 8 and caspase - 3 activation and reduced X - linked inhibitor - of - apoptosis protein ( P98170 ) levels in these cells . We showed using siRNA that the enhanced apoptosis in E6 - supressed cells was related to reduced P98170 levels and not due to reduced P38936 levels . In conclusion , targeting E6 or P98170 in combination with cisplatin can efficiently potentiate rhTRAIL - induced apoptosis in HPV - positive cervical cancer cells .", "MAPK inhibition by 1alpha , 25 ( OH ) 2 - DB00169 in breast cancer cells . Evidence on the participation of the P11473 and Src . 1alpha , 25 - Dihydroxyvitamin D ( 3 ) [ 1alpha , 25 ( OH )( 2 ) D ( 3 ) ] , the hormonally active form of Vitamin D ( 3 ) , has been shown to be a potent negative growth regulator of breast cancer cells both in vitro and in vivo . 1alpha , 25 ( OH )( 2 ) D ( 3 ) acts through two different mechanisms . In addition to regulating gene transcription via its specific intracellular receptor ( Vitamin D receptor , P11473 ) , 1alpha , 25 ( OH )( 2 ) D ( 3 ) induces , rapid , non - transcriptional responses involving activation of transmembrane signal transduction pathways . The mechanisms that mediate the antiproliferative effects of 1alpha , 25 ( OH )( 2 ) D ( 3 ) in breast cancer cells are not fully understood . Particularly , there is no information about the early non - genomic signal transduction effectors modulated by the hormone . The present study shows that 1alpha , 25 ( OH )( 2 ) D ( 3 ) rapidly inhibits serum induced activation of P27361 and P28482 Q96HU1 kinases . The non - receptor tyrosine kinase Src is involved in the pathway leading to activation of P29323 1 / 2 by serum . Furthermore , 1alpha , 25 ( OH )( 2 ) D ( 3 ) increases the tyrosine - phosphorylated state of Src as well as it inhibits its kinase activity and induces the association of the P11473 with Src . These data suggest that 1alpha , 25 ( OH )( 2 ) D ( 3 ) inhibits MAPK by inactivating Src tyrosine kinase through a so far unknown mechanism that seems to be mediated by the P11473 .", "Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation : implications for the pathogenesis and treatment of bone metastasis . Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor gefitinib in breast cancer . Osteoclast activation and differentiation are regulated by bone marrow stromal cells ( BMSC ) , a heterogeneous cell compartment that comprehends undifferentiated DB05914 ( O60682 ) and their specialized progeny . In this regard , we found that human primary BMSCs express immunoreactive P00533 . Expression of P00533 mRNA and protein was also demonstrated in two human , continuous O60682 - like cell lines , Q86SQ9 - 1 and Q86SQ9 - 2 cells . Treatment of Q86SQ9 cells with P01133 produced a significant increase in the levels of activated P00533 which was not observed in the presence of gefitinib . A significant reduction in the basal levels of activation of the P00533 and of Akt was observed in Q86SQ9 cells following treatment with gefitinib . Treatment of Q86SQ9 cells with gefitinib produced a significant reduction in the levels of secreted macrophage colony - stimulating factor ( P09603 ) and cell - associated receptor activator of NF - kappaB ligand ( O14788 ) in both cell lines , as assessed by using specific ELISA and Western blotting techniques . Finally , the ability to sustain the differentiation of pre - osteoclasts of conditioned medium from gefitinib - treated Q86SQ9 cells was reduced by approximately 45 % as compared with untreated Q86SQ9 cells . These data have demonstrated for the first time that the P00533 regulates the ability of BMSCs to induce osteoclast differentiation and strongly support clinical trials of gefitinib in breast cancer patients with bone disease .", "Overexpression of transcriptional coactivator Q9Y6Q9 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness . Amplified in breast cancer 1 ( Q9Y6Q9 ) is a transcriptional coactivator for nuclear receptors and other transcription factors . Q9Y6Q9 has an important role in malignancy of several cancers such as breast and prostate cancers . However , its involvement in human hepatocellular carcinoma ( HCC ) progression remains unclear . Here , we found that Q9Y6Q9 protein was overexpressed in 23 of 34 human HCC specimens ( 68 % ) . Down - regulation of Q9Y6Q9 reduced HCC cell proliferation , migration , invasion , colony formation ability and tumorigenic potential in nude mice . These phenotypic changes caused by Q9Y6Q9 knockdown correlated with increased expression of the cell cycle inhibitor P38936 ( Cip1 / Waf1 ) and decreased Akt activation and the expression of proliferating cell nuclear antigen ( P12004 ) and matrix metallopeptidase P14780 . In agreement with these findings , clinical Q9Y6Q9 - positive HCC expressed higher levels of P12004 than Q9Y6Q9 - negative HCC . A positive correlation was established between the levels of Q9Y6Q9 protein and P12004 protein in HCC , suggesting that Q9Y6Q9 may contribute to HCC cell proliferation . In addition , P14780 expression in Q9Y6Q9 - postive HCC was significantly higher than that in Q9Y6Q9 - negative HCC , suggesting that Q9Y6Q9 - postive HCC may be more invasive . Collectively , our results show that overexpression of Q9Y6Q9 promotes human HCC progression by enhancing cell proliferation and invasiveness . Therefore , Q9Y6Q9 is a master regulator of human HCC growth and might be a useful molecular target for HCC prognosis and treatment .", "DB00169 suppresses the androgen - stimulated growth of mouse mammary carcinoma SC - 3 cells by transcriptional repression of fibroblast growth factor 8 . Active metabolites of vitamin A and D are well known to act as growth inhibitors in hormone - related prostate and breast cancers . When various concentrations of 1alpha , 25 - dihydroxyvitamin D3 ( vitamin D3 ) , all - trans - retinoic acid ( DB00755 ) and 9 - cis retinoic acid ( 9 - cis RA ) were examined , the androgen - stimulated growth of mouse mammary carcinoma SC - 3 cells was inhibited by vitamin D3 alone in a dose - dependent manner . A flow cytometer analysis showed that vitamin D3 leads SC - 3 cells to relative P55008 - growth arrest after 72 h . Characterization of vitamin D3 - responsive genes using an oligonucleotide microarray demonstrated that 220 genes were upregulated at more than threefold , and 84 genes were downregulated to less than one - third , compared with the testosterone - stimulated SC - 3 cells . Neither cyclin - dependent kinase inhibitors ( CDKIs ) nor the antiapoptotic bcl - 2 gene were induced in vitamin D3 - responsive genes , with the exception of a slight induction of p15 ( INK4B ) . Importantly , fgf8 was markedly repressed in response to vitamin D3 . The exogenous addition of P55075 canceled the growth suppression by vitamin D3 in SC - 3 cells , suggesting that the repression of fgf8 is an indispensable step in vitamin D3 - mediated growth inhibition . In reporter assays using the ARE - containing artificial construct and the natural androgen - regulated PSA promoter , co - transfection of the vitamin D receptor ( P11473 ) and androgen receptor ( AR ) suppressed AR - stimulated promoter activity . In addition , vitamin D3 also suppressed androgen - stimulated promoter activity in the stably transfected SC - 3 cells . Moreover , P11473 repressed the core promoter activity of fgf8 in COS1 cells and in the SC - 3 cells . All these findings strongly suggest that vitamin D3 serves as a negative regulator for both androgen - related and fgf8 transcriptions .", "P01308 suppresses IKs ( P51787 / P15382 ) currents , which require β - subunit P15382 . Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia . In an animal model of type 1 diabetes mellitus , several ion currents , including the slowly activating delayed rectifier potassium current ( IKs ) , are altered . The IKs channel is composed of P51787 and P15382 subunits , whose genetic mutations are well known to cause long QT syndrome . Although insulin is known to affect many physiological and pathophysiological events in the heart , acute effects of insulin on cardiac ion channels are poorly understood at present . This study was designed to investigate direct electrophysiological effects of insulin on IKs ( P51787 / P15382 ) currents . P51787 and P15382 were co - expressed in Xenopus oocytes , and whole cell currents were measured by a two - microelectrode voltage - clamp method . Acute application of insulin suppressed the P51787 / P15382 currents and phosphorylated Akt and extracellular signal - regulated kinase ( P29323 ) , the two major downstream effectors , in a concentration - dependent manner . Wortmannin ( 10 (- 6 ) M ) , a phosphoinositide 3 - kinase ( PI3K ) inhibitor , attenuated the suppression of the currents and phosphorylation of Akt by insulin , whereas U0126 ( 10 (- 5 ) M ) , a mitogen - activated protein kinase kinase ( MEK ) inhibitor , had no effect on insulin - induced suppression of the currents . In addition , insulin had little effect on P51787 currents without P15382 , which indicated an essential role of P15382 in the acute suppressive effects of insulin . Mutagenesis studies revealed amino acid residues 111 - 118 within the distal third C - terminus of P15382 as an important region . P01308 has direct electrophysiological effects on IKs currents , which may affect cardiac excitability .", "miR - 124 functions as a tumor suppressor in the endometrial carcinoma cell line O14777 - 1B partly by suppressing P40763 . MicroRNAs ( miRNAs ) play an important role in the development and progression of endometrial carcinoma ( EC ) . Recently , several studies have shown that microRNA - 124 ( miR - 124 ) is downregulated in various cancers , which can affect tumor initiation and maintenance . However , the effects of miR - 124 on EC are largely unknown . In this study , we identified the under - expression of miR - 124 in 35 paired EC tissues and adjacent normal tissues . Further , functional experiments found that ectopic expression of miR - 124 markedly suppressed cell proliferation , migration , and invasion of EC cells . It also induced cell apoptosis and P55008 - phase cell cycle arrest . Moreover , we identified signal transducer and activator of transcription 3 ( P40763 ) as a direct target of miR - 124 , and over expression of miR - 124 not only induced changes in P40763 expression but also altered expression of its target genes , cyclin D2 and matrix metalloproteinase 2 , in the human endometrial carcinoma cell line O14777 - 1B . In addition to targeting P40763 directly , we found that miR - 124 suppresses phosphorylation of P40763 through targeting IL - 6R indirectly . Restored P40763 expression through treatment with P05231 cytokine partly abolished miR - 124 - mediated cell cycle arrest and apoptosis induction . These results combined with the tumorigenetic role of P40763 in O14777 - 1B cells suggest that the antitumor effects of miR - 124 are achieved , at least partly , through down regulation of P40763 mRNA and its downstream target genes . Therefore , inhibition of constitutively activated P40763 by ectopic expression of miR - 124 in EC may provide a novel therapeutic strategy for the treatment of EC .", "Characterization of vitamin D production by human ocular barrier cells . PURPOSE : DB00169 is a secosteroid mainly synthesized from the conversion of the skin precursor 7 - dehydrocholesterol ( 7DHC ) to vitamin D3 by ultraviolet ( UV ) B sunlight . Extrarenal synthesis of vitamin D3 has been reported in many tissues and cells , including barrier sites . This study characterizes the expression of components of vitamin D3 signaling in human ocular barrier cells . METHODS : Primary human scleral fibroblasts ( HSF ) , human corneal endothelial ( HCEC - 12 ) , nonpigmented ciliary body epithelial ( ODM - 2 ) , and adult retinal pigment epithelial ( ARPE - 19 ) cell lines were analyzed for the expression of vitamin D receptor ( P11473 ) , the vitamin D3 activating enzymes 1α - hydroxylase ( O15528 ) , 25 - hydroxylases ( Q02318 and Q6VVX0 ) , the vitamin D3 inactivating enzyme 24 - hydroxylase ( Q07973 ) , and the endocytic receptors cubilin and megalin using a combination of RT - PCR , immunocytochemistry , and enzyme immunoassay ( EIA ) . RESULTS : The HSF , HCEC - 12 , ODM - 2 , and ARPE - 19 express mRNA and protein for all vitamin D3 synthesizing and metabolizing components . The cell types tested , except HSF , are able to convert inactive 25 - hydroxyvitamin D3 ( 25 [ OH ] D3 ) into active 1 , 25 - hydroxyvitamin D3 ( 1 , 25 [ OH ] 2D3 ) . CONCLUSIONS : This novel study demonstrated that ocular barrier epithelial cells express the machinery for vitamin D3 and can produce 1 , 25 ( OH ) 2D3 . We suggest that vitamin D3 might have a role in immune regulation and barrier function in ocular barrier epithelial cells .", "RNA polymerase 1 - driven transcription as a mediator of P23560 - induced neurite outgrowth . Neurite outgrowth is essential for development of the nervous system . Neurotrophins including P23560 are among extracellular signals that regulate neurite outgrowth . The P27361 / 2 pathway contributes to intracellular signaling networks transducing the pro - neuritic effects of P23560 . In the nucleolus , RNA polymerase - 1 ( Pol1 ) - mediated transcription regulates ribosomal biogenesis , enabling cellular protein synthesis and growth . Hence , we tested the possibility that Pol1 is an effector for pro - neuritic signals such as P23560 . We report that Pol1 - mediated nucleolar transcription was increased by P23560 in an P27361 / 2 - dependent manner in rat forebrain neurons . Conversely , in cultured hippocampal neurons , knockdown of a Pol1 coactivator , transcription initiation factor 1A ( O15164 ) , attenuated P23560 - or P27361 / 2 - induced neurite outgrowth . Also , upon overexpression , a constitutively active mutant of O15164 strongly promoted neurite outgrowth , including increases in total neurite length and branching . Finally , overexpression of wild - type O15164 enhanced the pro - neuritic effects of P27361 / 2 activation . These observations indicate that the Pol1 - mediated nucleolar transcription regulates neurite outgrowth and serves as a major pro - neuritic effector of the P23560 - activated P27361 / 2 pathway . Thus , development of the nervous system appears critically dependent on the nucleolus .", "Inhibition of DB00169 metabolism enhances P11473 signalling in androgen - independent prostate cancer cells . Induction of growth arrest and differentiation by 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 -( OH )( 2 ) D ( 3 ) ) occurs in non - malignant cell types but is often reduced in cancer cells . For example , androgen - independent prostate cancer cells , DU - 145 and PC - 3 , are relatively insensitive to the anti - proliferative action of 1 , 25 -( OH )( 2 ) D ( 3 ) . This appears to be due to increased 1 , 25 -( OH )( 2 ) D ( 3 )- metabolism , as a result of Q07973 enzyme - induction , which in turn leads to decreased anti - proliferative efficacy . In the in vitro rat kidney mitochondria assay , the 2 -( 4 - hydroxybenzyl )- 6 - methoxy - 3 , 4 - dihydro - 2H - naphthalen - 1 - one ( 4 ) was found to be a potent inhibitor of Vitamin D ( 3 ) metabolising enzymes ( IC ( 50 ) 3 . 5 microM ) , and was shown to be a more potent inhibitor than the broad spectrum P450 inhibitor ketoconazole ( IC ( 50 ) 20 microM ) . The combination of the inhibitor and 1 , 25 -( OH )( 2 ) D ( 3 ) caused a greater inhibition of proliferation in DU - 145 cells than when treated with both agents alone . Examination of the regulation of P11473 target gene mRNA in DU - 145 cells revealed that co - treatment of 1 , 25 -( OH )( 2 ) D ( 3 ) plus inhibitor of Vitamin D ( 3 ) metabolising enzymes co - ordinately upregulated Q07973 , P38936 ( waf1 / cip1 ) and GADD45alpha .", "Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK37___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK37___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .", "Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK57___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .", "Dysregulation of vitamin D3 synthesis leads to enhanced cholangiocarcinoma growth . BACKGROUND : Cholangiocarcinoma is a deadly biliary tumour with limited treatment strategies . Vitamin ( 1 , 25 ( OH ) 2D ) has anti - proliferative effects on several cancers . DB00169 is synthesized by the enzyme , O15528 , and signals via the nuclear vitamin D3 receptor . The enzyme , Q07973 , degrades vitamin D3 . AIMS : ( i ) Measure the expression of O15528 , Q07973 , and vitamin D3 receptor in human nonmalignant and cholangiocarcinoma lines and biopsy control or tumour samples ; and ( ii ) evaluate the effects of vitamin D3 on vitamin D3 synthesis and cholangiocarcinoma growth . METHODS : In vitro studies were performed in malignant and nonmalignant cholangiocytes . P11473 , Q07973 and Q02318 expression was measured in cell lines and biopsy samples . Cell lines were stimulated with vehicle or vitamin D3 from 30min to 48h . Cell viability was assessed by MTS assays and BrdU incorporation . P11473 , Q07973 and O15528 expression was measured in cholangiocarcinoma cells stimulated with vehicle or vitamin D3 . RESULTS : In cholangiocarcinoma lines and biopsy samples , vitamin D3 receptor and Q07973 expression increased compared to controls , whereas O15528 expression was decreased or unchanged . DB00169 induced nuclear translocation of vitamin D3 receptor in cholangiocarcinoma and decreased cholangiocarcinoma growth . CONCLUSION : Treatment with vitamin D3 decreased Q07973 , whereas O15528 expression increased . Modulation of vitamin D3 synthesis may be important in the management of cholangiocarcinoma .", "Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .", "Synergy between vitamin D ( 3 ) and Toll - like receptor agonists regulates human dendritic cell response during maturation . Human dendritic cells ( DC ) can be differentiated from blood monocytes in the presence of GM - P04141 and P05112 and matured by lipopolysaccharide ( LPS ) . DB00169 inhibits the maturation of human DC measured by changes in surface expression of HLA - DR , P08571 , P25942 , P33681 , Q01151 , and P42081 . We here examine the function of vitamin D3 during DC maturation . One of the earliest changes to LPS - induced maturation was an increase in Q01151 expression . DB00169 inhibited the increase in expression of HLA - DR , P25942 , P33681 , Q01151 , and P42081 and the decrease in expression of P08571 , which was paralleled morphologically by vitamin D3 - induced inhibition of dendritic cell differentiation . DB00169 acted in synergy with the TLR agonists LPS and peptidoglycan ( Q9UQ90 ) in inducing P05231 , P10145 , and P22301 , whereas vitamin D3 completely inhibited LPS - induced secretion of IL - 12 . The synergy occurred at concentrations where neither vitamin D3 nor the TLR agonists alone induced measurable cytokine secretion . Both LPS and Q9UQ90 enhanced the level of the vitamin D3 receptor ( P11473 ) . Taken together , these data demonstrated that vitamin D3 and TLR agonists acted in synergy to alter secretion of cytokines from human DC in a direction that may provide an anti - inflammatory environment .", "Identification of a P13671 - Q96NT5 translocation chromosome by the Q - M and Giemsa banding techniques in a patient with Down ' s syndrome , with possible assignment of Gm locus .", "DNA methylation - related vitamin D receptor insensitivity in breast cancer . Calcitriol ( 1α , 25 ( OH )( 2 )- DB00169 ) binds to the vitamin D receptor ( P11473 ) and regulates differentiation of the normal mammary gland , and may therefore be useful in breast cancer treatment or prevention . Many breast cancer cells are , however , resistant to Calcitriol . In this study , we investigated the resistance mechanism and the role of epigenetic silencing of P11473 by promoter hypermethylation . Bisulfite sequencing of the P11473 promoter region revealed methylated CpG islands at - 700 base pairs ( bp ) upstream and near the transcription start site . P11473 CpG islands were demethylated by 5 ' deoxy - azacytidine treatment , and this was accompanied by a parallel increase in P11473 mRNA levels in breast cancer cell lines . Quantitative methylation - specific PCR analyses confirmed hypermethylation of these CpG islands in primary tumors , and its absence in normal breast tissue . P11473 transcripts detected in breast cancers were predominantly 5 '- truncated , while normal breast tissue expressed full - length transcripts . Consistent with this observation , genes containing the P11473 - responsive element ( VDRE ) , such as cytochrome p450 hydroxylases , P38936 or C / EBP were underexpressed in breast cancers compared to normal breast samples . Expression of the active longer transcripts of P11473 was restored with 5 ' deoxy - DB00928 ( AZA ) treatment , with a concurrent increase in expression of VDRE - containing genes . Thus , promoter methylation - mediated silencing of expression of the functional variants of P11473 may contribute to reduced expression of downstream effectors of the P11473 pathway and subsequent Calcitriol insensitivity in breast cancer . These data suggest that pharmacological reversal of P11473 methylation may re - establish breast cancer cell susceptibility to differentiation therapy using Calcitriol .", "Mechanisms of interleukin - 1beta - induced P39905 release from rat glioma cells . P39905 ( P39905 ) is highly expressed both in neurons and astrocytes in injured tissues . Astrocytes support neurons by releasing neurotrophic factors including P39905 . It has been reported that various agents including cytokines such as interleukin ( IL ) - 1beta induce P39905 mRNA expression and the release in astrocytes . However , the mechanism behind the P39905 synthesis and release remains unclear . Herein , we investigated the mechanisms of the IL - 1beta - induced P39905 release from rat P13671 glioma cells . IL - 1beta time dependently stimulated P39905 release from P13671 cells . IL - 1beta induced the phosphorylation of inhibitor kappa B ( IkappaB ) , p38 mitogen - activated protein ( Q96HU1 ) kinase , Q8TCB0 / Q8NFH3 Q96HU1 kinase , stress - activated protein kinase / c - Jun N - terminal kinase ( SAPK / JNK ) and signal transducer and activator of transcription ( P35610 ) 3 . The IL - 1beta - stimulated levels of P39905 were suppressed by wedelolactone , an inhibitor of O15111 , SB203580 , an inhibitor of p38 Q96HU1 kinase , PD98059 , an inhibitor of Q02750 / 2 or Janus family of tyrosine kinase ( JAK ) inhibitor I , an inhibitor of upstream kinase of P40763 . On the contrary , SP600125 , an inhibitor of SAPK / JNK , failed to reduce the IL - 1beta - effect . These results strongly suggest that IL - 1beta stimulates P39905 release through the pathways of IkappaB - nuclear factor kappa B , p38 Q96HU1 kinase , Q8TCB0 / Q8NFH3 Q96HU1 kinase and JAK - P40763 , but not through the SAPK / JNK pathway in glioma cells .", "Tissue remodeling in the acute otitis media mouse model . OBJECTIVES : Otitis media is an infectious , inflammatory process involving the middle ear space . Chronic inflammation is associated with fibrosis , scarring and osteogenesis within the middle ear , which may contribute to subsequent hearing loss and increase the difficulty of treatment . METHODS : Heat - killed Streptococcus pneumoniae was injected into the middle ears of 8 - 12 week old Balb / c mice . Control mice were treated with PBS middle ear injections . Middle ears were harvested at 1 , 3 , 5 and 7 days following injection ( n = 8 for each time point ) . The middle ears were processed using standard RT - PCR techniques . Up - and down - regulation of mRNA expression of various members of the Bone Morphogenetic Protein ( BMP ) , Fibroblast Growth Factor ( FGF ) and Matrix Metalloproteinase ( MMP ) families was quantified and compared to PBS treated controls ( n = 8 for each time point ) . RESULTS : Significant upregulation of P08253 , P08254 and P14780 was observed at varying time points ( p < 0 . 05 ) . Significant downregulation of P12645 , P12644 , P22003 P22004 and BMP8a was seen at varying time points ( p < 0 . 05 ) . Significant downregulation of P11487 , P10767 , O15520 and FGFr1 was observed at varying time points ( p < 0 . 05 ) . No significant expression of BMP8b , Q9UK05 , O95393 , P12034 , P55075 , MMP1a , P09237 and P50281 was detected within the middle ear . CONCLUSIONS : Inflammation within the middle ear following injection of bacterial products results in changes in the regulation of several tissue remodeling cytokines and proteinases in the mouse model . Further understanding of these molecular processes may allow for the development of treatment modalities aimed at preventing middle ear tissue remodeling .", "Cholecalciferol ( vitamin D3 ) inhibits growth and invasion by up - regulating nuclear receptors and 25 - hydroxylase ( Q02318 ) in human prostate cancer cells . Epidemiological evidence suggests an inverse relationship between prostate cancer and serum vitamin D levels . We examined the ability of cholecalciferol ( vitamin D ( 3 ) ) , a calcitriol precursor , to inhibit or reverse cellular changes associated with malignant transformation and invasion and explored its mechanisms of action . The RWPE2 - W99 human prostate epithelial cell line , which forms slow - growing tumors in nude mice , was used because it mimics the behavior of the majority of primary human prostate cancers . Cholecalciferol , at physiological levels : ( i ) inhibited anchorage - dependent and - independent growth ; ( ii ) induced differentiation by decreasing vimentin expression with a concomitant decrease in motility / chemotaxis ; ( iii ) decreased P14780 and P08253 activity with concomitant decrease in invasion ; and ( iv ) exerted its effects by up - regulating vitamin D receptor ( P11473 ) , retinoid - X receptor - alpha ( RXR - alpha ) , and androgen receptor ( AR ) in a dose - dependent manner . Furthermore , we found that RWPE2 - W99 prostate cancer cells , similar to RWPE - 1 cells ( Tokar and Webber . Clin Exp Metast 2005 ; 22 : 265 - 73 ) , constitutively express the enzyme 25 - hydroxylase Q02318 which is markedly up - regulated by cholecalciferol . Cholecalciferol has effects similar to those of calcitriol on growth , MMP activity , and P11473 . The ability of Q02318 to catalyze the conversion of cholecalciferol to 25 ( OH ) D ( 3 ) and of 25 ( OH ) D ( 3 ) to calcitriol has been reported . RWPE2 - W99 cells , similar to RWPE - 1 cells , appear to have the rare ability to locally convert cholecalciferol to the active hormone calcitriol . Because it can inhibit cellular changes associated with malignant transformation and invasion , we propose that cholecalciferol may be an effective agent for the treatment of prostate cancer .", "The 1alpha , 25 - dihydroxy P11473 preferentially recruits the coactivator Q15788 during up - regulation of the osteocalcin gene . Binding of 1alpha , 25 - dihydroxy DB00169 to the C - terminal domain ( LBD ) of its receptor ( P11473 ) , induces a conformational change that enables interaction of P11473 with transcriptional coactivators such as the members of the P52701 / P12931 family or the DRIP ( Vitamin D interacting complex ) / Mediator complex . These interactions are critical for P11473 - mediated transcriptional enhancement of target genes . Recent reports indicate that nuclear receptors , including P11473 , interact with P52701 / P12931 members and the DRIP / Mediator complex in a sequential , cyclical , and mutually exclusive manner when bound to a target promoter , exhibiting also a high exchange rate . Here , we present an overview of how these coactivators are recruited to the bone - specific osteocalcin ( OC ) gene in response to short and long exposures to 1alpha , 25 - dihydroxy DB00169 . We find that in intact osteoblastic cells P11473 and Q15788 rapidly bind to the OC promoter in response to the ligand . This recruitment correlates with transcriptional enhancement of the OC gene and with increased histone acetylation at the OC promoter . In contrast , binding of the Q15648 subunit , which anchors the DRIP / Mediator complex to the P11473 , is detected at the OC promoter after several hours of incubation with 1alpha , 25 - dihydroxy DB00169 . Together , our results indicate that P11473 preferentially recruits Q15788 to enhance basal bone - specific OC gene transcription . We propose a model where specific protein - DNA and protein - protein interactions that occur within the context of the OC gene promoter in osteoblastic cells stabilize the preferential association of the P11473 - Q15788 complex .", "___MASK84___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .", "Public awareness of the EMS system in Western Saudi Arabia : identifying the weakest link . BACKGROUND : The City of Jeddah is the major and largest city in the Western Region of the Kingdom of Saudi Arabia ( P16422 ) . Covering a total area of 748 km2 . The Saudi Red Crescent Organization ( P12931 ) makes up the major bulk of the Emergency Medical Service ( EMS ) system in the Kingdom . We have set out to investigate the level of public awareness of the EMS system in place in Western P16422 . METHOD : This study was an observational cross - sectional study that was done by interviewing the general public in public venues . The survey consisted of a two part questionnaire . The first part was completed for all subjects . The second part was completed only for those subjects that had previous experience with the P12931 service . RESULT : A total of 1534 subjects were interviewed by 5 data collectors . 33 % of people did not know the emergency dispatcher number to call in case of a medical emergency . The majority estimated the P25101 of an ambulance response to their home to be about 30 minutes or more . 94 % said that MEDEVAC is needed . 17 . 7 % of people still find it unacceptable for male paramedics to respond to a female emergency unescorted by a male family member . CONCLUSION : It is clear that the general public is aware of the deficit in EMS coverage that is present . To improve the public awareness of the EMS system , municipal , legislative , public guidance , as well as religious support , are needed to be utilized to improve the community ' s satisfaction and quality of care .", "Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK76___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .", "Suppression of P01160 gene transcription by liganded vitamin D receptor : involvement of specific receptor domains . We showed previously that liganded vitamin D receptor ( P11473 ) effects a suppression of human atrial natriuretic peptide ( hANP ) gene - promoter activity in cultured neonatal rat atrial myocytes . In the present study , we have attempted to identify the structural domains of the P11473 that are involved in mediating this suppression . We examined the effects of a series of P11473 mutants on a cotransfected hANP promoter - driven chloramphenicol acetyltransferase ( CAT ) reporter . Neither the native P11473 nor any of the mutants tested displayed inhibitory activity in the absence of the 1 , 25 - dihydroxyvitamin D3 ( VD3 ) ligand . Delta134 , a deletant harboring solely the DNA binding region of the P11473 , and L254G , a mutant shown to be defective in retinoid X receptor ( RXR ) heterodimer formation in other systems , were as effective as the native P11473 in reducing promoter activity . P02042 , a deletant containing only the hormone - binding domain of the P11473 , and K246G , a point mutant that is defective in the activation function of the receptor , did not attenuate reporter activity . A similar activity profile was displayed when a positively regulated promoter containing a direct - repeat vitamin D responsive element ( Q93038 - CAT ) was examined in these cells . Liganded P11473 , the delta134 mutant , and liganded L254G effected increases in Q93038 - CAT activity of 2 . 5 - , 2 - , and 4 - fold , respectively . Two nonhypercalcemic analogues of VD3 ( RO 23 - 7553 and RO 25 - 6760 ) displayed the same inhibitory activity as VD3 . These studies suggest that the inhibition of hANP promoter activity requires both the DNA binding and activation functions of the receptor but does not appear to require formation of a classic RXR alpha - P11473 heterodimer .", "Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .", "[ Establishment and characterization of the cell line derived from low differentiated adenocarcinoma of the endometrium ] . A new human carcinoma cell line ( O14777 - 1 ) , which was derived from low differentiated adenocarcinoma of the endometrium , has been established . Cells from tumor tissues grown in athymic mice were cultured in minimal essential medium supplemented with 20 % fetal calf serum . Contaminated mouse fibroblasts were removed from the culture by the absorption of anti - mouse serum . Continuous cell growth ( doubling time : 51 . 6 hrs ) could be observed during 64 passages . The cultured cells appeared monolayer and the cellular arrangement was a pavement - like pattern . The morphology of cells was analogous to the one of adenocarcinoma cells . The modal number of chromosomes of the original tumor cells were 46 . The t . dic ( 1 ; 16 ) ( P38936 ; q24 ) marker which had been identified as the clonal abnormality in the original tumor cells , was also observed consistently in cultured cells , though the loss of chromosome 19 was disappeared during the passage . This suggested that the rearrangements of the long arm of chromosome 1 played an important role for the endometrial carcinogenesis .", "The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .", "African swine fever virus P98170 induces the activation of nuclear factor kappa B . African swine fever virus ( ASFV ) encodes a homologue of the inhibitor of apoptosis ( IAP ) that promotes cell survival by controlling the activity of caspase - 3 . Here we show that ASFV IAP is also able to activate the transcription factor NF - kappaB . Thus , transient transfection of the viral IAP increases the activity of an NF - kappaB reporter gene in a dose - responsive manner in Jurkat cells . Similarly , stably transfected cells expressing ASFV IAP have elevated basal levels of c - rel , an NF - kappaB - dependent gene . NF - kappaB complexes in the nucleus were increased in A224L - expressing cells compared with control cells upon stimulation with phorbol myristate acetate ( PMA ) plus ionomycin . This resulted in greater NF - kappaB - dependent promoter activity in ASFV IAP - expressing than in control cells , both in basal conditions and after PMA plus ionophore stimulation . The elevated NF - kappaB activity seems to be the consequence of higher O15111 ( IKK ) basal activity in these cells . The NF - kappaB - inducing activity of ASFV IAP was abrogated by an IKK - 2 dominant negative mutant and enhanced by expression of tumor necrosis factor receptor - associated factor 2 .", "Inhibition of matrix metalloproteinase - 9 expression by docosahexaenoic acid mediated by heme oxygenase 1 in 12 - O - tetradecanoylphorbol - 13 - acetate - induced MCF - 7 human breast cancer cells . P14780 ( P14780 ) plays a crucial role in tumor metastasis . Previous studies showed that polyunsaturated fatty acids exhibit an anti - cancer effect in various human carcinoma cells , but the effect of docosahexaenoic acid ( DB01708 ) and linoleic acid ( LA ) on metastasis of breast cancer cells is not fully clarified . We studied the anti - metastasis potential of DB01708 and LA in 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) - induced MCF - 7 cells . We found that TPA ( 100 ng / ml ) induced P14780 enzyme activity both dose - and time - dependently , and 200 μM DB01708 and LA significantly inhibited P14780 mRNA and protein expression , enzyme activity , cell migration , and invasion . Treatment with PD98059 ( 10 μM ) , wortmannin ( 10 μM ) , and GF109203X ( 0 . 5 μM ) decreased TPA - induced P14780 protein expression and enzyme activity . TPA - induced activation of P27361 , Akt , and PKCδ was attenuated by DB01708 , whereas LA attenuated only P27361 activation . GF109203X also suppressed P27361 activation . EMSA showed that DB01708 , LA , PD98059 , and wortmannin decreased TPA - induced NF - κB and AP - 1 DNA - binding activity . Furthermore , DB01708 rather than LA dose - dependently increased P09601 expression . P09601 siRNA alleviated the inhibition by DB01708 of TPA - induced P14780 protein expression and enzyme activity in MCF - 7 cells , and P09601 knockdown reversed the DB01708 inhibition of cell migration . These results suggest that DB01708 and LA have both similar and divergent signaling pathways in the suppression of TPA - induced MCF - 7 metastasis .", "P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK66___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .", "DB00169 and its nuclear receptor increase the expression and activity of the human proton - coupled folate transporter . Folates are essential for nucleic acid synthesis and are particularly required in rapidly proliferating tissues , such as intestinal epithelium and hemopoietic cells . Availability of dietary folates is determined by their absorption across the intestinal epithelium , mediated by the proton - coupled folate transporter ( Q96NT5 ) at the apical enterocyte membranes . Whereas transport properties of Q96NT5 are well characterized , regulation of Q96NT5 gene expression remains less elucidated . We have studied the mechanisms that regulate Q96NT5 promoter activity and expression in intestine - derived cells . Q96NT5 mRNA levels are increased in Caco - 2 cells treated with 1 , 25 - dihydroxyvitamin D ( 3 ) ( vitamin D ( 3 ) ) in a dose - dependent fashion , and the duodenal rat Pcft mRNA expression is induced by vitamin D ( 3 ) ex vivo . The Q96NT5 promoter region is transactivated by the vitamin D receptor ( P11473 ) and its heterodimeric partner retinoid X receptor - alpha ( RXRalpha ) in the presence of vitamin D ( 3 ) . In silico analyses predicted a P11473 response element ( VDRE ) in the Q96NT5 promoter region - 1694 /- 1680 . DNA binding assays showed direct and specific binding of the P11473 : RXRalpha heterodimer to the Q96NT5 (- 1694 /- 1680 ) , and chromatin immunoprecipitations verified that this interaction occurs within living cells . Mutational promoter analyses confirmed that the Q96NT5 (- 1694 /- 1680 ) motif mediates a transcriptional response to vitamin D ( 3 ) . In functional support of this regulatory mechanism , treatment with vitamin D ( 3 ) significantly increased the uptake of [( 3 ) H ] folic acid into Caco - 2 cells at pH 5 . 5 . In conclusion , vitamin D ( 3 ) and P11473 increase intestinal Q96NT5 expression , resulting in enhanced cellular folate uptake . Pharmacological treatment of patients with vitamin D ( 3 ) may have the added therapeutic benefit of enhancing the intestinal absorption of folates .", "Granulocyte macrophage - colony stimulating factor increases the expression of histamine and histamine receptors in monocytes / macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage - colony - stimulating factor ( GM - P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine - producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM - P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM - P04141 - induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC - expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM - P04141 was also detected in the lesions . In U937 cells , GM - P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM - P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM - P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis - related genes in monocytes and smooth muscle cells . The presence of histamine - producing macrophages and gene expression of histamine receptors and GM - P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM - P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM - P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression .", "Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis ." ]

[ "___MASK21___", "___MASK37___", "___MASK57___", "___MASK61___", "___MASK62___", "___MASK66___", "___MASK76___", "___MASK84___", "___MASK85___" ]

[ "miR - 200c inhibits melanoma progression and drug resistance through down - regulation of BMI - 1 . MicroRNAs ( miRNAs ) are short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression . Melanoma is the most aggressive skin cancer that is resistant or rapidly develops resistance to a variety of chemotherapeutic agents . The role of miRNAs in melanoma progression and drug resistance has not been well studied . Herein , we demonstrate that miR - 200c is down - regulated in melanomas ( primary and metastatic ) compared with melanocytic nevi . Overexpression of miR - 200c in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity as well as drug resistance . miR - 200c overexpression resulted in significant down - regulation of BMI - 1 , Q9UNQ0 , Q9H222 , and P08183 expression and in a concomitant increase in P12830 levels . Knockdown of BMI - 1 showed similar effects as miR - 200c overexpression in melanoma cells . In addition , miR - 200c overexpression significantly inhibited melanoma xenograft growth and metastasis in vivo , and this correlated with diminished expression of BMI - 1 and reduced levels of P12830 in these tumors . The effects of miR - 200c on melanoma cell proliferation and migratory capacity and on self - renewal were rescued by overexpression of Bmi - 1 , and the reversal of these phenotypes correlated with a reduction in P12830 expression and increased levels of Q9UNQ0 , Q9H222 , and P08183 . Taken together , these findings demonstrate a key role for miR - 200c in melanoma progression and drug resistance . These results suggest that miR - 200c may represent a critical target for increasing melanoma sensitivity to clinical therapies .", "Dietary soy protein isolate attenuates metabolic syndrome in rats via effects on Q07869 , LXR , and SREBP signaling . To determine the effects of feeding soy or isoflavones on lipid homeostasis in early development , weanling rats were fed AIN - 93G diets made with casein , soy protein isolate ( SPI + ) , isoflavone - reduced SPI + ( SPI - ) , or casein supplemented with genistein or daidzein for 14 d . PPARalpha - regulated genes and proteins involved in fatty acid degradation were upregulated by SPI + ( P < 0 . 05 ) accompanied by increased promoter binding and expression of PPARalpha mRNA ( P < 0 . 05 ) . Feeding SPI - or pure isoflavones did not alter PPARalpha - regulated pathways . SPI + feeding had similar effects on PPARgamma signaling . SPI + , SPI - , and casein plus isoflavones all increased liver Q9UBH6 ( LXR ) alpha - regulated genes and enzymes involved in cholesterol homeostasis . Feeding SPI + increased promoter binding of LXRalpha , expression of the transcription factor mRNA , and protein ( P < 0 . 05 ) . In a second experiment , male Sprague - Dawley rats were fed casein diets from postnatal d ( P01160 ) 24 to PND64 or were fed high - fat Western diets containing 5 g x kg (- 1 ) cholesterol made with either casein or SPI + . P01308 resistance , steatosis , and hypercholesterolemia in the Western diet - fed rats were partially prevented by SPI + ( P < 0 . 05 ) . Nuclear sterol receptor element binding protein ( SREBP ) - 1c protein and mRNA and protein expression of enzymes involved in fatty acid synthesis were increased by feeding Western diets containing casein but not SPI + ( P < 0 . 05 ) . These data suggest that activation of Q07869 and LXR signaling and inhibition of SREBP - 1c signaling may contribute to insulin sensitization and improved lipid homeostasis in SPI +- fed rats after consumption of diets high in fat and cholesterol .", "Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study . BACKGROUND : Plasma total cholesterol ( TC ) levels are highly genetically determined . Although ample evidence of genetic determination of separate lipoprotein cholesterol levels has been reported , using TC level directly as a phenotype in a relatively large broad - gene based association study has not been reported to date . METHODS AND RESULTS : We genotyped 361 single nucleotide polymorphisms ( SNPs ) across 243 genes based on pathways potentially relevant to cholesterol metabolism in 3575 subjects that were examined thrice over 11 years . Twenty - three SNPs were associated with TC levels after adjustment for multiple testing . We used 12 of them ( rs7412 and rs429358 in P02649 , rs646776 in Q9HCU4 , rs1367117 in P04114 , rs6756629 in Q9H222 , rs662799 in Q6Q788 , rs688 in P01130 , rs10889353 in Q96N67 , rs2304130 in O14594 , rs3846662 in P04035 , rs2275543 in O95477 , rs7275 in P51532 ) that were confirmed in previous candidate association or genome - wide - association studies to define a gene risk score ( Q16548 ) . Average TC levels increased from 5 . 23 ± 0 . 82 mmol / L for those with 11 or less cholesterol raising alleles to 6 . 03 ± 1 . 11 mmol / L for those with 18 or more ( P for trend < 0 . 0001 ) . The association with TC levels was slightly stronger when the weighted Q16548 that weighted the magnitude of allelic effects was used . CONCLUSION : A panel of common genetic variants in the genes pivotal in cholesterol metabolism could possibly help identify those people who are at risk of high cholesterol levels .", "Relative expression of cholesterol transport - related proteins and inflammation markers through the induction of 7 - ketosterol - mediated stress in Caco - 2 cells . Human diets contain sterol oxidation products that can induce cytotoxic effects , mainly caused by cholesterol oxides . However , phytosterol oxides effects have been less extensively investigated . This study evaluates the production of inflammatory biomarkers ( IL - 1β , P10145 , P22301 , TNFα ) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism ( Q9UHC9 , Q9H222 / 8 , HMGCoA , ACAT ) produced by 7 - ketosterols ( stigmasterol / cholesterol ) in Caco - 2 cells . These effects were linked to intracellular signaling pathways by using several inhibitors . Results showed 7 - ketostigmasterol to have a greater proinflammatory potential than 7 - ketocholesterol . In non - pre - treated cells , only efflux transporters were down - regulated by 7 - ketosterols , showing a greater influence upon Q9H222 expression . Cell - pre - incubation with bradykinin induced changes in ABCG expression levels after 7 - ketostigmasterol - incubation ; however , the energetic metabolism inhibition reduced Q9UHC9 expression only in 7 - ketocholesterol - incubated cells . In non - pre - treated cells , HMG - DB01992 was up - regulated by both 7 - ketosterols . However , exposure to inhibitors down - regulated the expression levels , mainly in 7 - ketocholesterol - incubated cells . While ACAT expression values in non - pre - treated cells were unchanged , exposure to inhibitors caused down - regulation of mRNA levels . These results suggest that internalization and excretion of 7 - ketostigmasterol is probably influenced by [ Ca ] i , which also could mediate HMGCoA activity in POPs metabolism . However , energetic metabolism and reducing equivalents exert different influences upon the 7 - ketosterol internalization .", "Polymorphisms in autophagy genes and susceptibility to tuberculosis . Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis , and polymorphisms in the autophagy gene A1A4Y4 have been linked with susceptibility to tuberculosis ( TB ) among African - Americans , and with TB caused by particular M . tuberculosis genotypes in Ghana . We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls , and between patients infected with different M . tuberculosis genotypes , as determined by spoligotyping . The same autophagy polymorphisms were studied in correlation with ex - vivo production of P01375 , IL - 1β , P05231 , P10145 , IFN - γ and Q16552 in healthy volunteers . No association was found between TB and polymorphisms in the genes Q9H0Y0 , Q8NAA4 , Q96BY7 , Q9H1Y0 , Q674R7 , A1A4Y4 , P11279 , Q9UQV4 , Q99572 , Q5MNZ9 , P42345 and Q96DT6 . Associations were found between polymorphisms in P11279 ( p = 0 . 02 ) and P42345 ( p = 0 . 02 ) and infection with the successful M . tuberculosis Beijing genotype . The polymorphisms examined were not associated with M . tuberculosis induced cytokines , except for a polymorphism in Q9H0Y0 , which was linked with P10145 production ( p = 0 . 04 ) . All associations found lost statistical significance after correction for multiple testing . This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB , with M . tuberculosis Beijing genotype infection or with ex - vivo pro - inflammatory cytokine production .", "The molecular mechanisms underlying the reduction of LDL apoB - 100 by ezetimibe plus simvastatin . The combination of ezetimibe , an inhibitor of Niemann - Pick C1 - like 1 protein ( Q9UHC9 ) , and an P04035 inhibitor decreases cholesterol absorption and synthesis . In clinical trials , ezetimibe plus simvastatin produces greater LDL - cholesterol reductions than does monotherapy . The molecular mechanism for this enhanced efficacy has not been defined . P04114 ( apoB - 100 ) kinetics were determined in miniature pigs treated with ezetimibe ( 0 . 1 mg / kg / day ) , ezetimibe plus simvastatin ( 10 mg / kg / day ) , or placebo ( n = 7 / group ) . DB00973 decreased cholesterol absorption ( - 79 % ) and plasma phytosterols ( - 91 % ) , which were not affected further by simvastatin . DB00973 increased plasma lathosterol ( + 65 % ) , which was prevented by addition of simvastatin . The combination decreased total cholesterol ( - 35 % ) and LDL - cholesterol ( - 47 % ) . VLDL apoB pool size decreased 26 % , due to a 35 % decrease in VLDL apoB production . LDL apoB pool size decreased 34 % due to an 81 % increase in the fractional catabolic rate , both of which were significantly greater than monotherapy . Combination treatment decreased hepatic microsomal cholesterol ( - 29 % ) and cholesteryl ester ( - 65 % ) and increased P01130 ( P01130 ) expression by 240 % . The combination increased Q9UHC9 expression in liver and intestine , consistent with increased Q12772 expression . DB00973 plus simvastatin decreases VLDL and LDL apoB - 100 concentrations through reduced VLDL production and upregulation of P01130 - mediated LDL clearance .", "___MASK58___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .", "DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK73___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .", "LXR driven induction of HDL - cholesterol is independent of intestinal cholesterol absorption and O95477 protein expression . We investigated whether : ( 1 ) liver X receptor ( LXR ) - driven induction of high - density lipoprotein cholesterol ( HDL - C ) and other LXR - mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption ; and ( 2 ) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis . Mice were fed 0 . 2 % cholesterol and treated with GW3965 + ezetimibe , GW3965 or ezetimibe . GW3965 + ezetimibe treatment elevated serum HDL - C and Apolipoprotein ( Apo ) AI , effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols . No changes in intestinal DB00171 - binding cassette ( DB01048 ) A1 or Q9H222 protein expression were observed , despite increased mRNA expression , while hepatic O95477 was slightly reduced . The combined treatment caused a pronounced down - regulation of intestinal Niemann - Pick C1 - like 1 ( Q9UHC9 ) and reduced hepatic and intestinal cholesterol levels . GW3965 did not affect the intestinal cholesterol absorption , but increased serum HDL - C and ApoAI levels . GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1 - 6 cells . DB00973 reduced the intestinal cholesterol absorption , O95477 and Q9H222 , but did not affect the serum HDL - C or ApoAI levels . Thus , the LXR - driven induction of HDL - C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic O95477 was not required . Inhibited influx of cholesterol via Q9UHC9 and / or low levels of intracellular cholesterol prevented post - transcriptional expression of intestinal O95477 and Q9H222 , despite increased mRNA levels . Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol .", "P01308 - like growth factor - 1 attenuates cisplatin - induced gammaH2AX formation and DNA double - strand breaks repair pathway in non - small cell lung cancer . Because insulin - like growth factor - 1 ( DB01277 ) counteracts the anti - neoplastic effect of cisplatin that induces DNA damage and cell death through the formation of platinum - DNA adducts , we investigated the effects of DB01277 on the DNA double - strand breaks ( DSBs ) repair system induced by cisplatin . NCI - H1299 and H460 non - small cell lung cancer ( NSCLC ) cells treated with DB01277 recovered from cisplatin - derived inhibited proliferation and apoptosis . Decreased tail length in comet assay and suppressed phosphorylation of histone P16104 at Ser139 with DB01277 cotreatment indicates that DB01277 attenuates cisplatin - induced DNA damage . Cotreatment with DB01277 attenuates phosphorylation of ataxia - telangiectasia mutated ( Q13315 ) at Ser1981 , and Q13315 - Rad3 - related ( ATR ) at Ser428 and subsequent phosphorylation of Chk2 , Chk1 , and p53 also dwindled by DB01277 . On the other hand , suppression of the IGF system with AG1024 or siRNA of insulin receptor substrate - 1 ( P35568 ) , a major adaptor molecule of the IGF system , augmented cisplatin - induced gammaH2AX , Ser1981 - pATM , and Ser428 - pATR generation . Q13315 , which plays an important role in the phosphorylation of histone P16104 and Chk2 at Thr68 , strongly binds with P35568 under the influence of cisplatin , and the interaction was partially inhibited by DB01277 . Immunocytochemistry revealed that cisplatin induces nuclear translocation of P35568 with Ser1981 - pATM , which is suppressed by cotreatment with DB01277 . In conclusion , cisplatin - induced gammaH2AX formation , DNA DSBs repair , and damage checkpoint pathway is inhibited by DB01277 . DB00515 derives interaction between Q13315 and P35568 , which is suppressed by DB01277 . Modulation of biologic activity of the DB01277 system could be a promising modality that raises the response rate of conventional chemotherapy .", "P25942 blockade combines with ___MASK9___ and sirolimus to produce mixed chimerism in an MHC - defined rhesus macaque transplant model . In murine models , T - cell costimulation blockade of the P10747 : P33681 and CD154 : P25942 pathways synergistically promotes immune tolerance after transplantation . While P10747 blockade has been successfully translated to the clinic , translation of blockade of the CD154 : P25942 pathway has been less successful , in large part due to thromboembolic complications associated with anti - CD154 antibodies . Translation of P25942 blockade has also been slow , in part due to the fact that synergy between P25942 blockade and P10747 blockade had not yet been demonstrated in either primate models or humans . Here we show that a novel , nondepleting P25942 monoclonal antibody , 3A8 , can combine with combined ___MASK9___ and sirolimus in a well - established primate bone marrow chimerism - induction model . Prolonged engraftment required the presence of all three agents during maintenance therapy , and resulted in graft acceptance for the duration of immunosuppressive treatment , with rejection resulting upon immunosuppression withdrawal . Flow cytometric analysis revealed that upregulation of CD95 expression on both P01730 + and CD8 + T cells correlated with rejection , suggesting that CD95 may be a robust biomarker of graft loss . These results are the first to demonstrate prolonged chimerism in primates treated with P10747 / P42345 blockade and nondepletional P25942 blockade , and support further investigation of combined costimulation blockade targeting the P10747 and P25942 pathways .", "Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK73___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK73___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .", "Oxysterol binding protein induces upregulation of SREBP - 1c and enhances hepatic lipogenesis . BACKGROUND : Oxysterol binding protein ( P22059 ) has previously been implicated as a sterol sensor that regulates sphingomyelin synthesis and the activity of extracellular signal - regulated kinases ( P29323 ) . METHODS AND RESULTS : We determined the effects of adenovirus - mediated hepatic overexpression of P22059 and its homologues ORP1L and Q9H4L5 on mouse serum lipids . Whereas ORP1L and Q9H4L5 had no effect on serum lipids , P22059 induced a marked increase of VLDL triglycerides ( TG ) . Also , the liver tissue TG were elevated in the AdOSBP - injected mice , and their TG secretion rate was increased by 70 % . The messenger RNAs for enzymes of fatty acid synthesis and their transcriptional regulator , SREBP - 1c , as well as the Insig - 1 mRNA , were upregulated two - fold in the P22059 - expressing livers . No change occurred in the messages of liver X receptor target genes O95477 , Q9H222 , and P22680 , and the Insig - 2a mRNA was reduced . The phosphorylation of P29323 was decreased in AdOSBP - infected liver and cultured hepatocytes . Importantly , silencing of P22059 in hepatocytes suppressed the induction of P36956 - c by insulin and resulted in a reduction of TG synthesis . CONCLUSION : Our results demonstrate that P22059 regulates hepatic TG metabolism and suggest the involvement of P22059 in the insulin signaling pathways that control hepatic lipogenesis .", "Invasive Lobular Carcinomas Do Not Express Basal Cytokeratin Markers CK5 / 6 , CK14 and CK17 . The expression of basal cytokeratin markers CK5 / 6 in breast carcinomas has been associated with high histological grade and poor clinical outcome . A previous study has shown that CK5 / 6 can be detected in up to 17 % of invasive lobular carcinomas ( Q9Y4X3 ) . Here we study the expression of three basal cytokeratin markers ( CK5 / 6 , CK14 , and CK17 ) in 53 Q9Y4X3 cases diagnosed by histology and lack of P12830 expression . Among them , 42 were classic lobular carcinomas , 6 were tubular - lobular carcinoma , and 5 were pleomorphic lobular carcinomas . There was no significant difference among these three groups in patients ' age , tumor size , uni - and multi - focality , expression of ER and PR , lymphovascular invasion , perineural invasion and lymph node metastasis . The only statistically different factor was P04626 over - expression , which was observed only in pleomorphic Q9Y4X3 ( P = 0 . 0073 ) . None of the 53 cases expressed CK5 / 6 , CK14 or CK17 ; and 51 / 53 cases expressed luminal markers CK8 and CK18 , and the two negative cases were both classic lobular carcinoma , with positivity for ER and PR . In conclusion , all 53 cases of Q9Y4X3 failed to show expression by any of the three basal CK markers , suggesting that very few Q9Y4X3 will demonstrate a basal phenotype when assessed by immunohistochemistry ( IHC ) . More studies are needed to investigate molecular classification in lobular carcinoma of the breast .", "Wild - type O75581 inhibits , whereas atherosclerosis - linked LRP6R611C increases PDGF - dependent vascular smooth muscle cell proliferation . Vascular smooth muscle cell ( VSMC ) proliferation is an important event in atherosclerosis and other vasculopathies . PDGF signaling is a key mediator of SMC proliferation , but the mechanisms that control its activity remain unclear . We previously identified a mutation in P01130 - related protein 6 ( O75581 ) , O75581 ( R611C ) , that causes early atherosclerosis . Examination of human atherosclerotic coronary arteries showed markedly increased expression of O75581 and colocalization with PDGF receptor β ( P09619 - β ) . Further investigation showed that wild - type O75581 inhibits but O75581 ( R611C ) promotes VSMC proliferation in response to PDGF . We found that wild - type O75581 forms a complex with P09619 - β and enhances its lysosomal degradation , functions that are severely impaired in O75581 ( R611C ) . Further , we observed that wild - type and mutant O75581 regulate cell - cycle activity by triggering differential effects on PDGF - dependent pathways . These findings implicate O75581 as a critical modulator of PDGF - dependent regulation of cell cycle in smooth muscle and indicate that loss of this function contributes to development of early atherosclerosis in humans .", "Gender disparity in LDL - induced cardiovascular damage and the protective role of estrogens against electronegative LDL . BACKGROUND : Increased levels of the most electronegative type of LDL , Q15004 , have been observed in the plasma of patients with metabolic syndrome ( MetS ) and ST - segment elevation myocardial infarction and can induce endothelial dysfunction . Because men have a higher predisposition to developing coronary artery disease than do premenopausal women , we hypothesized that LDL electronegativity is increased in men and promotes endothelial damage . METHODS : Q15004 levels were compared between middle - aged men and age - matched , premenopausal women with or without MetS . We further studied the effects of gender - influenced LDL electronegativity on aortic cellular senescence and DNA damage in leptin receptor - deficient ( db / db ) mice by using senescence - associated - β - galactosidase and γ P16104 staining , respectively . We also studied the protective effects of 17β - estradiol and genistein against electronegative LDL - induced senescence in cultured bovine aortic endothelial cells ( BAECs ) . RESULTS : Q15004 levels were higher in MetS patients than in healthy subjects ( P < 0 . 001 ) , particularly in men ( P = 0 . 001 ) . LDL isolated from male db / db mice was more electronegative than that from male or female wild - type mice . In addition , LDL from male db / db mice contained abundantly more apolipoprotein CIII and induced more BAEC senescence than did female db / db or wild - type LDL . In the aortas of db / db mice but not wild - type mice , we observed cellular senescence and DNA damage , and the effect was more significant in male than in female db / db mice . Pretreatment with 17β - estradiol or genistein inhibited BAEC senescence induced by male or female db / db LDL and downregulated the expression of lectin - like oxidized P01130 - 1 and tumor necrosis factor - alpha protein . CONCLUSION : The gender dichotomy of LDL - induced cardiovascular damage may underlie the increased propensity to coronary artery disease in men .", "Gene expression profiles of DB00171 - binding cassette transporter A and C subfamilies in mouse retinal vascular endothelial cells . The purpose of this study was to quantify gene expression levels of the DB00171 - binding cassette ( DB01048 ) transporter A and C subfamilies O95477 - A9 , and P33527 - 6 / Mrp1 - 6 , Q99622 / Mrp7 in mouse retinal vascular endothelial cells ( RVEC ) using a combination of a magnetic isolation method for mouse RVEC and real - time quantitative PCR analysis . The transcript level of endothelial cell markers , such as CD31 , Tie - 2 , claudin - 5 , occludin , ABCB1a / mdr1a , and Q9UNQ0 , were more than 20 - fold higher than those in the non - RVEC fraction , suggesting that RVEC in the RVEC fraction are concentrated at least 20 - fold compared with those of the non - RVEC fraction . In the O95477 to A9 families , the transcript level of Q99758 and A9 in the RVEC fraction was 1 . 2 - and 32 - fold higher than that in the non - RVEC fraction . Although Q99758 was expressed in both the RVEC and non - RVEC fractions , A9 is predominantly expressed in the RVEC fraction . In the P33527 to P13671 and Q99622 families , the transcript level of O15438 , C4 , and P13671 in the RVEC fraction was 27 - , 251 - , and 242 - fold higher , respectively , than that in the non - RVEC fraction , suggesting that O15438 , C4 , and P13671 are predominantly expressed in the RVEC . In conclusion , Q99758 , Q8IUA7 , O15438 , O15439 , and O95255 mRNAs are predominantly expressed at the inner blood - retina barrier ( inner BRB ) and appear to play a major role in the efflux transport of their substrates at the inner BRB .", "TGFbeta1 , TNFalpha , and insulin signaling crosstalk in regulation of the rat cholesterol 7alpha - hydroxylase gene expression . The TGFbeta1 / Smad pathway plays a critical role in cholestasis and liver fibrosis . Previous studies show that TGFbeta1 , TNFalpha , and insulin inhibit cholesterol 7alpha - hydroxylase ( P22680 ) gene transcription and bile acid synthesis in human hepatocytes . In this study , we investigated insulin , TGFbeta1 , and TNFalpha regulation of rat Cyp7a1 gene transcription . In contrast to inhibition of human P22680 gene transcription , TGFbeta1 stimulates rat Cyp7a1 reporter activity . P84022 , FoxO1 , and HNF4alpha synergistically stimulated rat Cyp7a1 gene transcription . Mutations of the P84022 , FoxO1 , or HNF4alpha binding site attenuated the rat Cyp7a1 promoter activity . Furthermore , TNFalpha and cJun attenuated TGFbeta1 stimulation of rat Cyp7a1 . P01308 or adenovirus - mediated expression of constitutively active P31749 inhibited FoxO1 and P84022 synergy . In streptozotocin - induced diabetic rats , Cyp7a1 mRNA expression levels were induced and insulin attenuated P22680 mRNA levels . Chromatin immunoprecipitation assay showed that FoxO1 binding to Cyp7a1 chromatin was increased in diabetic rat livers and insulin reduced FoxO1 binding . These results suggest a mechanistic basis for induction of Cyp7a1 activity and bile acid synthesis in cholestatic rats and in diabetic rats . The crosstalk of insulin , TGFbeta and TNFalpha signaling pathways may regulate bile acid synthesis and lipid homeostasis in diabetes , fatty liver disease , and liver fibrosis .", "DB04540 - lowering effect of ezetimibe in uridine diphosphate glucuronosyltransferase 1A - deficient ( Gunn ) rats . DB00973 ( EZE ) selectively blocks intestinal cholesterol absorption by interacting with Niemann - Pick C1 Like 1 ( Q9UHC9 ) . After administration , EZE is extensively metabolized in liver and intestine to its phenolic glucuronide form ( EZE - G ) by uridine diphosphate glucuronosyltransferases ( UGTs ) , among which P22309 and 1A3 exhibit highest activity . EZE - G is excreted into bile and undergoes extensive enterohepatic recirculation . Considering the pharmacokinetic properties of EZE and an in vitro binding study showing the high affinity binding of EZE - G to Q9UHC9 , glucuronidation by UGTs has been believed to be essential for the pharmacological efficacy of EZE . To study the role of glucuronidation by UGTs for the cholesterol - lowering effect of EZE , in vitro and in vivo studies were performed using Gunn rats , which hereditarily lack the expression of P22309 enzymes . The biliary excreted amount of EZE - G was reduced by 73 % up to 3 h after administration of EZE ( 0 . 3 mg / kg ) in Gunn rats , which is consistent with the reduction of in vitro EZE glucuronidation activity found in liver and intestinal microsome from Gunn rats . These results indicate that the formation of EZE - G in Gunn rats is much lower than that in Wistar rats . However , in vivo study showed that 0 . 3 mg / kg EZE , which is the clinically relevant dose , reduced cholesterol absorption in both Wistar and Gunn rats to nearly the same degree and the dose dependence was not significantly different between Wistar and Gunn rats at the range 0 . 001 approximately 0 . 3 mg / kg . These results indicate that a deficiency of P22309 activity does not necessarily alter the cholesterol - lowering effect of EZE in rats at therapeutic doses .", "DB04540 and plant sterol absorption : recent insights . The recent discovery of transporters in the intestinal mucosa and the canalicular membrane has given new insights into the regulation of intestinal absorption as well as the biliary output of cholesterol and plant sterols . The 2 adenosine triphosphate ( DB00171 ) - binding cassette ( DB01048 ) half - transporters Q9H222 and Q9H221 are expressed in the mucosa cells and the canalicular membrane , and they resecrete sterols , especially absorbed plant sterols , back into the intestinal lumen and from the liver into bile . Defects of either of these cotransporters lead to the rare inherited disease of phytosterolemia , which is clinically defined by hyperabsorption and diminished biliary excretion of plant sterols . Furthermore , it has been recently demonstrated that the Niemann - Pick C1 - Like 1 ( Q9UHC9 ) transporter is most likely responsible for the transport of cholesterol and plant sterols from the brush border membrane into the intestinal mucosa . DB00973 interferes with Q9UHC9 , reducing the intestinal uptake of cholesterol and plant sterols . These new findings contribute to our understanding of cholesterol and plant sterol concentrations in serum , and the effect of dietary and drug intervention to reduce serum concentrations of sterols .", "Missense mutations in Q9H222 and Q9H221 disrupt heterodimerization and trafficking . Mutations in Q9H222 ( G5 ) or Q9H221 ( Q9UBA6 ) cause sitosterolemia , an autosomal recessive disease characterized by sterol accumulation and premature atherosclerosis . G5 and Q9UBA6 are DB00171 - binding cassette ( DB01048 ) half - transporters that must heterodimerize to move to the apical surface of cells . We examined the role of N - linked glycans in the formation of the G5 / Q9UBA6 heterodimer to gain insight into the determinants of folding and trafficking of these proteins . Site - directed mutagenesis revealed that two asparagine residues ( DB00174 ( 585 ) and DB00174 ( 592 ) ) are glycosylated in G5 and that Q9UBA6 has a single N - linked glycan attached to DB00174 ( 619 ) . N - Linked glycosylation of Q9UBA6 was required for efficient trafficking of the G5 / Q9UBA6 heterodimer , but mutations that abolished glycosylation of G5 did not prevent trafficking of the heterodimer . Both G5 and Q9UBA6 are bound by the lectin chaperone , calnexin , suggesting that the calnexin cycle may facilitate folding of the G5 / Q9UBA6 heterodimer . To determine the effects of 13 disease - causing missense mutations in G5 and Q9UBA6 on formation and trafficking of the G5 / Q9UBA6 heterodimer , mutant forms of the half - transporters were expressed in CHO - P04264 cells . All 13 mutations reduced trafficking of the G5 / Q9UBA6 heterodimer from the endoplasmic reticulum to the Golgi complex , and most prevented the formation of stable heterodimers between G5 and Q9UBA6 . We conclude that the majority of the molecular defects in G5 and Q9UBA6 that cause sitosterolemia impair transport of the sterol transporter to the cell surface .", "Roles of purinergic receptor P2Y , G protein - coupled 12 in the development of atherosclerosis in apolipoprotein E - deficient mice . OBJECTIVE : The aim of the study was to evaluate the role of purinergic receptor P2Y , G protein - coupled 12 ( Q9H244 ) , an ADP receptor , in the development of atherosclerotic lesions . METHODS AND RESULTS : P02649 - null mice were crossed with P2y12 (-/-) mice to generate double knockout mice . The double knockout mice and the control apolipoprotein E - null mice were fed a high - fat diet for 20 weeks . Assessment of the atherosclerotic lesions in the control and double knockout mice demonstrated that Q9H244 deficiency caused a diminished lesion area , an increased fibrous content at the plaque site , and decreased monocyte / macrophage infiltration of the lesions . Polymerase chain reaction studies revealed that white blood cells do not express significant levels of Q9H244 . Bone marrow transplantation experiments confirmed that Q9H244 expressed on platelets is a key factor responsible for atherosclerosis , but do not exclude a role of smooth muscle cell Q9H244 . Supernatant fluid from activated P2y12 (+/+) but not P2y12 (-/-) platelets was capable of causing monocyte migration . In vitro studies showed that platelet Q9H244 deficiency suppressed platelet factor 4 secretion and P16109 expression . Further work demonstrated that platelet Q9H244 , through inhibition of the DB02527 / protein kinase A pathway , critically regulates the release of platelet factor 4 , and thereby affects monocyte recruitment and infiltration . CONCLUSIONS : These results demonstrate that Q9H244 modulates atherogenesis , at least in part by augmenting inflammatory cell recruitment via regulation of platelet α - granule release .", "___MASK9___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK9___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK9___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK9___ inhibits activated T cells . We show that in vitro , ___MASK9___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK9___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK9___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK9___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK9___ to treat chronic inflammatory disease .", "Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .", "Nardosinone protects H9c2 cardiac cells from angiotensin II - induced hypertrophy . Pathological cardiac hypertrophy induced by angiotensin II ( AngII ) can subsequently give rise to heart failure , a leading cause of mortality . Nardosinone is a pharmacologically active compound extracted from the roots of Nardostachys chinensis , a well - known traditional Chinese medicine . In order to investigate the effects of nardosinone on AngII - induced cardiac cell hypertrophy and the related mechanisms , the myoblast cell line H9c2 , derived from embryonic rat heart , was treated with nardosinone ( 25 , 50 , 100 , and 200 μmol / L ) or AngII ( 1 μmol / L ) . Then cell surface area and mRNA expression of classical markers of hypertrophy were detected . The related protein levels in PI3K / Akt / P42345 and MEK / P29323 signaling pathways were examined by Western blotting . It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by AngII . The mRNA expression of P01160 , DB04899 and β - MHC was obviously elevated in AngII - treated H9c2 cells , which could be effectively blocked by nardosinone at the concentration of 100 μmol / L . Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K / Akt and MEK / P29323 signaling pathways . It was suggested that the inhibitory effect of nardosinone on Ang II - induced hypertrophy in H9c2 cells might be mediated by targeting PI3K / Akt and MEK / P29323 signaling pathways .", "The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK9___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .", "Hyperglycemia accelerates DB00171 - binding cassette transporter A1 degradation via an P29323 - dependent pathway in macrophages . An elevation in blood glucose concentration leads to increased risk of developing diabetes - associated atherosclerotic cardiovascular disease due to an excessive accumulation of cholesterol in arterial macrophages . DB00171 - binding cassette transporter A1 ( O95477 ) is an atheroprotective protein that mediates the export of cholesterol from macrophages . The present study aims to investigate the effect of hyperglycemia on the regulation of O95477 expression and to explore its underlying mechanisms of regulation in macrophages . Our results show that high glucose activates the extracellular signal - regulated kinases ( P29323 ) signaling pathway via reactive oxygen species ( ROS ) production , which in turn down - regulates O95477 mRNA and protein expression . This down - regulation is mediated by accelerating O95477 mRNA and protein degradation in macrophages exposed to high concentrations of glucose . Our results provide evidence for the first time that hyperglycemia inhibits O95477 expression by P29323 - modulated O95477 mRNA and protein stability . Overall , these results provide a mechanism for hyperglycemia - induced reduction in O95477 expression , which suggests a promising strategy for the treatment of diabetes - associated atherosclerosis .", "Current therapy for patients with sitosterolemia -- effect of ezetimibe on plant sterol metabolism . Sitosterolemia is a rare , autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations , caused by mutations in the adenosine triphosphate - bind - ing cassette ( DB01048 ) transporter Q9H222 or Q9H221 genes . Markedly increased serum concentration of plant sterols . such as sitosterol and campesterol , cause premature atherosclerosis and massive xanthomas . Hitherto known treatments for sitosterolemia , including a low - sterol diet , bile - salt binding resins , ileal bypass surgery and low density lipoprotein ( LDL ) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels , subsequently developing premature atherosclerotic cardiovascular diseases . DB00973 , an inhibitor of intestinal cholesterol absorption through its binding to Niemann - Pick C1 - like 1 ( Q9UHC9 ) , has been widely used for decreasing serum LDL - cholesterol levels in patients with hypercholesterolemia . DB00973 also reduces the gastrointestinal absorption of plant sterols , thereby also lowering the serum concentrations of plant sterols . This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia . In the current review , we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease , one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis . DB00973 administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51 . 3 % and 48 . 9 % , respectively , in the two patients , demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy .", "The stop transfer sequence of the human UDP - glucuronosyltransferase 1A determines localization to the endoplasmic reticulum by both static retention and retrieval mechanisms . Human UDP - glucuronosyltransferase 1A ( P22309 ) isoforms are endoplasmic reticulum ( ER ) - resident type I membrane proteins responsible for the detoxification of a broad range of toxic phenolic compounds . These proteins contain a C - terminal stop transfer sequence with a transmembrane domain ( TMD ) , which anchors the protein into the membrane , followed by a short cytosolic tail ( CT ) . Here , we investigated the mechanism of ER residency of P22309 mediated by the stop transfer sequence by analysing the subcellular localization and sensitivity to endoglycosidases of chimeric proteins formed by fusion of P22309 stop transfer sequence ( TMD / CT ) with the ectodomain of the plasma membrane P01730 reporter protein . We showed that the stop transfer sequence , when attached to C - terminus of the P01730 ectodomain was able to prevent it from being transported to the cell surface . The protein was retained in the ER indicating that this sequence functions as an ER localization signal . Furthermore , we demonstrated that ER localization conferred by the stop transfer sequence was mediated in part by the KSKTH retrieval signal located on the CT . Interestingly , our data indicated that P22309 TMD alone was sufficient to retain the protein in ER without recycling from Golgi compartment , and brought evidence that organelle localization conferred by P22309 TMD was determined by the length of its hydrophobic core . We conclude that both retrieval mechanism and static retention mediated by the stop transfer sequence contribute to ER residency of P22309 proteins .", "DB00973 as a potential treatment for non - alcoholic fatty liver disease : is the intestine a modulator of hepatic insulin sensitivity and hepatic fat accumulation ? Non - alcoholic fatty liver disease ( NAFLD ) is the hepatic component of the metabolic syndrome and is known to be associated with marked insulin resistance and increased risk of cardiovascular disease . DB00973 , an inhibitor of intestinal cholesterol absorption , inhibits Niemann - Pick C1 - like 1 ( Q9UHC9 ) . Interestingly , Q9UHC9 is abundantly expressed in human liver , as well as in the intestine . Recent reports suggest a potential benefit of ezetimibe in improving hepatic insulin sensitivity and decreasing hepatic inflammation and lipid accumulation . P01308 resistance and excess hepatic fat accumulation are regarded as key factors in the pathogenesis of NAFLD . We suggest , therefore , that urgent studies are needed to assess the potential therapeutic benefit of ezetimibe in treating NAFLD .", "Identification of an amino acid residue important for binding of methiothepin and sumatriptan to the human 5 - HT ( 1B ) receptor . Site - directed mutagenesis of the human P28222 receptor was performed to investigate the role of the amino acid residues cysteine 326 and tryptophan 327 in transmembrane region VI and aspartic acid 352 in transmembrane region VII in ligand binding . Binding studies were performed with the antagonist radioligand [ 3H ] GR125743 on mutant and wild - type receptors stably expressed in Chinese hamster ovary cells ( CHO ) - P04264 cells . Substitution of tryptophan 327 by alanine resulted in decreased affinities of all ligands tested . The most prominent changes in affinity were observed for the antagonist methiothepin and the antimigraine drug sumatriptan , which were reduced approximately 300 - and 60 - fold , respectively . Nevertheless , the affinity of 5 - HT remained the same . Replacement of the aspartic acid 352 by alanine reduced high - affinity binding of 5 - HT . Substitution of cysteine 326 by alanine had minor effects on ligand binding . Some of these results agree with the results from mutagenesis studies of the corresponding amino acids in other receptors . However , some notable differences also emerge showing that functional roles of individual amino acid residues must be tested experimentally in each receptor subtype .", "No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK77___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK77___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK77___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK77___ among adults with ADHD .", "Transporters in cholelithiasis . Gallstones are a common and costly disease with a projected increase in prevalence due to the increasing ageing population . Numerous endogenous and environmental factors are aetiologically related to this multifactorial disease , and genetic studies continue to unravel the pathobiological mechanisms related to gallstone formation . In particular , variants of genes encoding hepatobiliary transporters have been implicated in gallstone disease and , given their ability to influence biliary lipid composition , have undergone considerable investigation . Here we summarize the role of enterohepatic transporters in cholelithogenesis with a particular focus on pertinent DB00171 - binding cassette transporters ( P21439 , O95342 , P13569 , and Q9H222 / Q9UBA6 ) .", "The use of the VerifyNow Q9H244 point - of - care device to monitor platelet function across a range of Q9H244 inhibition levels following prasugrel and clopidogrel administration . Variability in response to antiplatelet agents has prompted the development of point - of - care ( POC ) technology . In this study , we compared the VerifyNow Q9H244 ( VN - Q9H244 ) POC device with light transmission aggregometry ( P01374 ) in subjects switched directly from clopidogrel to prasugrel . Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose ( LD ) followed by a 75 mg / d maintenance dose ( MD ) for 10 days . Subjects were then switched to a prasugrel 60 mg LD and then 10 mg / d MD for 10 days ( n = 16 ) , or to a prasugrel 10 mg / d MD for 11 days ( n = 19 ) . Platelet function was measured by P01374 and VN - Q9H244 at baseline and after dosing . DB00758 600 mg LD / 75 mg MD treatment led to a reduction in P2Y ( 12 ) reaction units ( PRU ) from baseline . A switch from clopidogrel MD to prasugrel 60 mg LD / 10 mg MD produced an immediate decrease in PRU , while a switch to prasugrel 10 mg MD resulted in a more gradual decline . Consistent with the reduction in PRU , device - reported percent inhibition increased during both clopidogrel and prasugrel regimens . Inhibition of platelet aggregation as measured by P01374 showed a very similar pattern to that found with VN - Q9H244 measurement , irrespective of treatment regimens . The dynamic range of VN - Q9H244 appeared to be narrower than that of P01374 . With two different thienopyridines , the VN - Q9H244 device , within a somewhat more limited range , reflected the overall magnitude of change in aggregation response determined by P01374 . The determination of the clinical utility of such POC devices will require their use in clinical outcome studies .", "___MASK98___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK98___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .", "Inhibition of Niemann - Pick - type C1 - like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant α1 - antitrypsin Z deposition . Autophagy can degrade aggregate - prone proteins , but excessive autophagy can have adverse effects . It would be beneficial if autophagy could be enhanced in a cell type - specific manner , but this has been difficult because the basic mechanism of autophagy is common . In the present study we found that inhibition of Niemann - Pick - type C1 - like 1 ( Q9UHC9 ) by ezetimibe activates autophagy only in hepatocytes and small intestinal epithelia , but not in other cells . DB00973 induced accumulation of free cholesterol in the late endosome / lysosome and increased partitioning of a Ragulator component , Q6IAA8 , in rafts . The latter change led to down - regulation of mammalian target of rapamycin ( P42345 ) C1 activity by decreasing P42345 recruitment to the late endosome / lysosome and activated autophagy . A primary effect of ezetimibe was found to be a decrease of free cholesterol in the plasma membrane , because all the results caused by ezetimibe were suppressed by supplementation of cholesterol as a methyl - β - cyclodextrin complex . By enhancing autophagy in human primary hepatocytes with ezetimibe , insoluble mutant α1 - antitrypsin Z was reduced significantly . CONCLUSION : Inhibition of Q9UHC9 by ezetimibe activates autophagy in human hepatocytes by modulating cholesterol homeostasis . DB00973 may be used to ameliorate liver degeneration in α1 - antitrypsin deficiency .", "Molecular - based choice of cancer therapy : realities and expectations . Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success . Molecular research provides some opportunities to personalize antitumor treatment . For example , life - threatening toxic reactions can be avoided by the identification of subjects , who carry susceptible genotypes of drug - metabolizing genes ( e . g . P51580 , P22309 , P42898 , Q12882 ) . Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response . Tailoring of antiestrogen and trastuzumab therapy based on hormone and P04626 receptor status has already become a classical example of customized medicine . Other predictive markers have been identified both for cytotoxic and for targeted therapies , and include , for example , expression of TS , TP , Q12882 , OPRT , P07992 , P16455 , P11388 , class III beta - tubulin molecules as well as genomic alterations of P00533 , P10721 , P00519 oncogenes .", "Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK68___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .", "Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK79___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .", "The role of nitric oxide in ischaemia / reperfusion injury of isolated hearts from severely atherosclerotic mice . DB00435 ( NO ) may play an essential role for maintenance of cardiac function and perfusion , while endothelial dysfunction of atherosclerotic vessels may aggravate ischaemia / reperfusion injury . This paper investigates the role of nitric oxide in ischaemia / reperfusion injury in hearts with coronary atherosclerosis . Hearts of apolipoprotein E / P01130 double knockout ( ApoE / LDLr KO ) mice fed an atherogenic diet for 7 - 9 months were isolated and Langendorff - perfused with 40 minutes of global ischaemia and 60 minutes reperfusion , and funtion and infarction compared with hearts of C57BL / 6 controls in the prescence or abscence of the NO - donor P60880 or the NOS inhibitor L - NAME . Hearts of animals with atherosclerosis were more susceptible to ischaemia / reperfusion injury than hearts of animals with healthy vessels , evident as more impaired left ventricular performance . P60880 protected function and reduced infarct size in atherosclerotic hearts , but the same concentration of P60880 was detrimental in normal hearts , perhaps due to NO - overproduction and peroxynitrite formation demonstrated immunohistochemically as increased formation of nitrosylated tyrosine . A low concentration of P60880 protected against ischaemia / reperfusion dysfunction in normal hearts . L - NAME decreased left ventricular performance in atherosclerotic hearts . These findings suggest that impaired endothelium dependent function contributes to reperfusion injury in coronary atherosclerosis .", "Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP - specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with ___MASK9___ , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with ___MASK9___ . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . ___MASK9___ treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . ___MASK9___ treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity .", "Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK98___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .", "HDL in infectious diseases and sepsis . During infection significant alterations in lipid metabolism and lipoprotein composition occur . Triglyceride and VLDL cholesterol levels increase , while reduced HDL cholesterol ( HDL - C ) and LDL cholesterol ( LDL - C ) levels are observed . More importantly , endotoxemia modulates HDL composition and size : phospholipids are reduced as well as apolipoprotein ( apo ) A - I , while serum amyloid A ( P0DJI8 ) and secretory phospholipase A2 ( sPLA2 ) dramatically increase , and , although the total HDL particle number does not change , a significant decrease in the number of small - and medium - size particles is observed . Low HDL - C levels inversely correlate with the severity of septic disease and associate with an exaggerated systemic inflammatory response . HDL , as well as other plasma lipoproteins , can bind and neutralize Gram - negative bacterial lipopolysaccharide ( LPS ) and Gram - positive bacterial lipoteichoic acid ( P01374 ) , thus favoring the clearance of these products . HDLs are emerging also as a relevant player during parasitic infections , and a specific component of HDL , namely , apoL - 1 , confers innate immunity against trypanosome by favoring lysosomal swelling which kills the parasite . During virus infections , proteins associated with the modulation of cholesterol bioavailability in the lipid rafts such as O95477 and Q8WTV0 have been shown to favor virus entry into the cells . Pharmacological studies support the benefit of recombinant HDL or apoA - I mimetics during bacterial infection , while apoL - 1 - nanobody complexes were tested for trypanosome infection . Finally , Q8WTV0 antagonism represents a novel and forefront approach interfering with hepatitis C virus entry which is currently tested in clinical studies . From the coming years , we have to expect new and compelling observations further linking HDL to innate immunity and infections .", "Nuclear hormone receptors and cholesterol trafficking : the orphans find a new home . There are many homeostatic mechanisms that contribute to the regulation of cellular and serum cholesterol levels in humans . Much of our understanding of this regulation arose from studies of the cellular pathways controlling cholesterol synthesis and the uptake and degradation of low - density lipoproteins . The physiology governing cholesterol disposition in whole animals , including the molecular mechanisms responsible for dietary uptake of cholesterol and its subsequent catabolism to bile acids , are only now being uncovered . This review summarizes recent studies that have used modern genetic techniques , as well as cell biological methods , to begin to elucidate the pathways responsible for cholesterol trafficking in vivo . This work has led to the realization that networks of nuclear hormone receptors , including the LXR , Q96RI1 , Q07869 , and RXR proteins , play critical roles in lipid metabolism by virtue of their transcriptional regulation of the genes that control sterol metabolic pathways . Some of the major downstream targets of these regulatory networks involve members of the ABC transporter family , including O95477 , P45844 , Q9H222 , Q9H221 , P21439 / Mdr2 , and SPGP / O95342 . These transporters contribute to the movement of sterols and biliary lipids across cellular membranes via mechanisms that have yet to be elucidated . The potential for manipulating these cholesterol trafficking pathways via drugs targeted to the nuclear hormone receptors has generated great interest in their biology and will undoubtedly lead to new therapeutic approaches to human disorders in the coming years .", "Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .", "Platelets mediate oxidized low - density lipoprotein - induced monocyte extravasation and foam cell formation . OBJECTIVE : A growing body of evidence indicates that platelets contribute to the onset and progression of atherosclerosis by modulating immune responses . We aimed to elucidate the effects of oxidized low - density lipoprotein ( OxLDL ) on platelet - monocyte interactions and the consequences of these interactions on platelet phagocytosis , chemokine release , monocyte extravasation , and foam cell formation . APPROACH AND RESULTS : Confocal microscopy and flow cytometric analysis revealed that in vitro and in vivo stimulation with OxLDL resulted in rapid formation of platelet - monocyte aggregates , with a preference for CD16 + monocyte subsets . This platelet - monocyte interaction facilitated OxLDL uptake by monocytes , in a process that involved platelet P16671 - OxLDL interaction , release of chemokines , such as CXC motif ligand 4 , direct platelet - monocyte interaction , and phagocytosis of platelets . Inhibition of cyclooxygenase with acetylsalicylic acid and antagonists of ADP receptors , P47900 and Q9H244 , partly abrogated OxLDL - induced platelet - monocyte aggregates and platelet - mediated lipid uptake in monocytes . Platelets also enhanced OxLDL - induced monocyte transmigration across an endothelial monolayer via direct interaction with monocytes in a transwell assay . Importantly , in P01130 (-/-) mice , platelet depletion resulted in a significant decrease of peritoneal macrophage recruitment and foam cell formation in a thioglycollate - elicited peritonitis model . In platelet - depleted wild - type mice , transfusion of ex vivo OxLDL - stimulated platelets induced monocyte extravasation to a higher extent when compared with resting platelets . CONCLUSIONS : Our results on OxLDL - mediated platelet - monocyte aggregate formation , which promoted phenotypic changes in monocytes , monocyte extravasation and enhanced foam cell formation in vitro and in vivo , provide a novel mechanism for how platelets potentiate key steps of atherosclerotic plaque development and plaque destabilization .", "5 - Aminoimidazole - 4 - carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via P29323 - dependent Q15717 binding to an AU - rich element . OBJECTIVE : 5 - Aminoimidazole - 4 - carboxamide ribonucleoside ( AICAR ) has pleiotropic and beneficial effects on metabolic disorders . However , the effects of AICAR on low density lipoprotein ( LDL ) metabolism are poorly understood . METHODS AND RESULTS : AICAR induces increased P01130 mRNA levels and increased P01130 protein production in hepatocytes . The AICAR - dependent P01130 mRNA increase was partially mediated by mRNA stabilization in an extracellular signal - regulated kinase1 / 2 ( P27361 / 2 ) - dependent manner , but not by the AMP - activated protein kinase ( AMPK ) activation . Reporter assays using a variety of constructs harboring the 3 '- untranslated region ( UTR ) of human P01130 mRNA revealed that the most upstream AU - rich element ( ARE ) was critical for these AICAR effects . Using UV cross - linking assays , we found increased binding of three cytoplasmic proteins to this ARE region in response to AICAR and identified a 35 - kDa protein as Human antigen R ( Q15717 ) . Blocking P29323 signaling pathway activation resulted in attenuated Q15717 binding . Silencing Q15717 expression by RNA interference hindered AICAR - induced P01130 mRNA stability , whereas its overexpression stabilized this mRNA . CONCLUSIONS : AICAR - dependent P01130 mRNA stabilization is mediated , at least in part , by Q15717 binding to the ARE1 region . Given that AICAR enhanced LDL uptake in hepatocytes , our findings warrant further studies using animal models to develop a novel LDL - cholesterol lowering agent as a possible strategy to treat atherosclerosis - related cardiovascular diseases .", "Apolipoprotein B100 danger - associated signal 1 ( ApoBDS - 1 ) triggers platelet activation and boosts platelet - leukocyte proinflammatory responses . Low - density lipoproteins ( LDL ) , occurring in vivo in both their native and oxidative form , modulate platelet function and thereby contribute to atherothrombosis . We recently identified and demonstrated that ' ApoB100 danger - associated signal 1 ' ( ApoBDS - 1 ) , a native peptide derived from P04114 ( ApoB100 ) of LDL , induces inflammatory responses in innate immune cells . Platelets are critically involved in the development as well as in the lethal consequences of atherothrombotic diseases , but whether ApoBDS - 1 has also an impact on platelet function is unknown . In this study we examined the effect of ApoBDS - 1 on human platelet function and platelet - leukocyte interactions in vitro . Stimulation with ApoBDS - 1 induced platelet activation , degranulation , adhesion and release of proinflammatory cytokines . ApoBDS - 1 - stimulated platelets triggered innate immune responses by augmenting leukocyte activation , adhesion and transmigration to / through activated HUVEC monolayers , under flow conditions . These platelet - activating effects were sequence - specific , and stimulation of platelets with ApoBDS - 1 activated intracellular signalling pathways , including Ca2 + , PI3K / Akt , P98160 , and p38 - and P29323 - MAPK . Moreover , our data indicates that ApoBDS - 1 - induced platelet activation is partially dependent of positive feedback from ADP on P47900 and Q9H244 , and TxA2 . In conclusion , we demonstrate that ApoBDS - 1 is an effective platelet agonist , boosting platelet - leukocyte ' s proinflammatory responses , and potentially contributing to the multifaceted inflammatory - promoting effects of LDL in the pathogenesis of atherothrombosis .", "Common variants near P42685 / Q03692 and P15692 are associated with advanced age - related macular degeneration . Despite significant progress in the identification of genetic loci for age - related macular degeneration ( AMD ) , not all of the heritability has been explained . To identify variants which contribute to the remaining genetic susceptibility , we performed the largest meta - analysis of genome - wide association studies to date for advanced AMD . We imputed 6 036 699 single - nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow - up replication of top signals in 5640 cases and 52 174 controls . We identified two new common susceptibility alleles , rs1999930 on 6q21 - q22 . 3 near P42685 / Q03692 [ odds ratio ( OR ) 0 . 87 ; P = 1 . 1 × 10 (- 8 ) ] and rs4711751 on 6p12 near P15692 ( OR 1 . 15 ; P = 8 . 7 × 10 (- 9 ) ) . In addition to the two novel loci , 10 previously reported loci in P0C7Q2 / Q92743 ( rs10490924 ) , P08603 ( rs1061170 , and rs1410996 ) , P00751 ( rs641153 ) , P01024 ( rs2230199 ) , P06681 ( rs9332739 ) , P05156 ( rs10033900 ) , P11150 ( rs10468017 ) , P35625 ( rs9621532 ) and P11597 ( rs3764261 ) were confirmed with genome - wide significant signals in this large study . Loci in the recently reported genes O95477 and P27658 were also detected with suggestive evidence of association with advanced AMD . The novel variants identified in this study suggest that angiogenesis ( P15692 ) and extracellular collagen matrix ( P42685 / Q03692 ) pathways contribute to the development of advanced AMD .", "P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK63___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .", "Targeting mitochondrial 18 kDa translocator protein ( TSPO ) regulates macrophage cholesterol efflux and lipid phenotype . The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein ( TSPO ) as a potential therapeutic target , capable of increasing macrophage cholesterol efflux to ( apo ) lipoprotein acceptors . Expression and activity of TSPO in human ( THP - 1 ) macrophages were manipulated genetically and by the use of selective TSPO ligands . Cellular responses were analysed by quantitative PCR ( Q - PCR ) , immunoblotting and radiolabelling , including [ 3H ] cholesterol efflux to ( apo ) lipoprotein A - I ( apoA - I ) , high - density lipoprotein ( HDL ) and human serum . Induction of macrophage cholesterol deposition by acetylated low - density lipoprotein ( AcLDL ) increased expression of TSPO mRNA and protein , reflecting findings in human carotid atherosclerosis . Transient overexpression of TSPO enhanced efflux ( E % ) of [ 3H ] cholesterol to apoA - I , HDL and human serum compared with empty vector ( EV ) controls , whereas gene knockdown of TSPO achieved the converse . Ligation of TSPO ( using PK11195 , FGIN - 1 - 27 and flunitrazepam ) triggered increases in [ 3H ] cholesterol efflux , an effect that was amplified in TSPO - overexpressing macrophages . Overexpression of TSPO induced the expression of genes [ Q07869 ( peroxisome - proliferator - activated receptor α ) , Q13133 ( nuclear receptor 1H3 / liver X receptor α ) , O95477 ( DB00171 - binding cassette A1 ) , Q9H172 ( DB00171 - binding cassette G4 ) and P02649 ( apolipoprotein E ) ] and proteins ( O95477 and PPARα ) involved in cholesterol efflux , reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL . Thus , targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation , via enhanced cholesterol efflux to ( apo ) lipoprotein acceptors .", "Q9Y5Q5 mutations K317E and S472G from preeclamptic patients alter zymogen activation and cell surface targeting . [ Corrected ] . Q9Y5Q5 is a membrane - bound serine protease that acts as the atrial natriuretic peptide ( P01160 ) convertase in the heart . Recent studies show that corin also activates P01160 in the pregnant uterus to promote spiral artery remodeling and prevent pregnancy - induced hypertension . Two Q9Y5Q5 gene mutations , K317E and S472G , were identified in preeclamptic patients and shown to have reduced activity in vitro . In this study , we carried out molecular modeling and biochemical experiments to understand how these mutations impair corin function . By molecular modeling , the mutation K317E was predicted to alter corin P01130 - 2 module conformation . Western blot analysis of K317E mutant in HEK293 cells showed that the mutation did not block corin expression on the cell surface but inhibited corin zymogen activation . In contrast , the mutation S472G was predicted to abolish a β - sheet critical for corin frizzled - 2 module structure . In Western blot analysis and flow cytometry , S472G mutant was not detected on the cell surface in transfected HEK293 cells . By immunostaining , the S472G mutant was found in the ER , indicating that the mutation S472G disrupted the β - sheet , causing corin misfolding and ER retention . Thus , these results show that mutations in the Q9Y5Q5 gene may impair corin function by entirely different mechanisms . Together , our data provide important insights into the molecular basis underlying corin mutations that may contribute to preeclampsia in patients .", "P01308 - like growth factor - 1 receptor signaling increases the invasive potential of human epidermal growth factor receptor 2 - overexpressing breast cancer cells via Src - focal adhesion kinase and forkhead box protein M1 . Resistance to the human epidermal growth factor receptor ( P04626 ) - targeted antibody trastuzumab is a major clinical concern in the treatment of P04626 - positive metastatic breast cancer . Increased expression or signaling from the insulin - like growth factor - 1 receptor ( IGF - 1R ) has been reported to be associated with trastuzumab resistance . However , the specific molecular and biologic mechanisms through which IGF - 1R promotes resistance or disease progression remain poorly defined . In this study , we found that the major biologic effect promoted by IGF - 1R was invasion , which was mediated by both Src - focal adhesion kinase ( Q05397 ) signaling and Q08050 ( FoxM1 ) . Cotargeting IGF - 1R and P04626 using either IGF - 1R antibodies or IGF - 1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition . Reduced invasion was the most significant biologic effect achieved by cotargeting IGF - 1R and P04626 in trastuzumab - resistant cells . Constitutively active Src blocked the anti - invasive effect of IGF - 1R / P04626 cotargeted therapy . Furthermore , knockdown of FoxM1 blocked DB01277 - mediated invasion , and dual targeting of IGF - 1R and P04626 reduced expression of FoxM1 . Re - expression of FoxM1 restored the invasive potential of IGF - 1R knockdown cells treated with trastuzumab . Overall , our results strongly indicate that therapeutic combinations that cotarget IGF - 1R and P04626 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1 .", "Excess nitric oxide impairs LXR ( α )- O95477 - dependent cholesterol efflux in macrophage foam cells . Excess nitric oxide ( NO ) promotes the progression of atherosclerosis by increasing the oxidation of low - density lipoprotein ( LDL ) and inflammatory responses . However , little is known about the impact of NO and its underlying molecular mechanism on lipid metabolism of macrophage foam cells . In this study , Oil - red O staining , cholesterol and triglyceride assay , Dil - oxidized LDL ( oxLDL ) binding assay , cholesterol efflux assay , real - time RT - PCR and Western blot analysis were used for in vitro experiments . P02649 - deficient ( apoE (-/-) ) and apoE and inducible nitric oxide synthase - deficient ( apoE (-/-) P35228 (-/-) ) mice were as our in vivo models . Treatment with S - nitroso - N - acetyl - D , L - penicillamine ( P60880 ) , an NO donor , exacerbated oxLDL - induced cholesterol accumulation in macrophages , because of reduced efficacy of cholesterol efflux . In addition , P60880 decreased the protein level of DB00171 - binding cassette transporter A1 ( O95477 ) without affecting scavenger receptor type A ( SR - A ) , P16671 , P45844 , or SR - B1 levels . This P60880 - mediated downregulation of O95477 was mainly through the effect of NO but not peroxynitrite . Furthermore , the P60880 - downregulated O95477 was due to the decrease in the liver X receptor α ( LXRα ) - dependent transcriptional regulation . Moreover , genetic deletion of P35228 increased the serum capacity of reverse cholesterol efflux and protein expression of LXRα , O95477 , and Q8WTV0 in aortas and retarded atherosclerosis in apoE (-/-) mice . Our findings provide new insights in the pro - atherogenic effect of excess NO on cholesterol metabolism in macrophages .", "Genetic demonstration of intestinal Q9UHC9 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels . OBJECTIVE : The correlation between intestinal cholesterol absorption values and plasma low - density lipoprotein - cholesterol ( LDL - C ) levels remains controversial . Niemann - Pick - C1 - Like 1 ( Q9UHC9 ) is essential for intestinal cholesterol absorption , and is the target of ezetimibe , a cholesterol absorption inhibitor . However , studies with Q9UHC9 knockout mice or ezetimibe can not definitively clarify this correlation because Q9UHC9 expression is not restricted to intestine in humans and mice . In this study we sought to genetically address this issue . METHODS AND RESULTS : We developed a mouse model that lacks endogenous ( Q9UHC9 ) and P01130 ( P01130 ) ( DKO ) , but transgenically expresses human Q9UHC9 in gastrointestinal tract only ( DKO / Q9NUQ9 ( IntOnly ) mice ) . Our novel model eliminated potential effects of non - intestinal Q9UHC9 on cholesterol homeostasis . We found that human Q9UHC9 was localized at the intestinal brush border membrane of DKO / Q9NUQ9 ( IntOnly ) mice . DB04540 feeding induced formation of Q9UHC9 - positive vesicles beneath this membrane in an ezetimibe - sensitive manner . Compared to DKO mice , DKO / Q9NUQ9 ( IntOnly ) mice showed significant increases in cholesterol absorption and blood / hepatic / biliary cholesterol . Increased blood cholesterol was restricted to very low - density lipoprotein ( VLDL ) and LDL fractions , which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48 . Additionally , DKO / Q9NUQ9 ( IntOnly ) mice displayed decreased fecal cholesterol excretion and hepatic / intestinal expression of cholesterologenic genes . DB00973 treatment virtually reversed all of the transgene - related phenotypes in DKO / Q9NUQ9 ( IntOnly ) mice . CONCLUSION : Our findings from DKO / Q9NUQ9 ( IntOnly ) mice clearly demonstrate that Q9UHC9 - mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B - containing atherogenic lipoproteins , at least in mice .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK96___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "Maxi - anion channel as a candidate pathway for osmosensitive DB00171 release from mouse astrocytes in primary culture . In the present study , we aimed to evaluate the pathways contributing to DB00171 release from mouse astrocytes during hypoosmotic stress . We first examined the expression of mRNAs for proteins constituting possible DB00171 - releasing pathways that have been suggested over the past several years . In RT - PCR analysis using both control and osmotically swollen astrocytes , amplification of cDNA fragments of expected size was seen for connexins ( P08034 , P35212 , P17302 ) , pannexin 1 ( Px1 ) , the Q99572 receptor , MRP1 and P08183 , but not P13569 . Inhibitors of exocytotic vesicular release , gap junction hemi - channels , P13569 , MRP1 , P08183 , the Q99572 receptor , and volume - sensitive outwardly rectifying chloride channels had no significant effects on the massive DB00171 release from astrocytes . In contrast , the hypotonicity - induced DB00171 release from astrocytes was most effectively inhibited by gadolinium ( 50 muM ) , an inhibitor of the maxi - anion channel , which has recently been shown to serve as a pathway for DB00171 release from several other cell types . Thus , we propose that the maxi - anion channel constitutes a major pathway for swelling - induced DB00171 release from cultured mouse astrocytes as well .", "[ Anti - cholesterol agents , new therapeutic approaches ] . Statins and fibrates constitute the two major families of lipid - lowering agents . Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia . Both drugs are also used for the treatment of mixed dyslipidemia . Some fibrates efficiently lower serum LDL - cholesterol . Statins inhibit P04035 and decrease cellular cholesterol synthesis . The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the P01130 gene . This over expression of the P01130 in the liver increases the clearance of circulating LDL thus decreasing the LDL - cholesterol plasma levels . The effects of fibrates on lipid metabolism are entirely due to their capacity to activate Q07869 and to induce the over expression of genes containing a PPRE in their promoter . Fibrates decrease triglyceride concentrations by increasing the beta - oxidation of fatty acids in the liver and by decreasing triglyceride - VLDL synthesis . Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C - III transcription , respectively . Fibrates could decrease triglycerides partly by inducing apo A - V over - expression . These molecules increase HDL - cholesterol by increasing apo A - I and apo A - II transcription . Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism .", "Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator - activated receptor / retinoid X receptor heterodimers in the absence and presence of ligand . In a global approach combining fluorescence recovery after photobleaching ( P42345 ) , fluorescence correlation spectroscopy ( FCS ) , and fluorescence resonance energy transfer ( FRET ) , we address the behavior in living cells of the peroxisome proliferator - activated receptors ( PPARs ) , a family of nuclear receptors involved in lipid and glucose metabolism , inflammation control , and wound healing . We first demonstrate that unlike several other nuclear receptors , PPARs do not form speckles upon ligand activation . The subnuclear structures that may be observed under some experimental conditions result from overexpression of the protein and our immunolabeling experiments suggest that these structures are subjected to degradation by the proteasome . Interestingly and in contrast to a general assumption , PPARs readily heterodimerize with retinoid X receptor ( RXR ) in the absence of ligand in living cells . Q07869 diffusion coefficients indicate that all the receptors are engaged in complexes of very high molecular masses and / or interact with relatively immobile nuclear components . PPARs are not immobilized by ligand binding . However , they exhibit a ligand - induced reduction of mobility , probably due to enhanced interactions with cofactors and / or chromatin . Our study draws attention to the limitations and pitfalls of fluorescent chimera imaging and demonstrates the usefulness of the combination of FCS , P42345 , and FRET to assess the behavior of nuclear receptors and their mode of action in living cells .", "Readjusting the localization of long QT syndrome gene on chromosome 11p15 . Long QT syndrome ( LQT ) is an autosomal dominant cardiac disease characterized by ventricular arrhythmia . A first locus for LQT has been identified on chromosome 11p15 . 5 ( LQT1 ) , closely linked to P01112 . To refine the location of LQT1 , microsatellites were genotyped in 8 French families and the following order was determined : tel - P01112 - P21917 - D11S922 - D11S4046 - P01344 - P01308 - TH - D11S1318 - D11S1323 - D11S1338 - D11S90 9 - D11S1346 - cen . By haplotype analysis , 12 crossing - over events were identified in affected and unaffected subjects , delineating the LQT1 candidate region to 7 cM . This new delineated localization between D11S1318 and D11S1323 is in a more centromeric region than previously thought and is 5 cM proximal to P01112 .", "Current treatment strategies for non - alcoholic fatty liver disease ( NAFLD ) . Nonalcoholic fatty liver disease ( NAFLD ) is recognized as the most common cause of chronic liver disease worldwide . NAFLD is a clinicopathologic syndrome ranging from simple steatosis , which is relatively benign , to the more severe form known as nonalcoholic steatohepatitis ( NASH ) , which may progress to cirrhosis , liver failure , and hepatocellular carcinoma . NAFLD is associated with significant liver related morbidity and mortality , and its underlying pathophysiology is thought to result from a multiple hit process . The initial insult is the accumulation of hepatic fat secondary to insulin resistance . In the setting of hepatic steatosis , the second hit can be caused by reactive oxygen species , inflammatory cytokines , and adipokines . Several therapeutic modalities that target these mechanisms are under investigation , but no proven treatment has yet emerged . P01308 sensitizers such as thiazolidinediones and metformin show promise , and several studies have explored the role of lipid lowering agents , antioxidants , and cytoprotective agents . Novel agents such as anti - obesity drugs , selective cannabinoid - 1 receptor blockers , and dual Q07869 alpha and gamma agonists are also under investigation . Unfortunately , data on the long - term safety and efficacy of these agents and their impact on liver related histologic outcomes are currently lacking . NAFLD treatment currently focuses on reducing metabolic risk factors , with the mainstay of therapy focusing on life - style modifications such as gradual weight loss through diet and regular exercise .", "Isothiocyanate iberin modulates phase II enzymes , posttranslational modification of histones and inhibits growth of Caco - 2 cells by inducing apoptosis . The aim of presented study was to further investigate the concentration - dependent changes induced by isothiocyanate iberin ( IBN ) in human colon carcinoma Caco - 2 cells . The concentrations of IBN below IC ( 50 ) value ( 18 microM , 72 h ) triggered the augmentation of mRNA levels for phase II detoxification P08263 and P22309 enzymes and antioxidant thioredoxin reductase 1 gene in cells treated for 24 h . In addition a significant increase of acetylated H4 histone was detected . The mRNA induction peaked at IC ( 50 ) value and returned to level of control cells at 40 microM concentration of IBN . The cell cycle changes , gamma - P16104 stainability and the increase of phospho - H3 mitotic marker were induced at concentrations above IC ( 50 ) value . Appearance of P08758 positive apoptotic cells and sub - P55008 fragmented DNA as well as decrease of mitochondrial transmembrane potential confirmed cytotoxic effect of IBN observed in MTT assay . The predominance of necrotic cells and profound positivity of gamma - P16104 took place at the highest concentration of IBN . Thus , IBN represents the effective member of natural chemopreventive isothiocyanate family with which apoptotic potential can by employed to eliminate tumor cells .", "Neuronal involvement in muscular atrophy . The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation . Consequently , denervated myofibers manifest atrophy , which is preceded by an increase in sarcolemma permeability . Recently , de novo expression of hemichannels ( HCs ) formed by connexins ( Cxs ) and other none selective channels , including Q99572 receptors ( P2X7Rs ) , and transient receptor potential , sub - family V , member 2 ( Q9Y5S1 ) channels was demonstrated in denervated fast skeletal muscles . The denervation - induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45 . Nonetheless , the transduction mechanism by which the nerve represses the expression of the above mentioned non - selective channels remains unknown . The paracrine action of extracellular signaling molecules including DB00171 , neurotrophic factors ( i . e . , brain - derived neurotrophic factor ( P23560 ) ) , agrin / P01130 - related protein 4 ( Lrp4 ) / muscle - specific receptor kinase ( O15146 ) and acetylcholine ( Ach ) are among the possible signals for repression for connexin expression . This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression ." ]

[ "___MASK58___", "___MASK63___", "___MASK68___", "___MASK73___", "___MASK77___", "___MASK79___", "___MASK96___", "___MASK98___", "___MASK9___" ]

[ "Higher levels of activation markers and chemokine receptors on T lymphocytes in the cervix than peripheral blood of normal healthy women . Heterosexual transmission of human immunodeficiency virus ( HIV - 1 ) is the predominant mode of infection world - wide . To better understand sexual transmission of HIV - 1 in women we have analysed virus co - receptor and cellular activation marker expression on T lymphocyte subsets from the cervical epithelium and have made comparisons with peripheral blood T cells . Intraepithelial cervical T lymphocytes were obtained with a cytobrush , immunolabelled and analysed by flow cytometry . Activation markers ( Q07108 , CD25 and HLA - DR ) were found to be more highly expressed on cervical than on blood T lymphocytes . These higher levels of activation on cervical T lymphocyte subsets could facilitate HIV - 1 infection . P61073 was expressed at marginally higher levels than P51681 on T cells from the cervical epithelium and peripheral blood . Thus , the preferential transmission of macrophage tropic strains of HIV - 1 following sexual contact can not be explained solely on the expression of chemokine co - receptors by T lymphocyte subsets .", "The serotonin Q13639 receptor and the amyloid precursor protein processing . A large body of evidence supports a major role for the serotonin 5 - HT ( 4 ) receptor in learning and memory and it is suggested that 5 - HT ( 4 ) agonists may be beneficial for memory disorders such as Alzheimer ' s disease ( AD ) . The 5 - HT ( 4 ) receptors are members of the G protein - coupled receptor superfamily and are positively coupled to adenylyl cyclase . In this communication we show that a neuronal isoform of the human 5 - HT ( 4 ) receptor , h5 - HT ( 4 ( g )) regulates the metabolism of the amyloid precursor protein ( APP695 ) . This process is observed in Chinese hamster ovary ( CHO ) cells stably coexpressing the neuronal h5 - HT ( 4 ( g )) receptor isoform as well as the human APP695 . The 5 - HT ( 4 ) agonists strongly stimulate the release of the non - amyloidogenic soluble amyloid precursor protein sAPPalpha as detected by immunoblot . DB06480 was more potent than serotonin ( 5 - HT ) with regard to enhanced of sAPPalpha secretion . This process was blocked by a selective 5 - HT ( 4 ) antagonist , GR113808 . Furthermore , 5 - HT ( 4 ) ligands enhance sAPPalpha secretion via DB02527 - dependent and PKA - independent signalling pathways indicating there are alternative pathways by which the h5 - HT ( 4 ) receptor via DB02527 regulates P05067 metabolism . Because the alpha - cleavage event may preclude the formation of amyloidogenic peptides , and secreted sAPPalpha has putative neuroprotective and enhancing - memory properties , our present data suggest the 5 - HT ( 4 ) receptor as a novel target for the treatment of AD .", "A whole genome Bayesian scan for adaptive genetic divergence in West African cattle . BACKGROUND : The recent settlement of cattle in West Africa after several waves of migration from remote centres of domestication has imposed dramatic changes in their environmental conditions , in particular through exposure to new pathogens . West African cattle populations thus represent an appealing model to unravel the genome response to adaptation to tropical conditions . The purpose of this study was to identify footprints of adaptive selection at the whole genome level in a newly collected data set comprising 36 , 320 SNPs genotyped in 9 West African cattle populations . RESULTS : After a detailed analysis of population structure , we performed a scan for SNP differentiation via a previously proposed Bayesian procedure including extensions to improve the detection of loci under selection . Based on these results we identified 53 genomic regions and 42 strong candidate genes . Their physiological functions were mainly related to immune response ( MHC region which was found under strong balancing selection , P11912 , P61073 , P80370 , P48380 , Q9H3S1 , Q8IUC6 and P19474 ) , nervous system ( Q96NK8 , O95897 , MAGI1 , Q9H3S1 and Q13639 ) and skin and hair properties ( P24530 , TRSP1 and Q8IUC2 ) . CONCLUSION : The main possible underlying selective pressures may be related to climatic conditions but also to the host response to pathogens such as Trypanosoma ( sp ) . Overall , these results might open the way towards the identification of important variants involved in adaptation to tropical conditions and in particular to resistance to tropical infectious diseases .", "[ Bone metastasis in prostate cancer ] . Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients . In addition to established bone - targeted therapies , new drugs such as endothelin A receptor antagonists , MET and P35968 antagonists or radiopharmaceuticals are in the focus of development . The standard care in prostate cancer patients with bone metastases to prevent skeletal - related events ( SRE ) are bisphosphonates . ___MASK22___ , a human monoclonal antibody against O14788 , appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases - free survival . In contrast to zoledronic acid , denosumab clearance is not dependent on kidney function and can be administered subcutaneously . Similar rates of toxicity were observed for both substances ; however , long - term data for denosumab are limited .", "Antidepressant properties of the Q13639 receptor partial agonist , SL65 . 0155 : behavioral and neurochemical studies in rats . This study was undertaken to investigate the potential antidepressant - like properties of SL65 . 0155 , a serotonin 5 - HT ( 4 ) receptor partial agonist , in male rats of the Wistar strain tested in the forced swim test ( P19883 ) , an experimental model widely used to assess antidepressant - like activity . The expression of hippocampal neurotrophic factors , such as the brain - derived neurotrophic factor ( P23560 ) , the phosphorilated DB02527 response element - binding protein ( p - CREB ) , the B cell lymphoma - 2 ( Bcl - 2 ) , the Bax and the vascular endothelium growth factor ( P15692 ) were also evaluated by Western Blot analysis . Different groups of rats received intraperitoneally ( i . p . ) injections of SL65 . 0155 ( 0 . 1 , 0 . 5 and 1 mg / kg ) , clomipramine ( 50 mg / kg ) , citalopram ( 15 mg / kg ) or vehicle , respectively , 24 , 5 and 1 h prior to the P19883 . Compared to the control group , SL65 . 0155 ( 0 . 5 and 1 mg / kg ) , clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the P19883 . Interestingly , this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test . Western blot analysis of hippocampal homogenates showed an enhancement of p - CREB , P23560 Bcl - 2 and P15692 protein levels in SL65 . 0155 treated groups , but not in citalopram or clomipramine treated groups , used here as positive control . No change was found in Bax expression in any treated group . These findings give further support to the hypothesis that the stimulation of serotonin 5 - HT ( 4 ) receptors may be a therapeutic target for depression .", "Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK2___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK2___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .", "DB06480 for chronic constipation . Chronic constipation is a frequently reported medical disorder that reduces patients ' quality of life and imposes a significant economic burden on the health care system . Symptoms of constipation are diverse and include infrequent bowel movements , hard stool , straining at stool , sensations of anorectal obstruction and feelings of incomplete evacuation . Patients with chronic constipation can be categorized into one of three main groups based on their underlying pathophysiology : normal transit constipation ; colonic inertia ; and pelvic floor dyssynergia . Specialized tests ( i . e . , anorectal manometry , radio - opaque marker study ) may be required in some patients to help distinguish the different subtypes of constipation and to guide appropriate therapy . Although the underlying mechanism of constipation differs among patients , serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) appears to have an important role in colonic motility in some patients . Previous research has demonstrated that stimulation of Q13639 receptors improves symptoms of chronic constipation in some patients . DB06480 , a selective Q13639 agonist , relieved symptoms of constipation in phase II and phase III clinical trials . In this monograph , we review the pharmacology , mechanism of action , efficacy and safety of the selective Q13639 agonist prucalopride in patients with chronic constipation .", "Characterization of a novel Q13639 receptor antagonist of the azabicycloalkyl benzimidazolone class : DAU 6285 . Three chemical classes of serotonin Q13639 receptor agonists have been identified so far : 5 - substituted indoles ( e . g . 5 - HT ) , benzamides ( e . g . renzapride ) and benzimidazolones ( e . g . BIMU 8 ) . In a search for Q13639 receptor antagonists , we have discovered that the benzimidazolone derivative DAU 6285 ( for structure see text ) , is 3 - 5 times more potent than tropisetron in blocking 5 - HT , renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons . Schild plot analysis yielded Ki values of 220 , 181 and 255 nmol / l , respectively . In addition , DAU 6285 showed poor activity as a 5 - Q9H205 receptor ligand with respect to tropisetron , as demonstrated by in vitro binding studies ( Ki , 322 vs 2 . 8 nmol / l ) and by its antagonistic activity in the Bezold - Jarisch reflex test ( ID50 , 231 vs 0 . 5 micrograms / kg , i . v . ) . No significant binding ( Ki greater than 10 mumol / l ) of DAU 6285 to serotonergic P08908 , P28222 , P28335 , P28221 , and 5 - HT2 receptors as well as to adrenergic alpha 1 , alpha 2 , dopaminergic D1 , D2 or muscarinic M1 - M3 receptor subtypes was found . The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for Q13639 receptors , a property confirmed in functional tests , and much lower affinity than tropisetron for 5 - Q9H205 receptors . The compound represents a new interesting tool for investigating the pharmacological and physiological properties of Q13639 receptors .", "___MASK22___ for joints and bones . ___MASK22___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK22___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK22___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .", "Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK79___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .", "A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK25___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .", "Comparison of three GPCR structural templates for modeling of the Q9H244 nucleotide receptor . The P2Y ( 12 ) receptor ( P2Y ( 12 ) R ) is an ADP - activated G protein - coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y ( 12 ) R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A ( 2A ) adenosine receptor ( A ( 2A ) AR ) , and human P61073 ( P61073 ) . By criteria of sequence analysis ( 25 . 6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly - binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N - terminus , the P61073 - based model appeared to be the most consistent with known characteristics of P2Y ( 12 ) R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB - 0739 in the binding pocket of P2Y ( 12 ) R - CXC agree with previously published site - directed mutagenesis studies of Arg256 and Lys280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174 ( EL2 ) side chain . The docking poses of the irreversibly - binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist ___MASK29___ were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~ 4 . 7 Å ) to the sulfur atom of a disulfide bridge involving Cys175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 - based model of the P2Y ( 12 ) R predicted poses of both reversibly and irreversibly - binding small molecules , consistent with observed pharmacology and mutagenesis studies .", "Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK38___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .", "P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK92___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK92___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .", "5 - hydroxytryptamine and its receptors in systemic vascular walls . 5 - hydroxytryptamine ( 5 - HT ) in the bloodstream is largely contained in platelets and circulates throughout the entire vascular system . 5 - HT released from activated platelets dramatically changes the function of vascular smooth muscle cells ( VSMCs ) and endothelial cells ( ECs ) . In VSMCs , 5 - HT induces proliferation and migration via 5 - Q13049 receptors . These effects are further enhanced by vasoactive substances such as thromboxane A2 and angiotensin II . 5 - Q13049 receptor activation in VSMCs also causes both enhancement of prostaglandin I2 production by inducing cyclooxygenase - 2 and reduction of nitric oxide ( NO ) by suppressing inducible NO synthase . Evidence showing that 5 - HT in ECs plays a principal role in angiogenesis now exists . Stimulation of 5 - HT1 and / or 5 - HT2 receptors has been implicated in the angiogenic effect of 5 - HT . The extracellular signal - regulated kinase and endothelial NO synthase ( P29474 ) activation - dependent pathways are involved in the mechanisms . Moreover , Q13639 receptors in ECs have been shown to also regulate angiogenesis . Recent reports show sarpogrelate , a selective antagonist of the 5 - Q13049 receptor , indirectly enhances the function of P28222 receptors in ECs via inhibition of 5 - Q13049 receptors in VSMCs or platelets . This indirect action of P28222 receptors in ECs may increase NO production derived from P29474 and a vasodilator response . Furthermore , sarpogrelate and other 5 - Q13049 receptor antagonists have been shown to reduce the constitutive activity of 5 - Q13049 receptors . It is believed that increasing evidence on the role of 5 - HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate , and to the development of new 5 - HT receptor - related drugs for treating cardiovascular diseases .", "Effects of the enterokinetic prucalopride ( R093877 ) on colonic motility in fasted dogs . The novel enterokinetic drug prucalopride was tested at various intravenous and oral doses in fasted dogs to assess : ( i ) the effects on colonic contractile motility patterns ; and ( ii ) the mediation of these effects by 5 - hydroxytryptamine ( Q13639 ) receptors . Colonic motility patterns were assessed in conscious dogs with four chronically implanted strain - gauge force transducers that were sutured on the serosal side of the colon . DB06480 altered colonic contractile motility patterns in a dose - dependent fashion by stimulating high - amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon . DB06480 was equipotent after oral and intravenous administration , as reflected by the values for the effective dose that induced 50 % of maximum effect ( 95 % confidence limits ) : 0 . 04 mg kg (- 1 ) p . o . ( 0 . 01 - 0 . 1 mg kg (- 1 ) ) and 0 . 01 mg kg (- 1 ) i . v . ( 0 . 006 - 0 . 04 mg kg (- 1 ) ) . DB06480 also caused a dose - dependent decrease in the time to the first giant migrating contraction ( GMC ) ; at higher doses of prucalopride , the first GMC generally occurred within the first half - hour after treatment . Subcutaneous pretreatment with the Q13639 receptor antagonist GR125487 ( 40 microg kg (- 1 ) bodyweight ) completely prevented the effects of orally administered prucalopride ( 0 . 31 mg kg (- 1 ) bodyweight ) . DB06480 , given orally or intravenously , alters colonic motility in the fasted conscious dog in a dose - dependent fashion . It induces GMCs and causes proximal colon stimulation and distal colon inhibition of contractile motility patterns by stimulating Q13639 receptors .", "Role of prucalopride , a serotonin ( 5 - HT ( 4 ) ) receptor agonist , for the treatment of chronic constipation . Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden . Many patients with chronic constipation are dissatisfied with current therapy due to lack of long - term efficacy or side effects . Previous nonselective Q13639 ( 5 - HT ( 4 ) ) agonists have been associated with significant interactions with other receptors ( 5 - HT ( 1B ) , 5 - HT ( 1D ) , and 5 - HT ( 2B ) for tegaserod ; hERG for cisapride ) , leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market . DB06480 is a novel gastrointestinal prokinetic agent . It acts as a high affinity , highly - selective 5 - HT ( 4 ) agonist . Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit , bowel function , gastrointestinal symptoms , and quality of life , with benefit maintained for up to 24 months in open label , multicenter , follow - up studies . DB06480 ' s high selectivity for the 5 - HT ( 4 ) receptor may explain its favorable safety and tolerability profiles , even in elderly subjects with stable cardiovascular disease . DB06480 is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first - line treatments .", "Q13639 receptor agonists increase sAPPalpha levels in the cortex and hippocampus of male C57BL / 6j mice . BACKGROUND AND PURPOSE : A strategy to treat Alzheimer ' s disease ( AD ) is to increase the soluble form of amyloid precursor protein ( sAPPalpha ) , a promnesic protein , in the brain . Because strong evidence supports beneficial effects of 5 - hydroxytryptamine 5 - HT ( 4 ) receptor agonists in memory and learning , we investigated the role of 5 - HT ( 4 ) receptors on P05067 processing in 8 weeks - old male C57BL / 6j mice . EXPERIMENTAL APPROACH : Mice were given , subcutaneously , prucalopride or ML 10302 ( s . c . ) , two highly selective 5 - HT ( 4 ) receptor agonists and , up to 240 min later , the hippocampus and cortex were analysed by Western blot for sAPPalpha determination . KEY RESULTS : DB06480 ( 5 or 10 mg kg (- 1 ) ) significantly increased sAPPalpha levels in the hippocampus and cortex , but did not modify the expression level of P05067 mRNA as detected by quantitative RT - PCR . A selective 5 - HT ( 4 ) receptor antagonist , GR125487 ( 1 mg kg (- 1 ) , s . c . ) inhibited prucalopride induced - increase in sAPPalpha levels . In addition , levels of sAPPalpha were increased by ML10302 only at 20 mg kg (- 1 ) and was limited to the cortex . Also , prucalopride increased sAPPalpha levels in the cortex of a transgenic mouse model of AD , expressing the London mutation of P05067 . Furthermore , the combined injection of a selective acetylcholinesterase inhibitor , donepezil and prucalopride induced a synergic increase in sAPPalpha levels in the cortex and hippocampus . CONCLUSIONS AND IMPLICATIONS : Our results demonstrate that the 5 - HT ( 4 ) receptor plays a key role in the non - amyloidogenic pathway of P05067 metabolism in vivo and give support to the beneficial use of 5 - HT ( 4 ) agonists for AD treatment .", "Emerging pharmacologic therapies for irritable bowel syndrome . New therapies are being developed for irritable bowel syndrome ( IBS ) . These advances are based on understanding pathophysiology or the development of medications with greater selectivity in classes of agents with known efficacy . DB06480 , the newest European Medicines Agency - approved Q13639 ( 5 - HT ( 4 ) ) agonist , is effective in the treatment of chronic constipation with improved cardiovascular safety relative to older 5 - HT ( 4 ) drugs ; similarly , ramosetron , the P46098 ( 5 - HT ( 3 ) ) antagonist , appears efficacious in diarrhea - predominant IBS . Secretagogues with different mechanisms of action target apical domains in enterocytes that are involved in chloride secretion , such as chloride channels , the cystic fibrosis transmembrane regulator , and guanylate cyclase C . As a class , such secretagogues have high efficacy and safety for constipation . With more data obtained from phase 2 and 3 trials , we expect other classes of medications , including bile acid modulators , anti - inflammatory agents , visceral analgesics , and newer centrally acting agents to be efficacious and enter the armamentarium for the treatment of IBS in the future .", "DB06480 : safety , efficacy and potential applications . Chronic constipation is a very common functional gastrointestinal disorder which can be associated with significant impairments in quality of life for some people with the condition . Its management has , traditionally , been based on dietary and lifestyle changes and the use of a variety of laxative agents . The evidence base for the efficacy of the latter is , in many cases , slim . Not surprisingly , many patients remain dissatisfied with laxatives thus leading to the development of more pharmacological approaches . Among these approaches is the use of prokinetic agents ; while prior molecules have been troubled by lack of selectivity and cardiac side effects , the new agent , prucalopride , appears to be highly selective for the serotonin Q13639 receptor and is , therefore , a potent stimulator of gut motility . In three large pivotal randomized controlled trials , prucalopride has been effective in relieving the cardinal symptoms of chronic constipation ; these effects have been sustained in open - label follow up for as long as 18 months . The safety profile has been encouraging and , especially so , the absence of arrhythmogenic potential . Studies in men , in constipation - predominant irritable bowel syndrome and in other motor disorders are eagerly awaited .", "Q13639 receptors located on cholinergic nerves in human colon circular muscle . 5 - Hydroxytryptamine 4 ( Q13639 ) receptor agonists promote colonic propulsion . The alteration of circular muscle ( CM ) motility underlying this involves inhibition of contractility via smooth muscle Q13639 receptors and proximal colonic motility stimulation , the mechanism of the latter not having been characterized . Our aim was to identify and characterize a Q13639 receptor - mediated stimulation of human colon CM contractile activity . Q13639 receptor ligands were tested on electrical field stimulation ( O43281 ) - induced contractions of human colonic muscle strips cut in the circular direction ( called ' whole tissue ' strips ) . Additionally , after incubation of tissues with [ 3H ] - choline these compounds were tested on O43281 - induced release of tritium in whole tissue strips and in ' isolated ' CM strips , obtained by superficial cutting in the CM layer . DB05232 and atropine blocked O43281 - induced contractions of whole tissue CM strips . DB06480 ( 0 . 3 micromol L - 1 ) evoked a heterogenous response on O43281 - induced contraction , ranging from inhibition ( most frequently observed ) to enhancement . In the release experiments , O43281 - induced tritium efflux was blocked by tetrodotoxin . DB06480 increased O43281 - induced tritium and [ 3H ] - acetylcholine efflux in whole tissue and in isolated CM strips . All effects of prucalopride were antagonized by the selective Q13639 receptor antagonist GR113808 . The results obtained indicate the presence of excitatory Q13639 receptors on cholinergic nerves within the CM of human colon .", "Strain dependence of receptor regulation on chemical preconditioning in mice hippocampus . While one current focus for studying mechanisms of disease is investigation of transgenic mice confounding effects of the background strain often are neglected . We investigated mRNA expression of known markers of hypoxic tolerance by a semiquantitative RT - PCR ( adenosine receptors ( A1 and A3 ) , nitric oxide synthases ( P29474 and P29475 ) , P05067 production , progesterone receptor , and estrogen receptors alpha and beta ) in CD - 1 , C3H , and B6 mice . We found differences in the baseline mRNA expression of adenosine A3 receptors in C3H mice and neuronal NOS in B6 mice as well as a distinct regulation of adenosine A3 receptors and estrogen receptor beta ( no changes in C3H and B6 compared to upregulation in CD - 1 ) on treatment of animals with a low dosage of 3 - nitropropionate ( 20mg / kg body weight , i . p . ) . We conclude that the choice of background strain may confound interpretation of the effects of specific transgens in the study of the mechanisms of primary and induced hypoxic tolerance .", "[ Some practical questions on chronic stipsis treatment with prucalopride ] . Chronic constipation is a frequent pathological condition bearing relevant socioeconomic burdens , mainly due to uncertain management and unsatisfactory response to traditional laxatives . DB06480 is a novel enterokinetic drug , that has been demonstrated to improve bowel functions and relieve a broad spectrum of digestive symptoms in patients with severe chronic constipation who had failed to respond to various traditional laxatives . In this paper we discussed the practical aspects of chronic constipation treatment , in particular focusing on some questions about the practical use of prucalopride . DB06480 is a potent , selective , high - affinity agonist of the Q13639 receptors widely expressed in the gastrointestinal tract . Unlike other Q13639 agonists , such as cisapride and tegaserod , it is devoid of adverse cardiovascular effects . Furthermore , it is characterized by a low potential for interactions with other drugs , due to its pharmacokinetic characteristics . DB06480 was approved , in 2009 , by the European Medicines Agency for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief , however , there are ongoing studies to extend the use of the drug even to males .", "5 - HT₄ receptor stimulation leads to soluble AβPPα production through P14780 upregulation . Serotonin 4 ( Q13639 ) receptor signaling does not only have the physiological function of improving cognition , but might also be helpful in the therapy of Alzheimer ' s disease ( AD ) through regulation of the production of soluble amyloid - β protein precursor alpha ( sAβPPα ) . To analyze the relationship between Q13639 receptor signaling and sAβPPα production , we stably transfected H4 cells with AβPP and Q13639 receptor ( H4 / AβPP / Q13639 cells ) . We found that 24 - h incubation with the Q13639 receptor agonist RS - 67333 upregulates matrix metalloproteinase - 9 ( P14780 ) . Furthermore , P14780 overexpression enhanced sAβPPα levels , whereas knockdown with P14780 siRNA decreased sAβPPα levels . When RS - 67333 was injected for 10 days in Tg2576 mice , a model of amyloid - β peptide ( Aβ ) deposition , there was an increase in hippocampal levels of sAβPPα , C - terminal fragment α , and P14780 , as well as a decrease in hippocampal senile plaque number and levels of the 40 amino acid peptide , Aβ40 . Taken all together , these experiments demonstrate that Q13639 receptor stimulation induces expression of P14780 which cleaves AβPP through α - secretase - like activity , leading to an increase of sAβPPα levels and a reduction of Aβ load .", "Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .", "Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models . The neuroinflammatory process is thought to contribute to the progression of neurological disorders and brain pathologies . The release of pro - inflammatory cytokines and chemokines by activated glial cells , astrocytes and microglia plays an important role in this process . However , the role of hypoxia - inducible factor - 1α ( HIF - 1α ) , the key transcription factor regulating the expression of hypoxia - inducible genes , during glial activation is less known . Thus , we examined the significance of HIF - 1α in three experimental models : first in an acute model of inflammation induced by pro - inflammatory cytokines P01375 - α , IL - 1β and IFN - γ ; secondly , in a chronic model of inflammation using an APPswe / PS1dE9 ( P05067 / P49768 ) transgenic mouse model of Alzheimer ' s disease and thirdly via the inhibition of the PI3K / AKT pathway in a model of neuronal apoptosis . During acute glial inflammation induced by in vitro administration of P01375 - α , IL - 1β and IFN - γ , mRNA expression levels of HIF - 1α were significantly upregulated ; however , this effect was blocked by SP600126 , a pharmacological inhibitor of mitogen - activated protein kinases ( MAPKs ) . These data suggest that MAPKs could be involved in HIF - 1α regulation . In addition , we observed that HIF - 1α is not involved in the neuronal apoptotic process mediated by P19957 - kinase inhibition , which is regulated by c - Jun . Finally , we did not detect significant differences in the expression of HIF - 1α mRNA in P05067 / P49768 mice during the course of the study ( 3 - 12 months of age ) . Thus , we demonstrated that HIF - 1α has a prominent role in acute but not in chronic inflammatory processes , such as the one which occurs in the P05067 / P49768 experimental model of AD . Moreover , HIF - 1α is not involved in neuronal apoptosis after PI3K / AKT inhibition .", "DB06480 : a review of its use in the management of chronic constipation . The highly selective serotonin Q13639 receptor agonist prucalopride ( Resolor (®) , Resotran (®) , Resotrans (®) ) is indicated for the treatment of chronic constipation . In four randomized , double - blind , multicentre , 12 - week trials in patients ( predominantly women ) with chronic constipation , oral prucalopride 2 mg once daily improved bowel function to a significantly greater extent than placebo , with a significantly greater proportion of prucalopride than placebo recipients achieving an average of ≥ 3 spontaneous , complete bowel movements per week ( primary endpoint ) . Significantly greater improvements in health - related quality of life , patient satisfaction with treatment and bowel habit , and a range of constipation - related symptoms were also seen with prucalopride than with placebo . Satisfaction with treatment and bowel habit was maintained with prucalopride in the longer term . DB06480 was generally well tolerated in patients with chronic constipation , with the most commonly reported adverse events ( headache , nausea , abdominal pain , diarrhoea ) primarily occurring on the first day of treatment . During the clinical trials , no cardiovascular safety issues have arisen in patients with chronic constipation receiving prucalopride . In conclusion , prucalopride is an important option for use in patients with chronic constipation who have not experienced adequate relief with laxatives .", "Augmentation of antigen receptor - mediated responses by histamine H1 receptor signaling . DB11320 is considered one of the important mediators of immediate hypersensitivity and inflammation , and acts via G protein - coupled receptors . Here , we report that histamine may affect antigen receptor - mediated immune responses of T and B cells via a signal ( s ) from histamine H1 receptors ( H1Rs ) . DB11320 exhibited enhancing effects on the in vitro proliferative responses of anti - CD3epsilon - or anti - IgM - stimulated spleen T and B cells , respectively , at the culture condition that the fetal calf serum was dialyzed before culture and c - kit - positive cells were depleted from the spleen cells . In studies of histamine P35367 knockout mice , P35367 - deficient T cells had low proliferative responses to anti - CD3epsilon cross - linking or antigen stimulation in vitro . B cells from P35367 - deficient mice were also affected , demonstrating low proliferative responses to B cell receptor cross - linking . Antibody production against trinitrophenyl - Ficoll was reduced in P35367 - deficient mice . Other aspects of T and B cell function were normal in the P35367 knockout mice . P35367 - deficient T and B cells showed normal responses upon stimulation with interleukin ( IL ) - 2 , P05112 , P29965 , P29965 plus P05112 , and lipopolysaccharide . Collectively , these results imply that the signal generated by histamine through P35367 augments antigen receptor - mediated immune responses , suggesting cross - talk between G protein - coupled receptors and antigen receptor - mediated signaling .", "Experimental Staphylococcus aureus infection of the mammary gland induces region - specific changes in innate immune gene expression . Staphylococcus aureus is a prolific mastitis - causing bacterium that resides naturally in the environment of the dairy cow . The aim of this study was to profile immune gene expression in tissue from the alveolar , ductal , gland cistern and teat canal regions of the bovine mammary gland following intramammary infection with S . aureus . Quantitative real - time PCR ( qPCR ) was used to profile expression of innate immune genes including pattern recognition receptors ( PRRs ) , cytokines , antimicrobial peptides ( AMPs ) and acute phase proteins ( APPs ) . Consistent expression of Toll - like receptors ( TLRs ) 1 - 10 and NOD - like receptors ( NODs ) 1 - 2 was detected in all four tissue regions . Pro - inflammatory cytokines ( P05231 , Q16552 and P10145 ) and anti - inflammatory cytokine ( P22301 ) were induced in all 4 tissues . P05067 ( SAA3 and HP ) and AMP ( DEFB4 and Q8NG35 ) genes showed the greatest induction throughout the mammary gland in response to S . aureus , with particularly high expression in alveolar tissue ( SAA3 and HP > 133 - and > 80 - fold respectively , P < 0 . 05 ; DEFB4 and Q8NG35 > 9 - and > 27 - fold respectively , P < 0 . 05 ) . Collectively , our data show both sentinel and effector immune functions throughout the mammary gland in response to S . aureus challenge .", "Q9NQ38 and P07550 haplotypes are risk factors for asthma in Mexican pediatric patients . BACKGROUND : Asthma is one of the most common respiratory diseases worldwide , and the complexity of its etiology has been widely documented . Chromosome 5q31 - 33 is one of the main loci implicated in asthma and asthma - related traits . P35225 , P08571 and P07550 , which are located in this risk locus , are among the genes most strongly associated with asthma susceptibility . OBJECTIVES : This study evaluated whether single - nucleotide polymorphisms or haplotypes at 5q31 - 33 conferred risk for asthma in Mexican - Mestizo pediatric patients . METHODS : We performed a case - controlled study including 851 individuals , 421 of them affected with childhood - onset asthma and 430 ethnically matched unaffected subjects . We used the TaqMan Allelic Discrimination Assay to genotype 20 single - nucleotide polymorphisms within P05113 , Q92878 , P35225 , P05112 , P08571 , Q9NQ38 , Q13639 , P07550 and P29460 . RESULTS : Although no association was detected for any risk allele , three Q9NQ38 haplotypes ( O75223 : p = 6 × 10 (- 6 ) ; AATC : p = 0 . 0001 ; AGTT : p = 0 . 0001 ) and five P07550 haplotypes ( AGGACC : p = 0 . 0014 ; AGGAAG : p = 0 . 0002 ; TGAGAG : p = 0 . 0001 ; AGGAAC : p = 0 . 0002 ; AAGGAG : p = 0 . 003 ) were associated with asthma . Notably , the AGTT Q9NQ38 haplotype exhibited a male gender - dependent association ( p = 7 . 6 × 10 (- 5 ) ) . CONCLUSION : Our results suggest that Q9NQ38 and P07550 haplotypes might play a role in the susceptibility to childhood - onset asthma .", "P15692 - induced angiogenesis ameliorates the memory impairment in P05067 transgenic mouse model of Alzheimer ' s disease . Vascular endothelial growth factor ( P15692 ) was investigated in the present study to see whether it could provide a therapeutic opportunity for the treatment of Alzheimer ' s disease ( AD ) . PDGF - hAPP ( V717I ) transgenic mice were treated with P15692 or PBS by intraperitoneal injection for three consecutive days . The results showed that P15692 ameliorated the memory impairment of mice , accompanied by P28906 (+) cells increasing in peripheral blood , P04275 (+) vessels increasing in hippocampus , and P28906 (+)/ P35968 (+) , P04275 (+)/ P35968 (+) and BrdU (+)/ P04275 (+) cells expressing in hippocampus . Furthermore , the level of choline acetyltransferase ( P28329 ) was considerably enhanced and Aβ deposition was decreased in the brains of mice upon P15692 treatment . These observations suggest that P15692 should be pursued as a novel therapeutic agent for treatment of AD .", "P35968 - 5169 , a new gastrointestinal prokinetic agent , enhances gastric contractile and emptying activities in dogs and rats . P35968 - 5169 , 4 - amino - 5 - chloro - N -[ 1 -( 3 - fluoro - 4 - methoxybenzyl ) piperidin - 4 - yl ]- 2 -( 2 - hydroxyethoxy ) benzamide hydrochloride dihydrate , is a new prokinetic with a dual action , i . e . , stimulation of the Q13639 receptor and antagonism of the dopamine D2 receptor . In this study , we determined in vitro activities of P35968 - 5169 towards both receptors and demonstrated the effect of the compound on gastrointestinal motor activity in conscious dogs and rats . In dogs , intravenous P35968 - 5169 stimulated upper gastrointestinal motility in the fasting state and also eliminated the depressive effect of 3 , 4 - dihydroxyphenylalanine ( DB01235 ) on this motility in the postprandial state . The effect of P35968 - 5169 on gastric emptying was further characterized by the use of three rat gastroparesis models ( dopamine D2 receptor agonist ( quinpirol )- , abdominal surgery - , or combined - situation - induced ) . DB01184 ( a dopamine D2 receptor antagonist ) was effective in the quinpirol - delay and combination - delay models , and cisapride and mosapride ( Q13639 receptor agonists ) were effective in the surgery - delay model . Only P35968 - 5169 eliminated the delay of gastric emptying in all three models . In addition , P35968 - 5169 accelerated emptying to above the normal level in the combination - delay model . These results suggest that P35968 - 5169 would be effective in various types of gastric ileus caused by different mechanisms .", "DB06480 reduces the number of reflux episodes and improves subjective symptoms in gastroesophageal reflux disease : a case series . INTRODUCTION : Treatment of persistence to proton pump inhibitors or non - acid reflux episodes in patients with gastroesophageal reflux disease is challenging . DB06480 , a selective high affinity serotonin ( Q13639 ) receptor agonist , might offer a possible new therapeutic alterative . CASE PRESENTATIONS : We report four chronically constipated female gastroesophageal reflux disease - patients with reflux symptoms and an increased number of reflux episodes in combined esophageal pH and multichannel impedance monitoring treated with prucalopride ( 2mg per day ) . Symptoms were persistent to proton pump inhibitors and ranitidine . Gastroesophageal reflux was detected by pH or multichannel impedance ( MII ) monitoring . Numbers of all reflux episodes as well as non - acid reflux episodes were reduced in all of our patients . The objective findings were concordant with subjective reports of symptom relief . There were no major adverse events in any patient during therapy with prucalopride . CONCLUSION : Administration of prucalopride showed promising results in the treatment of persisting or weakly and / or non - acid reflux episodes in our case series in four constipated patients . Therefore , prucalopride can be regarded as a possible therapeutic option in the treatment of standard proton pump inhibitor - persistent reflux in the chronically constipated patient . However , further prospective trials are needed to prove our findings .", "Efficacy and safety of prucalopride in adults and children with chronic constipation . INTRODUCTION : Chronic constipation ( CC ) is a debilitating condition with high prevalence rates both in children and adults . Despite the broad range of medical and pharmaceutical treatments , the bowel function does not restore in a fair amount of patients . DB06480 is a first - in - class selective , high affinity serotonin 5 - hydroxytryptamine type 4 ( Q13639 ) receptor agonist promoting gastro - intestinal prokinetic activity and has been evaluated for the treatment of CC . AREAS COVERED : A PubMed search ( 1965 - 2014 ) using the following terms alone or in combination : prucalopride , Q13639 , R093877 , safety , toxicity , pharmacokinetics , pharmacodynamics , transit , cardiac , human ether - a - go - go related gene ( hERG ) , arrhythmia , potassium current , elderly , children . EXPERT OPINION : DB06480 , a highly selective Q13639 receptor agonist , stimulates gastrointestinal motility and has been proven to be effective in the treatment of CC in adults by increasing stool frequency , reducing constipation - related symptoms and improving quality of life ( QoL ) . The safety and tolerability have been proven to be excellent . More research would be preferable on the effect of prucalopride on men , children and in other gastrointestinal motility disorders .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "___MASK19___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK19___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .", "Effect of prucalopride on symptoms of chronic constipation . BACKGROUND : DB06480 is a Q13639 receptor agonist with gastrointestinal prokinetic activities . This integrated analysis of data from three 12 - week , double - blind trials evaluated the effect of prucalopride 2 mg q . d . on common constipation symptoms in women in whom laxatives had failed to provide adequate relief . The effect of prucalopride on bowel function was outside the scope of the analysis and has been described elsewhere . METHODS : Women with self - reported inadequate relief from laxatives and included in the prucalopride 2 mg or placebo arm of the trials were selected for analysis . Symptom severity was determined with the Patient Assessment of Constipation Symptoms ( PAC - SYM ) questionnaire . Observed changes from baseline in individual item scores were also evaluated by calculating Cohen ' s D effect sizes using baseline standard deviation ( SD ) ( > 0 . 2 - 0 . 5 , > 0 . 5 - 0 . 8 and > 0 . 8 for small , moderate and large effects , respectively ) . KEY RESULTS : Data were analyzed for 936 women . The proportion of women with a PAC - SYM severity score > 2 at baseline was 50 . 0 % for abdominal symptoms , 71 . 4 % for stool symptoms , and 15 . 5 % for rectal symptoms . Excluding the women without presence of a symptom at baseline from the effect size calculations showed that prucalopride 2 mg had a large effect ( > 0 . 8 ) on all PAC - SYM items , including abdominal pain , abdominal discomfort , bloating , straining , and painful bowel movements . For abdominal symptoms and stool symptoms , effect sizes with prucalopride 2 mg were 1 . 3 - 2 . 3 times larger than those with placebo . CONCLUSIONS & INFERENCES : DB06480 2 mg q . d . for 12 weeks alleviates common constipation symptoms in women in whom laxatives had failed to provide adequate relief .", "High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK29___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .", "New - generation Q13639 receptor agonists : potential for treatment of gastrointestinal motility disorders . IMPORTANCE OF THE FIELD : Gastrointestinal ( GI ) dysmotility is an important mechanism in functional GI disorders ( FGIDs ) including constipation , irritable bowel syndrome , functional dyspepsia , and gastroparesis . 5 - hydroxytryptamine ( 4 ) ( 5 - HT ( 4 ) ) receptors are targets for the treatment of GI motility disorders . However , older 5 - HT ( 4 ) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac Q12809 potassium channel . AREAS COVERED IN THIS REVIEW : We conducted a PubMed search using the following key words alone or in combination : 5 - HT ( 4 ) , safety , toxicity , pharmacokinetics , pharmacodynamics , clinical trial , cardiac , hERG , arrhythmia , potassium current , elderly , prucalopride , ATI - 7505 , and velusetrag ( DB05655 ) , to review mechanisms of action , clinical efficacy , safety and tolerability of three new - generation 5 - HT ( 4 ) receptor agonists . WHAT THE READER WILL GAIN : DB06480 , ATI - 7505 , and velusetrag ( DB05655 ) are highly selective , high - affinity 5 - HT ( 4 ) receptor agonists that are devoid of action on other receptors within their therapeutic range . Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and , to a variable degree , in clinical trials that significantly relieve chronic constipation . Currently available evidence shows that the new 5 - HT ( 4 ) receptor agonists have safe cardiac profiles . TAKE HOME MESSAGE : New - generation 5 - HT ( 4 ) receptor agonists and future drugs targeting organ - specific splice variants are promising approaches to treat GI dysmotility , particularly colonic diseases .", "Phospho - dependent ubiquitination and degradation of P25116 regulates synaptic morphology and tau - mediated Aβ toxicity in Drosophila . The conserved kinases P25116 / Q9P0L2 are critically involved in processes such as asymmetric cell division , cell polarity and neuronal differentiation . Their deregulation has been implicated in diseases including Alzheimer ' s disease and cancer . Given the importance of P25116 / Q9P0L2 in health and disease , their activities need to be tightly controlled . However , little is known about the molecular mechanisms underlying their regulation in vivo . Here we show that in Drosophila , a phosphorylation - dependent ubiquitination mechanism restrains P25116 activation . Active P25116 generated by Q15831 - controlled phosphorylation is targeted for ubiquitination and degradation by P21583 ( Skp , Cullin , F - box containing complex ) ( Slimb ) , whose action is antagonized by the deubiquitinating enzyme fat facets . This newly identified P25116 - modifying module critically regulates synaptic morphology and tau - mediated postsynaptic toxicity of amyloid precursor protein ( P05067 ) / Aβ - 42 , the causative agents of Alzheimer ' s disease , at the Drosophila neuromuscular junction . Our results provide new insights into the regulation of P25116 in various physiological processes and offer new therapeutic strategies for diseases involving P25116 / Q9P0L2 deregulation .", "APPswe / Aβ regulation of osteoclast activation and RAGE expression in an age - dependent manner . Alzheimer ' s disease ( AD ) , one of the most dreaded neurodegenerative disorders , is characterized by cortical and cerebrovascular amyloid β peptide ( Aβ ) deposits , neurofibrillary tangles , chronic inflammation , and neuronal loss . Increased bone fracture rates and reduced bone density are commonly observed in patients with AD , suggesting one or more common denominators between both disorders . However , very few studies are available that have addressed this issue . Here , we present evidence for a function of amyloid precursor protein ( P05067 ) and Aβ in regulating osteoclast ( OC ) differentiation in vitro and in vivo . Tg2576 mice , which express the Swedish mutation of P05067 ( APPswe ) under the control of a prion promoter , exhibit biphasic effects on OC activation , with an increase of OCs in younger mice ( < 4 months old ) , but a decrease in older Tg2576 mice ( > 4 months old ) . The increase of OCs in young Tg2576 mice appears to be mediated by Aβ oligomers and receptor for advanced glycation end products ( RAGE ) expression in bone marrow macrophages ( BMMs ) . However , the decrease of OC formation and activity in older Tg2576 mice may be due to the increase of soluble rage ( sRAGE ) in aged Tg2576 mice , an inhibitor of O14788 - induced osteoclastogenesis . These results suggest an unexpected function of APPswe / Aβ , reveal a mechanism underlying altered bone remodeling in AD patients , and implicate P05067 / Aβ and RAGE as common denominators for both AD and osteoporosis .", "Modulation of hippocampal excitability by Q13639 receptor agonists persists in a transgenic model of Alzheimer ' s disease . 5 - HT ( 4 ) receptors are widely distributed in both peripheral and central nervous systems where they couple , via a G - protein , to the activation of adenylate cyclase . In the brain , the highest 5 - HT ( 4 ) receptor densities are found in the limbic system , including the hippocampus and frontal cortex . It has been suggested that activation of these receptors may be of therapeutic benefit in diseases that produce cognitive deficits such as Alzheimer ' s disease ( AD ) . Previous electrophysiological studies have shown that the 5 - HT ( 4 ) agonist , Zacopride , can increase population spike amplitude recorded in region P00915 of rat hippocampal slices in a cyclic AMP ( DB02527 ) / DB02527 - dependent protein kinase A - dependent manner . We report here that the 5 - HT ( 4 ) agonist , DB06480 , and the 5 - HT ( 4 ) partial agonist , SL65 . 0155 , produce a similar effect in rat hippocampal slices and that the specific 5 - HT ( 4 ) antagonist , GR113808 , blocks these effects . To investigate the potential use of 5 - HT ( 4 ) agonists in the treatment of AD , DB06480 was applied to hippocampal slices from a transgenic mouse line that overexpresses the Abeta peptide . Despite the deficit in synaptic transmission present in these mice , the percentage increase of the P00915 population spike induced by DB06480 was the same as that observed in wild - type mice . These data support 5 - HT ( 4 ) receptors as a target for cognitive enhancement and suggest that a partial agonist would be sufficient to produce benefits , while reducing potential peripheral side effects . In addition , we show that 5 - HT ( 4 ) receptors remain functional in the presence of excess Abeta peptide and may therefore be a useful target in AD .", "___MASK69___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK69___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .", "Human and mouse trace amine - associated receptor 1 have distinct pharmacology towards endogenous monoamines and imidazoline receptor ligands . TAARs ( trace amine - associated receptors ) are G - protein - coupled receptors that respond to low abundance , endogenous amines such as tyramine and tryptamine , and represent potential targets for neuropsychiatric diseases . However , some members of this receptor subfamily either have no ligand identified or remain difficult to express and characterize using recombinant systems . In the present paper we report the successful expression of human and mouse Q96RJ0 , and the characterization of their responses to various natural and synthetic agonists . In P29320 ( human embryonic kidney ) - 293 / CRE - bla cells , mouse Q96RJ0 showed a robust response to trace amines as measured using either a DB02527 assay or a beta - lactamase reporter assay , whereas human Q96RJ0 showed a weaker , but still measurable , response . When certain fragments of human Q96RJ0 were replaced with the corresponding regions of mouse Q96RJ0 , the chimaeric receptor showed a much stronger response in DB02527 production . Examination of a series of agonists on these receptors revealed that the human and the chimaeric receptor are almost identical in pharmacology , but distinct from the mouse receptor . We also screened small libraries of pharmacologically active agents on Q96RJ0 and identified a series of synthetic agonists , some of which are also ligands of the enigmatic imidazoline receptor . The findings of the present study not only shed light on the pharmacological species difference of Q96RJ0 , but also raise new possibilities about the mechanism of some of the imidazoline - related agents .", "P04150 - mediated regulation of P14780 gene expression in human ovarian surface epithelial cells . OBJECTIVE : To obtain proof - of - concept that locally produced anti - inflammatory steroids suppress ovulation - associated extracellular matrix proteases in human ovarian surface epithelial ( OSE ) cells . DESIGN : Primary OSE cell cultures treated with interleukin - 1alpha ( IL - 1alpha ) ( 500 pg / mL ) as proxy for inflammation , with / without anti - inflammatory steroid ( cortisol or progesterone [ P ] , 0 . 01 - 1 . 0 microM ) . SETTING : Academic medical center . PATIENT ( S ) : Sixteen premenopausal women ( 29 - 46 years ) undergoing surgery for nonmalignant gynecological conditions . MAIN OUTCOME MEASURE ( S ) : Semiquantitative extracellular matrix protease gene expression profiling with verification by real - time quantitative reverse transcription polymerase chain reaction ( qRT - PCR ) and gelatinase zymography . RESULT ( S ) : Treatment with IL - 1alpha stimulated messenger RNA ( mRNA ) expression of several ovulation - associated matrix metalloproteinase genes by OSE cell cultures , including gelatinase B ( P14780 ) but not gelatinase A ( P08253 ) . The IL - 1alpha - stimulated P14780 mRNA production was suppressed by cortisol but not P . ___MASK19___ but not P also dose - dependently suppressed IL - 1alpha - stimulated P14780 gelatinase activity and this effect was blocked by the glucocorticoid receptor antagonist DB00834 . CONCLUSION ( S ) : In human OSE cells , stimulation of P14780 gene expression and proteolytic activity by IL - 1alpha is suppressed by anti - inflammatory cortisol through a glucocorticoid receptor - mediated mechanism . Because IL - 1alpha also generates cortisol formation in OSE by stimulating cortisone reductase activity , these results support a role for intracrine cortisol in minimizing proteolytic damage to the OSE at ovulation .", "Changes in the levels of some acute - phase proteins in human immunodeficiency virus - 1 infected patients , following interleukin - 2 treatment . Intermittent interleukin ( IL ) - 2 administration to human immunodeficiency virus ( HIV ) - 1 infected patients is well documented and generally used , but there is limited information about the changes of acute - phase protein ( P05067 ) levels in response to this treatment . Fifteen patients undergoing highly active anti - retroviral therapy ( HAART ) treatment , with undetectable viral load , but low P01730 + cell count ( < 300 / microl ) , have been treated with 3 . 6 M IU Proleukine administered twice daily by subcutaneous injection over 5 days . P02741 ( CRP ) , D - dimer , P01024 , P02748 , C1 - inh and alpha - 2HS glycoprotein levels were measured immediately before P60568 administration , as well as on day 5 and 2 - 3 weeks thereafter . After P60568 administration , both mean D - dimer and CRP levels increased significantly ( P < 0 . 001 ) , but returned ( P < 0 . 001 ) to baseline within the subsequent 2 - 3 weeks . Alpha - 2HS glycoprotein decreased immediately after P60568 administration . No significant differences were detected in the levels of P01024 , P02748 and C1 - inh . A significant , positive correlation ( r = 0 . 5178 , P = 0 . 0008 ) was ascertained between the changes of CRP level , measured immediately before as well as 5 days after P60568 administration , and changes in P01730 T cell counts measured 2 - 3 weeks before and after treatment , respectively . P60568 administration induces rapid elevation of two major APPs ( CRP , D - dimer ) . The positive correlation observed between the changes of CRP levels and P01730 + cell counts after P60568 administration may indicate that the abrupt , but transitory overproduction of CRP might contribute to the P01730 + cell count - increasing effect of the drug and / or may be associated with serious side effects .", "Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5 - HT ligands . The brominated cyclodipeptides barettin ( cyclo [( 6 - bromo - 8 - entryptophan ) arginine ] ) and 8 , 9 - dihydrobarettin ( cyclo [( 6 - bromotryptophan ) arginine ] ) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose - dependent manner in concentrations ranging from 0 . 5 to 25 microM . To further establish the molecular target and mode of action of these compounds , we investigated their affinity to human serotonin receptors . The tryptophan residue in the barettins resembles that of endogenous serotonin [ 5 - hydroxytryptamine ] . A selection of human serotonin receptors , including representatives from all subfamilies ( 1 - 7 ) , were transfected into P29320 - 293 cells . Barettin selectively interacted with the serotonin receptors 5 - Q13049 , P28335 , and Q13639 at concentrations close to that of endogenous serotonin , with the corresponding Ki values being 1 . 93 , 0 . 34 , and 1 . 91 microM , respectively . 8 , 9 - Dihydrobarettin interacted exclusively with the P28335 receptor with a Ki value of 4 . 63 microM ; it failed to show affinity to 5 - Q13049 and Q13639 , indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins ." ]

[ "___MASK19___", "___MASK22___", "___MASK25___", "___MASK29___", "___MASK2___", "___MASK38___", "___MASK69___", "___MASK79___", "___MASK92___" ]

[ "P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK68___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .", "Leishmania major protein disulfide isomerase as a drug target : enzymatic and functional characterization . Leishmaniasis is a major health problem worldwide and tools available for their control are limited . Effective vaccines are still lacking , drugs are toxic and expensive , and parasites develop resistance to chemotherapy . In this context , new antimicrobials are urgently needed to control the disease in both human and animal . Here , we report the enzymatic and functional characterization of a Leishmania virulence factor , Leishmania major Protein disulfide isomerase ( LmPDI ) that could constitute a potential drug target . LmPDI possesses domain structure organization similar to other P07237 family members ( a , a ' , b , b ' and c domains ) , and it displays the three enzymatic and functional activities specific of P07237 family members : isomerase , reductase and chaperone . These results suggest that LmPDI plays a key role in assisting Leishmania protein folding via its capacity to catalyze formation , breakage , and rearrangement of disulfide bonds in nascent polypeptides . Moreover , DB00626 , a reductase activity inhibitor , and DB03615 , a chaperone activity inhibitor , were tested in LmPDI enzymatic assays and versus Leishmania promastigote in vitro cultures and Leishmania amastigote multiplication inside infected THP - 1 - derived macrophages . DB00626 inhibited both isomerase and reductase activities , while DB03615 had no effect on the chaperone activity . Interestingly , DB00626 blocked in vitro promastigote growth as well as amastigote multiplication inside macrophages with EC ( 50 ) values of 39 μM . These results suggest that LmPDI may constitute an interesting target for the development of new anti - Leishmania drugs .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK83___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .", "Referral practices in patients suffering from non - malignant chronic pain . This paper presents the results of a prospective observational cohort study investigating referral practices to six specialized pain centres ( SPCs ) in 303 patients with headache ( HD ) , low back pain ( P18428 ) , and neuropathic pain ( NP ) . The study was divided into three parts . Part 1 : The pain health care history ( contacts with general practitioners and specialists , further referrals , time spans , therapies ) before first contact with the Q969E3 . Part 2 : Reality of pain therapy and management in the Q969E3 ( patients ' attrition , interdisciplinarity of therapy and novel therapeutic strategies instigated ) . Part 3 : Follow - up and assessment of pain levels ( NRS , SES ) , disability scores ( P07237 ) , QoL scores ( SF 12 ) , and anxiety and depression scores ( HADS ) at 0 , 6 and 12 months . Using an ordinal linear regression model , factors predicting a good treatment outcome were identified . On average it took 3 years of pain symptoms before first consultation with GP . The median time period from the first pain sensations until the appointment in the Q969E3 was 12 years . Nearly half of the referrals to specialists or SPCs were initiated by a non - professional . In the Q969E3 the medication was changed in 71 % of cases . Care was interdisciplinary in only 32 % . At 6 and 12 months after the first contact with the Q969E3 , only 20 % of the patients had improved with respect to levels of pain and psychometric data . A high degree of chronicity , a history of pain - associated surgeries and low social support were negative predictors for treatment outcome .", "Cotranslational glycosylation of proteins in systems depleted of protein disulphide isomerase . The role of protein disulphide isomerase ( P07237 ) and other resident proteins of the endoplasmic reticulum ( ER ) lumen in co - and post - translational modification of secretory proteins has been studied in experiments on translation in vitro . We have devised procedures for extracting the lumenal content proteins of dog pancreas microsomal vesicles by alkaline buffer , or detergent washing , and for reconstitution of the depleted membrane fraction . When microsomal membranes are depleted of content by washing at pH 9 . 1 , they are able to co - translationally glycosylate human interferon - gamma ( P01579 ) and yeast pro - alpha - factor and the products appear to be identical to those produced by control microsomes . However , when microsomal membranes are depleted of content by washing with saponin they are still able to co - translationally translocate and glycosylate human P01579 , but the products were of higher apparent Mr than those generated by control microsomes . When saponin - washed microsomal membranes were reconstituted with homogeneous protein disulphide isomerase ( P07237 ) , the generated vesicles gave the same pattern of co - translationally glycosylated P01579 as saponin - washed microsomal membranes lacking P07237 . These results are discussed in relation to the roles of resident ER proteins in co - translational modification ; they suggest that P07237 is not an essential component of the machinery of co - translational N - glycosylation , but that detergent washing may inactivate or remove some ER glycosidases .", "Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK85___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK85___ who were treated with a single dose of mifepristone .", "Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK69___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .", "Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK36___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "P37840 oligomerization in manganese - induced nerve cell injury in brain slices : a role of NO - mediated S - nitrosylation of protein disulfide isomerase . Over - exposure to manganese ( Mn ) has been known to induce endoplasmic reticulum ( ER ) stress involving protein misfolding . The proper maturation and folding of native proteins rely on the activity of protein disulfide isomerase ( P07237 ) . However , the exact mechanism of Mn - induced alpha - synuclein oligomerization is unclear . To explore whether alpha - synuclein oligomerization was associated with S - nitrosylation of P07237 , we made the rat brain slice model of manganism and pretreated slices with L - Canavanine , a selective P35228 inhibitor . After slices were treated with Mn ( 0 , 25 , 100 , and 400 μM ) for 24 h , there were dose - dependent increases in apoptotic percentage of cells , lactate dehydrogenase ( LDH ) releases , production of NO , inducible nitric oxide synthase ( P35228 ) activity , the mRNA and protein expressions of P35228 , and P07237 . Moreover , S - nitrosylated P07237 and alpha - synuclein oligomerization also increased . However , there was a significant increase in the P07237 activity of 25 - μM Mn - treated slices . Then , P07237 activity and the affinity between P07237 and alpha - synuclein decreased significantly in response to Mn ( 100 and 400 μM ) , which was associated with S - nitrosylation of P07237 . The results indicated that S - nitrosylated P07237 could affect its activity . We use the L - Canavanine pretreatment brain slices to inhibit S - nitrosylation of P07237 . The results showed that L - Canavanine pretreatment could reduce Mn - induced nerve cell injury and alpha - synuclein oligomerization . Additionally , there was a significant recovery in P07237 activity in L - Canavanine - pretreated slices . The findings revealed that Mn induced nitrosative stress via the activation of P35228 and subsequent S - nitrosylation of P07237 in cultured slices . Moreover , S - nitrosylation of P07237 is an important signaling event in the Mn - induced alpha - synuclein oligomerization in brain slices .", "The antiangiogenic effects of a vascular endothelial growth factor decoy receptor can be monitored in vivo using contrast - enhanced ultrasound imaging . The development of antiangiogenic therapies has stimulated interest in noninvasive imaging methods to monitor response . We investigated whether the effects of a vascular endothelial growth factor decoy receptor ( DB08885 , Regeneron Pharmaceuticals , Tarrytown , NY ) could be monitored in vivo using contrast - enhanced ultrasonography ( CEUS ) . Twenty nude mice ( in two groups ) were implanted with a human melanoma cell line ( DB - 1 ) . The active group received DB08885 ( 4 × 25 mg / kg over 2 weeks ) , whereas the control group received an inactive protein . An ultrasound contrast agent was injected followed by power Doppler imaging ( P07237 ) and pulse inversion harmonic imaging ( PIHI ; regular and intermittent ) . Specimens were sectioned in the same planes as the images and stained for endothelial cells ( CD31 ) , cyclooxygenase - 2 ( P35354 ) , P15692 , and hypoxia ( Glut1 ) . Measures of tumor vascularity obtained with the different imaging modes were compared to immunohistochemical markers of angiogenesis . Mean tumor volume was smaller in the active group than in the control group ( 656 ± 225 vs 1 , 160 ± 605 mm3 ) . Overall , P07237 and P15692 correlated ( r = . 34 ; p = . 037 ) . Vascularity decreased from control to treated mice with intermittent PIHI , as did the expression of CD31 and P35354 ( p ≤ . 02 ) , whereas P15692 increased ( p = . 05 ) . CEUS appears to allow in vivo monitoring of the antiangiogenic effects of DB08885 in the DB - 1 human melanoma xenograft model .", "P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .", "Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .", "Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK71___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .", "Endoplasmic reticulum calcium depletion impacts chaperone secretion , innate immunity , and phagocytic uptake of cells . A number of immunological functions are ascribed to cell surface - expressed forms of the endoplasmic reticulum ( ER ) chaperone calreticulin ( CRT ) . In this study , we examined the impact of ER stress - inducing drugs upon cell surface CRT induction and the resulting immunological consequences . We showed that cell surface expression of CRT and secretion of CRT , P11021 , gp96 , and P07237 were induced by thapsigargin ( THP ) treatment , which depletes ER calcium , but not by tunicamycin treatment , which inhibits protein glycosylation . Surface expression of CRT in viable , THP - treated fibroblasts correlated with their enhanced phagocytic uptake by bone marrow - derived dendritic cells . Incubation of bone marrow - derived dendritic cells with THP - treated fibroblasts enhanced sterile P05231 production and LPS - induced generation of IL - 1β , IL - 12 , IL - 23 , and P01375 - α . However , extracellular CRT is not required for enhanced proinflammatory responses . Furthermore , the pattern of proinflammatory cytokine induction by THP - treated cells and cell supernatants resembled that induced by THP itself and indicated that other ER chaperones present in supernatants of THP - treated cells also do not contribute to induction of the innate immune response . Thus , secretion of various ER chaperones , including CRT , is induced by ER calcium depletion . CRT , previously suggested as an eat - me signal in dead and dying cellular contexts , can also promote phagocytic uptake of cells subject to ER calcium depletion . Finally , there is a strong synergy between calcium depletion in the ER and sterile P05231 , as well as LPS - dependent IL - 1β , IL - 12 , IL - 23 , and P01375 - α innate responses , findings that have implications for understanding inflammatory diseases that originate in the ER .", "Distinct subcellular expression of endogenous polycystin - 2 in the plasma membrane and Golgi apparatus of MDCK cells . Q13563 is a predicted integral membrane protein with non - selective cation channel activity . The protein is encoded by the PKD2 gene , which is mutated in approximately 15 % of patients with autosomal dominant polycystic kidney disease ( ADPKD ) . Q13563 can interact with the transmembrane protein polycystin - 1 , the product of the PKD1 gene . However , endoplasmic reticulum ( ER ) localization was reported for ( heterologously expressed ) polycystin - 2 in cultured cells and baso - lateral localization has been reported in renal tissues . Using two polyclonal antisera raised against polycystin - 2 we demonstrated distinct expression of the endogenous protein in the Golgi apparatus and the plasma membrane of MDCK cells . In contrast , most of the heterologously expressed polycystin - 2 ( P16519 - EGFP ) remained in the ER , substantially overlapping with the staining pattern of protein - disulfide isomerase ( P07237 ) , a marker for the ER . Only in a small subset of these cells weak plasma membrane signals were observed . Membrane staining was also suggested by immunoelectron microscopy and was confirmed by subcellular fractionation on sucrose density gradients . The plasma membrane staining disappeared following extraction with a buffer containing Triton X - 100 , whereas signals for polycystin - 1 and P12830 remained visible , suggesting that polycystin - 2 is neither tightly bound to the Triton X - 100 insoluble cytoskeleton , nor to these proteins . We conclude that endogenous polycystin - 2 is transported via the Golgi apparatus to the plasma membrane and has a broader membrane localization than polycystin - 1 . These data suggest that polycystin - 2 can move freely in certain regions of the membrane where it probably functions as a channel , activated by , or in complex with , polycystin - 1 .", "DB03615 inhibits the chaperone activity of protein disulfide isomerase . In the process of screening of proteins binding to ribostamycin in bovine liver using the affinity column chromatography , we found that ribostamycin inhibited the chaperone activity of protein disulfide isomerase ( P07237 ) , but it did not inhibit the isomerase activity . P07237 was identified by SDS - PAGE , Western blotting , and N - terminal amino acid sequence analysis . A 100 : 1 molar ratio of ribostamycin to P07237 was almost sufficient to completely inhibit the chaperone activity of P07237 . The binding affinity of ribostamycin to purified bovine P07237 was determined by the Biacore system , which gave a K ( D ) value of 3 . 19 x 10 (- 4 ) M . This suggests that ribostamycin binds to region distinct from the CGHC motif of P07237 . This is the first report to describe the inhibitor of the chaperone activity of P07237 .", "___MASK64___ : kinetic and dynamic profile in the treatment of pain . ___MASK64___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK64___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK64___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK64___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .", "P07237 - mediated ER retention and proteasomal degradation of procollagen I in corneal endothelial cells . Procollagen I in corneal endothelial cells ( CECs ) is intracellularly degraded immediately after its synthesis . In this study , we investigated the mechanism of intracellular degradation of procollagen I by determining the role of protein disulfide isomerase ( P07237 ) in endoplasmic reticulum ( ER ) retention and further determined the degradation pathway of procollagen I in CECs . When association of P07237 to monomeric proalpha chains or the trimeric procollagen I carboxyl propeptides ( PICPs ) was analyzed , immune complex precipitated with anti - PICP antibody contained more P07237 than that precipitated with antibodies to monomeric chains . PICPs were completely colocalized with P07237 . When CECs were transfected with P07237 vector , procollagen I and the recombinant P07237 were colocalized in the ER , whereas CECs transfected with P07237 minus KDEL ( the ER retrieval sequence ) vector demonstrated that the two proteins were localized in the Golgi and were subsequently secreted into the medium . DB03615 ( an inhibitor of the chaperone activity of P07237 ) blocked colocalization of P07237 and procollagen I . Cells treated with chloroquine ( lysosome inhibitor ) did not alter the subcellular localization of procollagen I , because the inhibitor failed to induce the accumulation of procollagen I at Golgi . On the other hand , procollagen I was colocalized with ubiquitin in the cytoplasm , and proteasomal inhibitors further facilitated the colocalization of the two proteins and accumulation of ubiquitinated procollagen I ladders . These results suggest that association of P07237 with procollagen I , whether monomeric or trimeric , leads to ER retention of procollagen I before intracellular degradation via the ubiquitin - proteasome pathway .", "Thiol / disulfide exchange is a prerequisite for P61073 - tropic HIV - 1 envelope - mediated T - cell fusion during viral entry . Attachment of gp120 to P01730 during HIV - 1 entry triggers structural rearrangement in gp120 that enables binding to an appropriate coreceptor . Following coreceptor engagement , additional conformational changes occur in the envelope ( Env ) , resulting in fusion of virion and cell membranes . Catalysts with redox - isomerase activity , such as protein disulfide isomerase ( P07237 ) , facilitate Env conversion from its inactive to its fusion - competent conformation . We report here that anti - P07237 agents effectively block P61073 Env - mediated fusion and spread of virus infection . Exogenously added P07237 , in turn , can rescue fusion from this blockade . We further find that P07237 facilitates thiol / disulfide rearrangement in gp120 during conformational change , whereas inhibition of this redox shuffling prevents gp41 from assuming the fusogenic 6 - helix bundle conformation . At the virus - cell contact site , gp120 induces assembly of P07237 , P01730 , and P61073 into a tetramolecular protein complex serving as a portal for viral entry . Our findings support the hypothesis that Env conformational change depends on a well - coordinated action of a tripartite system in which P07237 works in concert with the receptor and the coreceptor to effectively lower the activation energy barrier required for Env conformational rearrangement .", "Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case - control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population - based case - control study . We examined nutrient density - adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0 . 026 ) , cooked by pan - frying ( trend P = 0 . 035 ) , and cooked until well - done ( trend P = 0 . 013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0 . 023 ) . A gene - by - diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0 . 008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .", "Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK11___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK11___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK11___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK11___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK11___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK11___ increased the protein expression of hepatic P05181 and ___MASK11___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK11___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK11___ and RFP - induced hepatotoxicity .", "Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK8___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .", "P10275 as a therapeutic target . Androgens function as sex hormone primarily via activation of a single androgen receptor ( AR , or P10275 ) . AR is an important therapeutic target for the treatment of diseases such as hypogonadism and prostate cancer . AR ligands of different chemical structures and / or pharmacological properties are widely used for these therapeutic applications , and all of the AR ligands currently available for therapy modulate AR function via direct binding to the ligand - binding pocket ( P18428 ) of the receptor . In the past ten years , our understanding of AR structure and molecular mechanism of action has progressed extensively , which has encouraged the rapid development of newer generation of AR ligands , particularly tissue - selective AR ligands . With improved tissue selectivity , future generations of AR ligands are expected to greatly expand the therapeutic applications of this class of drugs . This review will provide an overview of the common therapeutic applications of currently available AR ligands , and discussion of the major challenges as well as novel therapeutic strategies proposed for future drug development ." ]

[ "___MASK11___", "___MASK36___", "___MASK64___", "___MASK68___", "___MASK69___", "___MASK71___", "___MASK83___", "___MASK85___", "___MASK8___" ]

[ "Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .", "P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK12___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Endotoxin - induced liver damage in rats is minimized by beta 2 - adrenoceptor stimulation . OBJECTIVE AND DESIGN : To investigate the effects of beta ( 2 )- adrenoceptor ( beta ( 2 )- AR ) stimulation on endotoxin - induced liver damage and systemic cytokine levels in rats . SUBJECTS : Standard male Wistar rats . TREATMENT : A disease - model of lipopolysaccharide ( LPS ) - induced acute systemic inflammation was used . The beta ( 2 )- selective AR agonist clenbuterol was administered before , during , and after LPS - challenge to investigate its effects on the acute inflammatory response and associated liver - failure . METHODS : The following parameters have been measured in plasma : P01375 alpha , P01584 , P05231 , P22301 , Q9NRA2 , ALT , and Bilirubin . Liver histological examination was performed to look for changes in tissue morphology . RESULTS : Administration of clenbuterol ( p . o . ) one hour before , or intravenous at the same time as LPS - challenge resulted in a marked reduction of plasma levels of P01375 alpha , P01584 , and P05231 . A change both in plasma - level and in time - concentration profile of the anti - inflammatory cytokine P22301 was found . DB01407 minimized LPS - induced liver damage , as represented by significantly lowered concentrations of several parameters for liver - failure ( Q9NRA2 , ALT , Bilirubin ) , and improved hepatic tissue morphology . DB01407 administration after LPS challenge failed to inhibit P01375 alpha - release but reduced liver - damage . Simultaneous use of the beta ( 2 )- AR antagonist propranolol augmented LPS - induced liver failure , suggesting a role of endogenous adrenoceptor - agonists in prevention of organ - failure during systemic inflammation . CONCLUSIONS : The results indicate that a selective beta ( 2 )- AR agonist might be used as an additional therapeutic agent in the clinic for the treatment of ( acute ) systemic inflammatory disorders in order to reduce or prevent subsequent liver failure .", "Intercellular adhesion molecule - 1 ( P05362 ) expression and soluble P05362 ( sICAM - 1 ) production by cytokine - activated human aortic endothelial cells : a possible role for P05362 and sICAM - 1 in atherosclerotic aortic aneurysms . The interactions of inflammatory cells , cytokines , and cell adhesion molecules ( P62158 ) may be important in the pathogenesis of vascular diseases such as abdominal aortic aneurysms ( AAA ) , in which inflammation plays a role . The aim of this study was to investigate the pathogenic role of P05362 , a molecule involved in leucocyte - endothelial interactions , in vascular inflammation . ELISA of human explant culture supernatants revealed a four - fold increase in sICAM - 1 production by AAA ( n = 9 ) versus normal ( n = 8 ) aortic explants . Human aortic endothelial cell ( hAEC ) culture was used for further studies as an in vitro model for aortic inflammatory conditions . Tumour necrosis factor - alpha ( P01375 ) or P01584 treatment of hAEC resulted in an up to 1 . 8 - fold significant increase in sICAM - 1 production compared with resting cells . In addition , the expression of P05362 on cytokine - stimulated versus resting hAEC was measured by radioimmunoassay . P01375 significantly induced P05362 expression on these cells . These results suggest that different forms of P05362 , present on or released by the activated aortic endothelium , may be involved in leucocyte adhesion to and migration into the vessel wall .", "Mechanisms of epithelial barrier impairment in HIV infection . Diarrhea and malabsorption due to intestinal dysfunction are common symptoms in HIV infection . The pathophysiologic mechanisms of these alterations are often not known , and the role of HIV per se is still controversially discussed . We measured the epithelial transport and barrier function by means of a miniaturized Ussing chamber system in the duodenum of HIV - infected patients in different disease stages , determined by the P01730 cell count in the serum as well as symptoms in patients with and without diarrhea . We could show that diarrhea induced by HIV per se is caused by a leak flux mechanism due to impaired epithelial barrier function . Antisecretory therapy does not seem to be useful in these patients , because we did not find increased active ion secretion . Along the course of the HIV infection , the epithelial transport and barrier function varies with HIV disease stage ( expressed by P01730 cell status ) . In addition , an in vitro model was studied to characterize the effect of HIV - infected human immune cells on the epithelial barrier function using the human colonic epithelial cell line HT - 29 / B6 . HIV infection of human immune cells induced an increase in cytokine release -- for example , P01375 , P01584 , IFN - alpha , and P01579 -- downregulating the epithelial barrier function of the human colonic epithelial cell line HT - 29 / B6 . Taken together we postulate a specific stage - dependent cytokine pattern released from HIV - infected immune cells in the mucosa , which , corresponding to the HIV disease stage , is responsible for the variation in epithelial function .", "DB01407 affects the expression of messenger RNA for interleukin 10 in peripheral leukocytes from horses challenged intrabronchially with lipopolysaccharides . On four occasions , four horses with heaves and four horses with small airway inflammatory diseases inhaled 0 . 9 % saline based aerosol mixtures with or without lipopolysaccharides ( LPS ) . Prior to the first saline and LPS inhalation , horses were untreated , while three and a half days prior to the third and forth inhalation horses had received 0 . 8 microg / kg clenbuterol intravenously twice daily . The messenger RNA ( mRNA ) expression of tumour necrosis factor - alpha ( P01375 ) , interleukin ( IL ) - 1beta , P05112 , P05231 , P10145 , P22301 and interferon - gamma ( IFN - gamma ) was investigated by RT - PCR , all of which were expressed in the white blood cells of samples collected . Inhalation of LPS only changed the cytokine expression profile of P22301 , P05112 and P01375 mRNA which were higher after challenge with LPS . However in those horses that were treated with clenbuterol the LPS - induced P22301 mRNA expression was shown to be suppressed . Further changes in P05112 and P01375 were not significant . Thus the results of this study indicated that clenbuterol can modulate the expression of P22301 mRNA in peripheral white blood cells in those horses with small airway diseases that have been exposed to LPS .", "Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .", "DB01407 induces growth factor mRNA , activates astrocytes , and protects rat brain tissue against ischemic damage . The induction of growth factor synthesis in brain tissue by beta2 - adrenoceptor agonists , such as clenbuterol , is a promising approach to protect brain tissue from ischemic damage . DB01407 ( 0 . 01 - 0 . 5 mg / kg ) reduced the cortical infarct volume in Long - Evans rats as measured 7 days after permanent occlusion of the middle cerebral artery . Dosages of clenbuterol higher than 1 mg / kg showed no cerebroprotective effect due to a decrease in blood pressure and an increase in plasma glucose level . The increase in the mRNA level of nerve growth factor ( P01138 ) , basic fibroblast growth factor ( basic FGF ) , and transforming growth factor - beta1 ( TGF - beta1 ) mRNA in cortical and hippocampal tissue occurred earlier after middle cerebral artery occlusion and was more pronounced in animals treated with clenbuterol than in controls . In addition , glial fibrillary acidic protein ( P14136 ) mRNA expression was enhanced in astrocytes 6 h after ischemia in clenbuterol - treated animals . The results suggest that growth factor synthesis is enhanced in activated astrocytes and that this could be the mechanism of clenbuterol - induced cerebroprotection after ischemia .", "The hypothalamus - pituitary -- adrenocortical axis : epigenetic determinants changes with aging , involvement of P01138 . In order to study the hypothesis that maternal corticosterone ( B ) influences the hippocampus / hypothalamus - pituitary - adrenocortical axis system in the adult rat , we induced a moderate increase in maternal plasma level of B by adding the hormone to the drinking water of the dams ( 200 micrograms / ml ) from the day of delivery to weaning . B - nursed male rats had , at 3 months of age , a lower basal concentration of DB01285 and B , as well as a lower stress ( 2 min restraint ) induced increase . The reduced stress response was also present at 12 months . These endocrine differences were parallel to behavioural modifications . In the adult offspring of mothers that were hypercorticosteronemic during lactation , an improved spatial learning ability , a reduced emotional performance in a conflict procedure and a better performance in a conditioned active avoidance test was observed . Finally , the analysis of hippocampal adrenocorticoid receptors revealed that the postnatal endocrine manipulation induced an increase in the Type I receptor density in the adult offspring . Our findings point to an epigenetic effect of maternal B on the maturational process of the hypothalamus - pituitary - adrenocortical ( Q9Y251 ) axis and the hippocampus with endocrine and behavioural consequences in adulthood . The aging process has been shown to alter the normal functioning of the Q9Y251 axis . This alteration might arise from a reduced hippocampal negative feedback control , as suggested by the age - dependent loss of hippocampal adrenocorticoid receptors . Among the hypothalamic factors endowed with corticotropin secretagogue activity , corticotropin - releasing hormone ( P06850 ) and vasopressin are considered the major physiological mediators of hypothalamic control of DB01285 release . ( ABSTRACT TRUNCATED AT 250 WORDS )", "[ DB01407 in amyotrophic lateral sclerosis . No indication for a positive effect ] . The anabolic effects of clenbuterol have been recognized for a long time . DB01407 augments the expression of specific muscle proteins with a differential effect on type I and type II fibres . Furthermore , clenbuterol induces the synthesis of endogenous nerve growth factor ( P01138 ) and may itself be a myotrophic factor released by neuron endings . Side effects include tremor and headache and dose dependent abnormalities of laboratory values ( hypokalemia , hypoglycemia ) . After long - term medication increasing fatigue of muscles has been observed . Decreased expression of beta 2 - adrenergic receptors may limit the expected functional improvement . The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved . Controlled treatment trials are warranted to assess this question .", "The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK13___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK13___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .", "Stimulation of CD25 (+) P01730 (+) regulatory T cells through Q9Y5U5 breaks immunological self - tolerance . CD25 (+) P01730 (+) regulatory T cells in normal animals are engaged in the maintenance of immunological self - tolerance . We show here that glucocorticoid - induced tumor necrosis factor receptor family - related gene ( Q9Y5U5 , also known as Q9Y5U5 ) -- a member of the tumor necrosis factor - nerve growth factor ( P01375 - P01138 ) receptor gene superfamily -- is predominantly expressed on CD25 (+) P01730 (+) T cells and on CD25 (+) P01730 (+) CD8 (-) thymocytes in normal naïve mice . We found that stimulation of Q9Y5U5 abrogated CD25 (+) P01730 (+) T cell - mediated suppression . In addition , removal of Q9Y5U5 - expressing T cells or administration of a monoclonal antibody to Q9Y5U5 produced organ - specific autoimmune disease in otherwise normal mice . Thus , Q9Y5U5 plays a key role in dominant immunological self - tolerance maintained by CD25 (+) P01730 (+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease .", "Stimulation of central β2 - adrenoceptors suppresses NFκB activity in rat brain : a role for IκB . In this study we examined the impact of systemic treatment with the long - acting brain penetrant β2 - adrenoceptor agonist clenbuterol on NFκB activity and IκB expression in rat brain . DB01407 decreased NFκB activity ( p65 DNA binding ) in nuclear extracts prepared from rat cortex and hippocampus for up to 8h following a single treatment . This was accompanied by increased expression of IκBα mRNA and protein . The temporal increase in IκB protein expression paralleled the suppression of NFκB activity , suggesting that IκBα mediates the suppression NFκB activity observed . These actions of clenbuterol were prevented by pre - treatment with the non - selective β - adrenoceptor antagonist propranolol , the β2 - adrenoceptor antagonist ICI - 118 , 551 , but not the β1 - adrenoceptor antagonist metoprolol , suggesting that the effects of clenbuterol on IκBα expression and NFκB activity are mediated specifically by the β2 - adrenoceptor . In addition , the actions of clenbuterol were mimicked by systemic administration of another highly selective long - acting β2 - adrenoceptor agonist formoterol . As neurodegenerative diseases are associated with inflammation we determined if clenbuterol could suppress NFκB activation that occurs in response to an inflammatory stimulus . In this regard we demonstrate that clenbuterol inhibited IκB phosphorylation and IκB degradation and inhibited NFκB activity in hippocampus and cortex of rats following a central injection of the inflammagen bacterial lipopolysaccharide ( LPS ) . In tandem , clenbuterol blocked expression of the NFκB - inducible genes P01375 - α and P05362 following LPS administration . Our finding that clenbuterol and formoterol inhibit NFκB activity in the CNS further supports the idea that β2 - adrenoceptors may be an attractive target for treating neuroinflammation and combating inflammation - related neurodegeneration .", "Modulation of proteolytic activity during neuritogenesis in the PC12 nerve cell : differential control of plasminogen activator and plasminogen activator inhibitor activities by nerve growth factor and dibutyryl - cyclic AMP . Extracellular proteolysis is considered to be required during neuritic outgrowth to control the adhesiveness between the growing neurite membrane and extracellular matrix proteins . In this work , PC12 nerve cells were used to study the modulation of proteolytic activity during neuronal differentiation . PC12 cells were found to contain and release a 70 - 75 - kDa tissue - type plasminogen activator ( tPA ) and a much less abundant 48 - kDa urokinase - type plasminogen activator . A plasminogen activator inhibitor ( P05121 ) activity with molecular sizes of 54 and 58 kDa was also detected in PC12 cell conditioned medium and formed high - molecular - mass complexes with released tPA . Release of P05121 activity was dependent on treatment with nerve growth factor ( P01138 ) , whereas tPA synthesis and release were under control of a cyclic AMP - dependent mechanism and increased on treatment with dibutyryl - cyclic AMP [ ( But ) 2cAMP ] or cholera toxin . Simultaneous treatment with P01138 and ( But ) 2cAMP resulted in increases of both tPA and P05121 release and enhancement of tPA - P05121 complex formation . The resulting plasminogen activator activity in conditioned medium was high in ( But ) 2cAMP - treated cultures with short neuritic outgrowth but remained low in P01138 - or P01138 plus ( But ) 2cAMP - treated cultures , where neurite extension was , respectively , large and very large . These results suggest that excess proteolytic activity may be detrimental to neuritic outgrowth and that not only P05121 release but also tPA - P05121 complex formation is associated with production of large and stable neuritic outgrowth . This can be understood as an involvement of P05121 in the protection against neurite - destabilizing proteolytic activity .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK65___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "Developmental trauma is associated with behavioral hyperarousal , altered Q9Y251 axis activity , and decreased hippocampal neurotrophin expression in the adult rat . Effects of early - life trauma on adult behavioral responses , corticosterone ( O00230 ) concentration , and levels of nerve growth factor ( P01138 ) , brain - derived neutrophic factor ( P23560 ) , and neurotrophin - 3 ( P20783 ) in hippocampus and frontal cortex were investigated . Traumatized animals showed an increase in rearing in both the elevated plus maze and open field after adult restress , higher basal levels of O00230 , lower levels of P23560 in dorsal hippocampus , and lower levels of P20783 in dorsal and ventral hippocampus . Trauma - related behavioral hyperarousal and altered hypothalamic - pituitary - adrenal ( Q9Y251 ) axis activity may be mediated by decreases in hippocampal neurotrophin expression .", "A diarylheptanoid from lesser galangal ( Alpinia officinarum ) inhibits proinflammatory mediators via inhibition of mitogen - activated protein kinase , Q8TCB0 / 42 , and transcription factor nuclear factor - kappa B . The diarylheptanoid 7 -( 4 '- hydroxy - 3 '- methoxyphenyl )- 1 - phenylhept - 4 - en - 3 - one ( Q16891 ) is a naturally occurring phytochemical found in lesser galangal ( Alpinia officinarum ) . In the present study , we have demonstrated the anti - inflammatory properties of this compound on mouse macrophage cell line ( RAW 264 . 7 ) and human peripheral blood mononuclear cells ( PBMCs ) in vitro . Treatment of RAW 264 . 7 cells with Q16891 ( 6 . 25 - 25 microM ) significantly inhibited lipopolysaccharide ( LPS ) - stimulated nitric oxide ( NO ) production . This compound also inhibited the release of LPS - induced proinflammatory cytokines interleukin - 1 beta ( P01584 ) and tumor necrosis factor - alpha ( P01375 ) from human PB - MCs in vitro . In addition , Western blotting and reverse transcription - polymerase chain reaction analysis demonstrated that Q16891 decreased LPS - induced inducible nitric - oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) protein and mRNA expression in RAW 264 . 7 cells . Furthermore , Q16891 treatment also reduced nuclear factor - kappa B ( NF - kappa B ) DNA binding induced by LPS in RAW 264 . 7 cells . To elucidate the molecular mechanism for inhibition of proinflammatory mediators by Q16891 ( 25 microM ) , we have studied the effect of Q16891 on LPS - induced p38 and Q8TCB0 / 42 mitogen - activated protein kinase ( MAPK ) . We observed that the phosphorylation of Q8TCB0 / 42 MAPK in LPS - stimulated RAW 264 . 7 cells was markedly inhibited by Q16891 , whereas activation of p38 MAPK was not affected . These results suggested that Q16891 from lesser galangal suppressed the LPS - induced production of NO , P01584 , and P01375 and expression of P35228 and P35354 gene expression by inhibiting NF - kappa B activation and phosphorylation of Q8TCB0 / 42 MAPK .", "Regulatory effect of nerve growth factor in alpha9beta1 integrin - dependent progression of glioblastoma . In the present study we described the role of alpha9beta1 integrin in glioblastoma progression following its interaction with nerve growth factor ( P01138 ) . The level of expression of alpha9beta1 on astrocytomas is correlated with increased grade of this brain tumor and is highest on glioblastoma , whereas normal astrocytes do not express this integrin . Two glioblastoma cell lines , LN229 and LN18 , that are alpha9beta1 integrin positive and negative , respectively , were used for alpha9beta1 integrin - dependent P01138 - induced tumor progression . P01138 was a significant promoter of promigratory and pro - proliferative activities of glioblastoma cells through direct interaction with alpha9beta1 integrin and activation of MAPK Erk1 / 2 pathway . The level of P01138 increases approximately threefold in the most malignant glioma tissue when compared with normal brain . This increase is related to secretion of P01138 by tumor cells . Specific inhibitors of alpha9beta1 integrin or gene silencing inhibited P01138 - induced proliferation of LN229 cell line to the level shown by LN18 cells . VLO5 promoted alpha9beta1 - dependent programmed cell death by induction of intrinsic apoptosis pathway in cancer cells . LN229 cells were rescued from proapoptotic effect of VLO5 by the presence of P01138 . This disintegrin significantly inhibited tumor growth induced by implantation of LN229 cells to the chorioallantoic membrane ( P62158 ) of quail embryonic model , and this inhibitory effect was significantly abolished by the presence of P01138 . alpha9beta1 integrin appears to be an interesting target for blocking the progression of malignant gliomas , especially in light of the stimulatory effect of P01138 on the development of these tumors and its ability to transfer proapoptotic signals in cancer cells .", "Local secretion of urocortin 1 promotes microvascular permeability during lipopolysaccharide - induced inflammation . P55089 1 ( Ucn1 ) is a neuropeptide that regulates vascular tone and is implicated in both the vascular and immune cell - mediated responses to inflammation . The role of Ucn1 in regulating microvascular permeability has not been determined . We hypothesized that local Ucn1 release promotes microvascular permeability and that this effect augments the local gastrointestinal vascular response to lipopolysaccharide ( LPS ) - induced systemic inflammation . We measured hydraulic ( L ( p ) ) and macromolecule permeability in mesenteric venules . We show that a continuous infusion of 10 (- 7 ) m Ucn1 in a postcapillary venule increased L ( p ) 2 - fold over baseline , as did LPS - induced inflammation . However , simultaneous infusion of Ucn1 and LPS markedly increased L ( p ) by 7 - fold . After local knockdown of Ucn1 using RNA interference , infusion of Ucn1 with LPS resulted in return to 2 - fold increase , confirming that Ucn1 synergistically augments hydraulic permeability during inflammation . LPS and Ucn1 treatment also resulted in increased numbers of interstitial microspheres , which colocalized with CD31 (+) immune cells . Ucn1 activity is mediated through two receptor subtypes , P06850 - R ( 1 ) and P06850 - R ( 2 ) . P06850 - R ( 1 ) receptor blockade exacerbated , whereas P06850 - R ( 2 ) receptor blockade decreased the LPS - induced increase in L ( p ) . Finally , treatment with the c - P05412 N - terminal kinase ( JNK ) antagonist SP600125 during infusion of LPS , but not Ucn1 , decreased L ( p ) . These findings suggest that Ucn1 increases microvascular permeability and acts synergistically with LPS to increase fluid and macromolecule losses during inflammation . Knockdown of endogenous Ucn1 during inflammation attenuates synergistic increases in L ( p ) . Ucn1 ' s effect on L ( p ) is partially mediated by the P06850 - R ( 2 ) receptor and acts independently of the c - P05412 N - terminal kinase signal transduction pathway .", "___MASK58___ prevents growth factor - induced proliferation of bovine retinal endothelial cells under hypoxia . Ocular diseases such as proliferative diabetic retinopathy are the major cause of blindness in industrialized countries . The main pathologic features of these diseases are hypoxia and overproduction of growth factors resulting in pathologic proliferation of endothelial cells and new vessel formation . Particularly , hypoxia and growth factors , such as P15692 , DB01277 , P09038 and TGF beta ( 2 ) , show a complex interaction in the onset and progression of the diseases . Therefore , to date , most therapeutic strategies for proliferative retinopathies have targeted proliferation of endothelial cells evoked by growth factors . Recently , a synthetic analog of somatostatin , octreotide , has been shown to inhibit the proliferation of various cells in vitro , including endothelial cells . In this study , we have investigated the proliferative response of bovine retinal endothelial cells ( BREC ) to growth factors under hypoxic conditions and the modulation by octreotide . We found a dose - dependent increase of cell proliferation with P15692 , DB01277 and P09038 , and inhibition of hypoxia - induced cell proliferation with TGF beta ( 2 ) . Moreover , growth factor - induced , but not hypoxia - induced , cell proliferation was attenuated in the presence of octreotide . In contrast , TGF beta ( 2 ) abolished hypoxia - induced BREC proliferation . Similar to octreotide BIM23027 , a somatastatin receptor subtype 2 ( P30874 ) receptor agonist was able to attenuate the growth factor - induced proliferation of BREC expressing mRNA and protein for P30874 . Therefore , we postulate that octreotide exerts its effects mainly through binding to the P30874 . Taken together , our findings point to octreotide as a promising candidate for the treatment of eye disorders involving growth factor - dependent proliferation of endothelial cells .", "Induction of nerve growth factor and basic fibroblast growth factor mRNA following clenbuterol : contrasting anatomical and cellular localization . RNase protection assay and in situ hybridization were used to analyze the temporal and cellular changes in nerve growth factor ( P01138 ) and basic fibroblast growth factor ( P09038 ) mRNA content evoked by the lipophilic beta - adrenergic receptor agonist clenbuterol in adult rat brain . DB01407 elicited a threefold increase in P01138 mRNA expression which was limited to the cerebral cortex . This increase was maximal at 5 h , still evident by 10 h , and declined to control levels by 24 h . By 10 h P01138 protein was also increased . Elevated P01138 mRNA hybridization following clenbuterol was localized in the superficial cortical layers II and III in large Nissl - pale cells , suggesting that P01138 mRNA induction occurs in neurons . In the same animals , clenbuterol induced a twofold increase in the levels of P09038 mRNA in cerebral cortex and hippocampus . This increase was localized primarily in glial cells as demonstrated by P09038 mRNA hybridization over all cortical regions and by labeling of the stratum lacunosum moleculare of the hippocampus . Our results suggest that enhanced noradrenergic tone regulates expression of these two trophic factors by different synaptic mechanisms and suggest that neurotransmitter ( s ) can coordinate trophic influences on different cell populations .", "[ ___MASK3___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK3___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .", "Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .", "Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK54___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .", "Intrahypothalamic perfusion with interleukin - 1 - beta stimulates the local release of corticotropin - releasing hormone and arginine vasopressin and the plasma adrenocorticotropin in freely moving rats : a comparative perfusion of the paraventricular nucleus and the median eminence . It is almost generally accepted that an acute - phase DB01285 response induced by interleukin ( IL ) - 1 is mediated principally by P06850 release from the hypothalamus . However , the precise cellular site of action of IL - 1 in activating the P06850 neuronal system remains to be determined . Two likely candidates comprise the paraventricular nucleus ( PVN ) where P06850 neuronal cell bodies are located , and the median eminence ( ME ) where their nerve endings are terminated . Therefore , in this study we performed a comparative perfusion of the ME and the PVN with increasing concentrations of recombinant human P01584 utilizing the push - pull perfusion technique in freely moving rats . We measured the plasma DB01285 and ME and PVN levels of P06850 , and also of AVP , because AVP , another secretagogue of DB01285 , has its cell body in the PVN and axon terminals partly in the ME . In control groups , the ME or the PVN was perfused with artificial cerebrospinal fluid between 12 : 00 and 15 : 00 h , and perfusates and blood samples were collected every 20 min . In the other groups , either the ME or the PVN was perfused with three increasing concentrations ( 0 . 1 , 1 . 0 , and 10 nM ) of recombinant human P01584 dissolved in artificial cerebrospinal fluid only between 13 : 00 and 14 : 00 h with all the other procedures run in the same way as in the controls . In the control perfusions , the hypothalamic release of P06850 and AVP and the plasma DB01285 did not change significantly during the entire period of observation . ( ABSTRACT TRUNCATED AT 250 WORDS )", "The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .", "Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors . Neurotrophins and other neurotrophic factors have been shown to support the survival and differentiation of many neuronal populations of the central and peripheral nervous system . Therefore , administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chronic brain disorders . However , the delivery of neurotrophic factors to the brain is one of the largest obstacles in the development of effective therapy for neurodegenerative disorders , because these proteins are not able to cross the blood - brain barrier . The induction of growth factor synthesis in the brain tissue by systemically administered lipophilic drugs , such as beta - adrenoceptor agonists , shown to increase endogenous nerve growth factor ( P01138 ) synthesis in the brain , would be an elegant way to overcome these problems of application . Stimulation of beta - adrenoceptors with clenbuterol led to increased P01138 synthesis in cultured central nervous system ( CNS ) cells and rat brain tissue . DB01407 - induced P01138 expression was reduced to the control levels by coadministration of beta - adrenoceptor antagonist propranolol . Furthermore , clenbuterol protected rat hippocampal neurons subjected to excitotoxic damage . The neuroprotective effect of clenbuterol in vitro depended on increased P01138 synthesis , since the neuroprotection was abolished by P01138 antisense oligonucleotide as well as by antibodies directed against P01138 itself . In vivo , clenbuterol protected rat hippocampus in a model of transient forebrain ischemia and reduced the infarct volume in a rat model of permanent middle cerebral artery occlusion ( MCAo ) . The neuroprotective effect of clenbuterol in vivo was accompanied by enhanced P01138 synthesis in brain tissue . These findings support our hypothesis that orally active P01138 inducers may have a potential as therapeutic agents for the treatment of neurodegenerative disorders and stroke .", "The P08908 receptor agonist Bay x 3702 inhibits apoptosis induced by serum deprivation in cultured neurons . We examined whether the highly selective P08908 receptor agonist (-)-( R )- 2 - [ 4 - [ [ ( 3 , 4 - dihydro - 2H - 1 - benzopyran - 2 - yl ) methyl ] - amino ] butyl ] - 11 , 2 - benz - isothiazol - 3 ( 2H )- one 1 , 1 - dioxide monohydrochloride ( Bay x 3702 ) could inhibit neuronal apoptosis induced by serum deprivation . In primary cultures of chick embryonic neurons and in mixed neuronal / glial cultures from neonatal rat hippocampus , Bay x 3702 ( 1 microM ) rescued serum - deprived neurons from apoptosis . The antiapoptotic effect of Bay x 3702 ( 1 microM ) was blocked in chick neurons by the selective P08908 receptor antagonists 4 - iodo - N -[ 2 -[ 4 -( methoxyphenyl )- 1 - piperazin ] ethyl ]- N - 2 - pyridinyl - be nzamide hydrochloride ( p - MPPI , 10 microM ) and 4 -[ 3 - benzotriazol - 1 - propyl ]- 1 -( 2 - methoxyphenyl )- piperazine ( BPMP , 10 microM ) as well as by anti - nerve growth factor ( anti - P01138 ) antibodies and in rat neurons by N -[ 2 - 4 -( 2 - methoxy )- 1 - piperazinyl ] ethyl ] - N -( 2 - pyridinyl ) cyclohexane - carbo xamide trihydrochloride ( WAY 100635 , 10 microM ) . We found only under control conditions ( medium with serum ) , but not in serum - deprived cultures , that P01138 secretion was 6 - fold increased by Bay x 3702 ( 1 microM ) compared to untreated cultures . Additionally , Bay x 3702 ( 4 microg / kg i . v . ) , infused within a period of 4 h , significantly increased the P01138 content of the rat hippocampus , but not of the striatum . In summary , our data suggest that Bay x 3702 inhibited growth factor withdrawal - induced apoptosis by the stimulation of P08908 receptors and that the P01138 signalling pathway is involved in the mechanism of action .", "Evaluation of human astrocytoma and glioblastoma cell lines for nerve growth factor release . Nerve growth factor ( P01138 ) prevents degeneration of cholinergic neurons in the central nervous system ( CNS ) , and has potential as a therapeutic treatment for Alzheimer ' s disease . The inability of P01138 to cross the blood - brain barrier has prompted pharmacological approaches investigating peripherally administered compounds that stimulate release of endogenous P01138 . This study describes the P01138 - releasing properties of six human astrocytoma and glioblastoma cell lines ( SW 1088 , SW 1783 and CRL 1718 astrocytomas , and U - 138 , U - 373 , and T98G glioblastomas ) . Using a highly specific two - site ELISA for human P01138 , basal P01138 release could be detected in all cell lines , with the lowest level in the T98G line ( approximately 80 pg P01138 / ml ) . Cell lines tested with a variety of compounds for 24 h in serum - free media demonstrated stimulation of P01138 release by distinct mechanisms . P01138 levels were markedly elevated ( up to 8 - fold above vehicle - treated cells ) when stimulated with the cytokine interleukin - 1 beta ( P01584 ) . Phorbol ester stimulated P01138 release 4 - fold . DB01407 , 4 - methyl catechol , and propentofylline had little activity , while 6 -( 4 - hydroxybutyl )- 2 , 3 , 5 ,- trimethyl - 1 , 4 , benzoquinone ( DB01157 ) , dexamethasone and 1 , 25 - dihydroxyvitamin D3 elevated P01138 levels 3 - fold . These data indicate differences in the ability of human astrocytoma and glioblastoma cells to release P01138 when stimulated with mechanistically distinct compounds .", "Multiple antigenic polypeptide composed of heparanase B ‑ cell epitopes shrinks human hepatocellular carcinoma in mice . The purpose of this study was to evaluate the anti ‑ growth effect of the self ‑ designed multiple antigenic polypeptide ( Q96HU1 ) vaccine comprising B ‑ cell epitopes of heparanase ( Q9Y251 ) on HCC97 ‑ H hepatocellular carcinoma ( HCC ) in mice . The polyclonal antibodies against the B ‑ cell epitopes of Q9Y251 were prepared by immunizing rabbits with freshly synthesized Q96HU1 vaccine . HCC ‑ bearing models were constructed on BALB / c nude mice . Anti ‑ Q96HU1 antibodies were administrered to the models to assess the effects on Q9Y251 activity , HCC growth , the expression of P15692 / P09038 and the value of micro ‑ vessel density ( P53602 ) . The anti ‑ Q96HU1 antibodies were harvested , purified and identified . These antibodies were able to specifically bind with the dominant epitopes of the precursor protein and large subunit monomer of Q9Y251 , decrease Q9Y251 activity , suppress the expressions of P15692 and P09038 , reduce the P53602 , and markedly shrink the HCC volume . Based on these findings , Q96HU1 vaccine based on the B ‑ cell epitopes of Q9Y251 seemed to provide theoretical evidence for further study of the synthesized Q9Y251 Q96HU1 vaccine in the treatment of HCC .", "___MASK58___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .", "Fibroblast growth factor - 2 in hyperplastic pituitaries of D2R knockout female mice . P14416 ( D2R ) knockout ( KO ) female mice develop chronic hyperprolactinemia and pituitary hyperplasia . Our objective was to study the expression of the mitogen fibroblast growth factor ( P09038 ) and its receptor , P11362 , comparatively in pituitaries from KO and wild - type ( WT ) female mice . We also evaluated P09038 subcellular localization and P09038 effects on pituitary function . P09038 - induced prolactin release showed a similar response pattern in both genotypes , even though basal and P09038 - stimulated release was higher in KO . P09038 stimulated pituitary cellular proliferation ( MTS assay and [( 3 ) H ] thymidine incorporation ) , with no differences between genotypes . P09038 concentration ( measured by ELISA ) in whole pituitaries or cultured cells was lower in KO ( P < 0 . 00001 and 0 . 00014 ) . Immunofluorescence histochemistry showed less P09038 in pituitaries from KO females and revealed a distinct P09038 localization pattern between genotypes , being predominantly nuclear in KO and cytosolic in WT pituitaries . Finally , P09038 could not be detected in the conditioned media from pituitary cultures of both genotypes . P11362 levels ( Western blot and immunohistochemistry ) were higher in pituitaries of KO . Basal concentration of phosphorylated ERKs was lower in KO cells ( P = 0 . 018 ) . However , when stimulated with P09038 , a significantly higher increment of P29323 phosphorylation was evidenced in KO cells ( P < or = 0 . 02 ) . We conclude that disruption of the D2R caused an overall decrease in pituitary P09038 levels , with an increased distribution in the nucleus , and increased P11362 levels . These results are important in the search for reliable prognostic indicators for patients with pituitary dopamine - resistant prolactinomas , which will make tumor - specific therapy possible .", "Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK69___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .", "Combined anti - inflammatory effects of β2 - adrenergic agonists and DB05876 inhibitors on astrocytes by upregulation of intracellular DB02527 . Inflammation is an important hallmark of all neurodegenerative diseases and activation of different glial populations may be involved in the progression of some of these disorders . Especially , the activation of astroglia can lead to long - term detrimental morphological changes , such as scar formation . Therefore , improved strategies to modulate inflammation in these cells are currently being investigated . We investigated the interaction of phosphodiesterase ( PDE ) 4 inhibitors , such as rolipram , with other agents raising cellular DB02527 levels . When used alone , none of the DB05876 inhibitors increased DB02527 levels . The adenylate cyclase activator forskolin , the β ( 2 )- adrenergic agonist clenbuterol and the mixed β ( 1 )/ β ( 2 )- adrenergic agonist isoproterenol increased intracellular DB02527 levels of cortical murine astrocytes . This increase was synergistically elevated by rolipram or the DB05876 inhibitor RO - 201724 , but not by inhibition of PDE3 . Inflammatory stimulation of the cells with the cytokines P01375 - α , IL - 1β and IFN - γ strongly induced Q07343 and augmented overall DB05876 activity , while PDE3 activity was low . DB01407 and forskolin caused downregulation of cytokines and chemokines such as P05231 and P13500 . This effect was further enhanced by rolipram , but not by the PDE3 inhibitor milrinone . The DB02527 - raising drug combinations attenuated the upregulation of P01375 - α and P05231 mRNA and the secretion of P05231 , but did not affect initial NF - κB signalling triggered by the stimulating cytokines . These results indicate that DB05876 may be a valuable anti - inflammatory target in brain diseases , especially under conditions associated with stimulation of DB02527 - augmenting astrocyte receptors as is observed by clenbuterol treatment .", "Transcriptional regulation of cyclo - oxygenase expression : three pillars of control . Blocking cyclo - oxygenase ( P36551 ) isoform activities with non - steroidal anti - inflammatory drugs ( NSAIDS ) is widely employed in the treatment of arthritis . These agents also hold great promise in the context of pre and post - neoplastic diseases such as colorectal cancer ( CRC ) . Nevertheless , issues of isoform specificity and delivery necessitate the exploration of other strategies to specifically block expression of the P36551 genes . Approaches that target gene transcription may complement enzyme inhibition . Thus , understanding the regulation of P36551 isoform transcription may improve the specific inhibition of expression . Three tiers of transcriptional regulation are evident : initiation , alternative splicing and messenger RNA stability . Transcription factors that activate P35354 expression are elevated in certain disease states and emergency responses such as infection and are therefore potential targets . These factors include C / EBP - beta , phospho - CREB , NF - P05231 , P05412 , NFkB , and TCF - 4 / Q9UJU2 . In this review we highlight another factor , c - P10242 as a key P35354 regulator in CRC . Alternative exon usage is another tier of regulation that has not received much attention . For instance , P23219 splice variants ( also known as P36551 - 3 and PCOX - 1a ) may broaden the spectrum of P36551 activities in disease . Similarly , whilst mRNA stability is clearly modulated by steroids in the case of P35354 , the wider implications of targeting mRNA stability have not been afforded the same attention . Finally , it seems that some NSAIDS exert part of their action directly on P35354 transcriptional regulation explaining why such agents display greater effects on this isoform than enzyme inhibition data would suggest .", "Effect of isoproterenol and dexamethasone on the lipopolysaccharide induced expression of CD11b on bovine neutrophils . The present experiments investigate the changes in expression of CD11b on bovine neutrophils and its modulation by isopropylnoradrenaline ( IPN , isoproterenol ) , dexamethasone ( DX ) , phenylephrine ( alpha - agonist ) and clenbuterol ( beta - agonist ) . Both IPN and DX caused a dose - dependent inhibition of LPS - induced CD11b expression . A combination of IPN and DX elicited a synergistical decrease of the CD11b expression . DB01407 mimicked the effect of IPN , whereas phenylephrine did not . The effect of IPN and DX could at least partly be mediated through a decreased P01375 production by monocytes since tumor necrosis factor - alpha ( P01375 ) is shown to mediate a dose - dependent CD11b up - regulation . Stimulation of stress hormone receptors partly immuno - suppresses neutrophil functions by inhibition of CD11b expression on the neutrophil surface upon LPS stimulation . This inhibition is probably related to a decrease in P01375 production . A similar mechanism of immuno - suppression could contribute to the higher susceptibility of cattle to Gram - negative bacterial infections of the udder and lung during periods of stress .", "The AP - 1 transcription factor Batf controls T ( H ) 17 differentiation . P05412 ( AP - 1 , also known as P05412 ) transcription factors are dimers of P05412 , P01100 , O75444 and activating transcription factor ( P39905 ) family proteins characterized by basic region and leucine zipper domains . Many AP - 1 proteins contain defined transcriptional activation domains , but Q16520 and the closely related Q9NR55 ( refs 2 , 3 ) contain only a basic region and leucine zipper , and are considered to be inhibitors of AP - 1 activity . Here we show that Batf is required for the differentiation of Q16552 - producing T helper ( T ( H ) 17 ) cells . T ( H ) 17 cells comprise a P01730 (+) T - cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity . Batf (-/-) mice have normal T ( H ) 1 and T ( H ) 2 differentiation , but show a defect in T ( H ) 17 differentiation , and are resistant to experimental autoimmune encephalomyelitis . Batf (-/-) T cells fail to induce known factors required for T ( H ) 17 differentiation , such as RORgamma t ( encoded by Rorc ) and the cytokine Q9HBE4 ( refs 14 - 17 ) . Neither the addition of Q9HBE4 nor the overexpression of RORgamma t fully restores Q16552 production in Batf (-/-) T cells . The Il17 promoter is Q16520 - responsive , and after T ( H ) 17 differentiation , Q16520 binds conserved intergenic elements in the Il17a - Il17f locus and to the Il17 , Il21 and Il22 ( ref . 18 ) promoters . These results demonstrate that the AP - 1 protein Q16520 has a critical role in T ( H ) 17 differentiation .", "Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK28___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .", "Pharmacological modulation of nerve growth factor synthesis : a mechanistic comparison of vitamin D receptor and beta ( 2 )- adrenoceptor agonists . Increasing nerve growth factor ( P01138 ) in the PNS is a rational strategy for treating certain neurodegenerative disorders . The present studies were undertaken to compare two compounds , a vitamin D ( 3 ) analogue ( CB1093 ) with minimal calcaemic effects , and clenbuterol , a long - acting beta ( 2 )- adrenoceptor agonist , both of which induce P01138 synthesis in vivo . DB01407 caused significant increases in both P01138 mRNA and protein in 3T3 cells ; with maxima at 10 nM and at 8 - 12 h exposure . Effects of clenbuterol on P01138 mRNA were antagonized by propranolol . Mobility shift assays on whole cell extracts showed that clenbuterol increased P05412 binding in 3T3 cells prior to increasing P01138 synthesis . DB01407 was without effect on P01138 mRNA levels in L929 cells , whereas CB1093 caused significant increases in both P01138 mRNA and protein levels in both 3T3 and L929 cells . Stimulation was almost maximal at 24 h exposure and was sustained for at least 72 h . The magnitude of the increase was much greater in L929 ( 700 % increase ) than in 3T3 cells ( 80 % ) . Binding to the vitamin D nuclear receptor ( P11473 ) , which acts as a transcription factor itself , was increased as early as 30 min after exposure to of CB1093 and maintained up to 24 h . Increased P11473 binding preceded increased P01138 mRNA . A 150 % increase in AP - 1 binding was also evident . This study demonstrates that CB1093 and clenbuterol stimulate P01138 levels in vitro and that AP - 1 binding could be a commonality between the mechanism of P01138 induction of these two compounds .", "Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .", "Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .", "Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK26___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .", "The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease . Superantigens have been implicated in a number of diseases including Kawasaki disease ( KD ) , a multi - system vasculitis resulting in coronary artery aneurysms . We have characterized a murine disease model in which coronary arteritis is induced by a novel superantigen found in Lactobacillus casei cell wall extract ( LCWE ) . Using this animal model of KD , we have identified three pathogenic steps leading to coronary artery aneurysm formation . These steps include T cell activation and proliferation , production of the proinflammatory cytokine tumour necrosis factor ( P01375 ) - α and up - regulation of matrix metalloproteinase 9 ( P14780 ) , an elastolytic protease . In addition to their cholesterol - lowering effects , 3 - hydroxy - 3 - methylglutaryl ( HMG ) coenzyme A ( DB01992 ) reductase inhibitors ( statins ) have pleotropic immunomodulatory properties . Thus , we examined the effect of atorvastatin in modulating each of these three critical pathogenic processes leading to aneurysm formation in the disease model . ___MASK54___ inhibited lymphocyte proliferation in response to superantigen stimulation in a dose - dependent manner . This inhibition was also observed for production of soluble mediators of inflammation including interleukin ( IL ) - 2 and P01375 - α . The inhibitory effect on proliferation was rescued completely by mevalonic acid , confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of P04035 . Similarly , P01375 - α - induced P14780 production was reduced in a dose - dependent manner in response to atorvastatin . Inhibition of extracellular - regulated kinase ( P29323 ) phosphorylation appears to be the mechanism responsible for inhibition of P14780 production . In conclusion , atorvastatin is able to inhibit critical steps known to be important in the development of coronary aneurysms , suggesting that statins may have therapeutic benefit in patients with KD .", "Evaluation of cytokine production by equine alveolar macrophages exposed to lipopolysaccharide , Aspergillus fumigatus , and a suspension of hay dust . OBJECTIVE : To evaluate cytokine production by equine alveolar macrophages after exposure to lipopolysaccharide ( LPS ) , Aspergillus fumigatus , and hay dust , and determine the effect of clenbuterol on the cytokine response . ANIMALS : 6 horses . PROCEDURE : Alveolar macrophages were exposed to PBS solution ( negative control ) , LPS , hyphae and conidia of Aspergillus fumigatus ( AF ) , or a suspension of hay dust ( Q86SQ9 ) and incubated for 24 hours at 37 degrees C . Concentrations of tumor necrosis factor ( P01375 ) - alpha and interleukin ( IL ) - 1beta were measured in the supernatant . The procedure was repeated with cells that were concurrently incubated with 0 . 5 microM clenbuterol . RESULTS : Exposure to Q86SQ9 and AF significantly increased production of P01375 by equine alveolar macrophages . The increase in P01375 produced in response to Q86SQ9 and AF was 5 and 7 times as great , respectively , as the increase measured in response to LPS . The concentration of IL - 1beta in the supernatant was significantly increased after exposure of cells to AF . DB01407 was effective at inhibiting P01375 production by cells exposed to LPS , Q86SQ9 , or AF . CONCLUSIONS AND CLINICAL RELEVANCE : Increased production of P01375 and IL - 1 indicated that the pro - inflammatory cytokines produced by alveolar macrophages in response to allergens may play a role in recurrent airway obstruction ( O75106 ) in horses . Equine alveolar macrophages are not only a primary pulmonary defense mechanism but may also influence the pathogenesis of equine O75106 . The beta2 - adrenoceptor agonist clenbuterol , a drug that is commonly used for treatment of equine O75106 , promotes immediate bronchodilation and may also contribute to downward modulation of the inflammatory response .", "Sexually dimorphic stress and pro - inflammatory cytokine responses to an intravenous corticotropin - releasing hormone challenge of Brahman cattle following transportation . This study was designed to characterize potential sexually dimorphic stress and immunological responses following a corticotropin - releasing hormone ( P06850 ) challenge in beef cattle . Six female ( heifers ) and six male ( bulls ) Brahman calves ( 264 ± 12 d of age ) were administered P06850 intravenously ( 0 . 5 µg of P06850 / kg body mass ) after which serum concentrations of cortisol increased from 0 . 5 h to 4 h . From 1 h to 4 h after P06850 administration , serum cortisol concentrations were greater in heifers than in bulls . In all cattle , increased serum concentrations of P01375 - α , P05231 and IFN - γ were observed from 2 . 5 h to 3 h after P06850 , with greater concentrations of IFN - γ and P05231 in heifers than bulls . Heifer total leukocyte counts decreased 1 h after P06850 administration , while bull leukocyte counts and percent neutrophils decreased 2 h after P06850 administration . Heifers had greater rectal temperatures than bulls , yet rectal temperatures did not change following administration of P06850 . There was no effect of P06850 administration on heart rate . However , bulls tended to have increased heart rate 2 h after P06850 administration than before P06850 . Heifer heart rate was greater than bulls throughout the study . These data demonstrate that acute P06850 administration can elicit a pro - inflammatory response , and cattle exhibit a sexually dimorphic pro - inflammatory cytokine and cortisol response to acute P06850 administration .", "Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .", "DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "P04035 inhibitors up - regulate anti - aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age - related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age - suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real - time RT - PCR . ___MASK54___ and pitavastatin increased the expression of klotho mRNA in a dose - dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho - kinase by Y27632 up - regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down - regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II - induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over - expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .", "Predictive value of circulating interleukin - 6 and heart - type fatty acid binding protein for three months clinical outcome in acute cerebral infarction : multiple blood markers profiling study . INTRODUCTION : There is no single blood marker for predicting the prognosis in ischemic stroke . A combination of multiple blood markers may enhance the ability to predict long - term outcome following ischemic stroke . METHODS : Blood concentrations of neuronal markers ( neuron - specific enolase , visinin - like protein 1 , heart type fatty acid binding protein ( hFABP ) and neuroglobin ) , astroglial markers ( P04271 and glial fibrillary acidic protein ) , inflammatory markers ( P05231 , P01375 - α , and P02741 ) , blood - brain barrier marker ( matrix metalloproteinase 9 ) , and haemostatic markers ( D - dimer and P05121 ) were measured within 24 hours after stroke onset . The discrimination and reclassification for favorable and poor outcome were compared after adding individual or a combination of blood markers to the clinical model of stroke outcome . RESULTS : In multivariate analysis , natural log - transformed ( log ) P05231 ( odds ratio ( OR ) : 1 . 75 , 95 % CI : 1 . 25 to 2 . 25 , P = 0 . 001 ) and loghFABP ( OR : 3 . 23 , 95 % CI : 1 . 44 to 7 . 27 , P = 0 . 005 ) were independently associated with poor outcome . The addition of a single blood marker to the clinical model did not improve the discriminating ability of the clinical model of stroke outcome . However , the addition of the combination of logIL - 6 and loghFABP to the clinical model showed improved discrimination ( area under receiver operating characteristic ( AUROC ) curve : 0 . 939 versus 0 . 910 , P = 0 . 03 ) and reclassification performance ( net reclassification improvement index : 0 . 18 , P = 0 . 005 ) . CONCLUSIONS : A combination of circulating P05231 and hFABP level has an additive clinical value for the prediction of stroke outcome .", "FGF and P29323 signaling coordinately regulate mineralization - related genes and play essential roles in osteocyte differentiation . To examine the roles of FGF and P29323 MAPK signaling in osteocyte differentiation and function , we performed microarray analyses using the osteocyte cell line MLO - Y4 . This experiment identified a number of mineralization - related genes that were regulated by P09038 in an P29323 MAPK - dependent manner . Real - time PCR analysis indicated that P09038 upregulates Ank , Enpp1 , Mgp , Slc20a1 , and Dmp1 in MLO - Y4 cells . Consistent with this observation , the selective FGF receptor inhibitor PD173074 decreased Ank , Enpp1 , Slc20a1 , and Dmp1 mRNA expression in mouse calvaria in organ culture . Since Dmp1 plays a central role in osteocyte differentiation and mineral homeostasis , we further analyzed FGF regulation of Dmp1 . Similar to P09038 , Q9GZV9 upregulated Dmp1 expression in MLO - Y4 cells in the presence of Q9UEF7 . Furthermore , increased extracellular phosphate levels partially inhibited P09038 - induced upregulation of Dmp1 mRNA expression , suggesting a coordinated regulation of Dmp1 expression by FGF signaling and extracellular phosphate . In MLO - Y4 osteocytes and in MC3T3E1 and primary calvaria osteoblasts , U0126 strongly inhibited both basal expression of Dmp1 mRNA and P09038 - induced upregulation . Consistent with the in vitro observations , real - time PCR and immunohistochemical analysis showed a strong decrease in Dmp1 expression in the skeletal elements of P27361 (-/-) ; P28482 ( flox / flox ) ; Prx1 - Cre mice . Furthermore , scanning electron microscopic analysis revealed that no osteocytes with characteristic dendritic processes develop in the limbs of P27361 (-/-) ; P28482 ( flox / flox ) ; Prx1 - Cre mice . Collectively , our observations indicate that FGF signaling coordinately regulates mineralization - related genes in the osteoblast lineage and that P29323 signaling is essential for Dmp1 expression and osteocyte differentiation .", "The effects of adulthood olanzapine treatment on cognitive performance and neurotrophic factor content in male and female rats neonatally treated with quinpirole . Male and female Sprague - Dawley rats were administered quinpirole ( 1 mg / kg , i . p . ) or saline once daily from postnatal day ( P ) 1 to P21 . This drug treatment has been shown to produce long - term priming of the D2 receptor . Beginning on P62 , rats were administered the atypical antipsychotic olanzapine ( 2 . 5 mg / kg ) or saline twice daily ( i . p . ) for 28 days . One day after olanzapine treatment ceased , rats were tested on the place and match - to - place versions of the Morris water maze ( MWM ) for seven consecutive days . P14416 priming was verified through a yawning behavioural test , a D2 receptor - mediated event , before olanzapine was administered as well as after olanzapine treatment and behavioural testing were complete . Results showed that neonatal quinpirole treatment induced D2 priming that was eliminated by olanzapine treatment . On the MWM place version , D2 - primed rats demonstrated a significant impairment that was eliminated by olanzapine treatment , but olanzapine treatment to animals neonatally treated with saline produced a significant deficit on the place version of the MWM . There were no significant deficits on the match - to - place version . Brain tissue analyses revealed that neonatal quinpirole treatment produced a significant decrease in hippocampal P01138 , P23560 and P28329 that was eliminated by olanzapine treatment . Neonatal quinpirole treatment produced a significant decrease in P23560 and P28329 in the frontal cortex that was unaffected by olanzapine treatment . These results show that olanzapine eliminates D2 receptor priming and cognitive impairment and also alleviates decreases in neurotrophins and acetylcholinergic markers produced by D2 priming in the hippocampus .", "Anxiety - like behavior in the elevated - plus maze tests and enhanced IL - 1β , P05231 , NADPH oxidase - 1 , and P35228 mRNAs in the hippocampus during early stage of adjuvant arthritis in rats . We studied anxiety - like behavior in the elevated plus - maze ( EPM ) tests in male Lewis rats on days 2 and 4 of adjuvant arthritis ( AA ) . In plasma we analyzed P02741 ( CRP ) , albumin , DB01285 , corticosterone , in the hippocampus the mRNA expression of interleukin - 1β ( IL - 1β ) , interleukin - 6 ( P05231 ) , corticotrophin releasing factor ( P06850 ) , NADPH oxidases Q9Y5S8 and P04839 , and inducible NO - synthase ( P35228 ) . EPM tests showed a higher anxiety index in AA rats on days 2 and 4 and reduction of total entries . On days 2 and 4 we found reduced plasma albumin , enhanced CRP , DB01285 and corticosterone , and in the hippocampus enhanced mRNA for Q9Y5S8 and IL - 1β in AA rats , on day 4 we found enhanced mRNAs for P35228 and P05231 , and reduced mRNA for P06850 . The mRNA for P04839 did not change on any experimental day . These results suggest enhanced anxiety , as well as locomotor impairment during the early phase of AA that correlate with enhanced mRNA expressions of parameters of oxidative stress Q9Y5S8 , P35228 , and inflammatory cytokines IL - 1β and P05231 in the hippocampus .", "P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .", "The β2 - adrenoceptor agonist clenbuterol elicits neuroprotective , anti - inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity . Excitotoxicity is a mechanism of neuronal cell death implicated in a range of neurodegenerative conditions . Systemic administration of the excitotoxin kainic acid ( KA ) induces inflammation and apoptosis in the hippocampus , resulting in neuronal loss . Evidence indicates that stimulation of glial β ( 2 )- adrenoceptors has anti - inflammatory and neurotrophic properties that could result in neuroprotection . Consequently , in this study we examined the effect of the β ( 2 )- adrenoceptor agonist clenbuterol on KA - induced inflammation , neurotrophic factor expression and apoptosis in the hippocampus . DB01407 ( 0 . 5mg / kg ) was administered to rats one hour prior to KA ( 10mg / kg ) . Epileptic behaviour induced by KA was assessed for three hours following administration using the Racine scale . Twenty - four hours later TUNEL staining in the P07451 hippocampal subfield and hippocampal caspase - 3 activity was assessed to measure KA - induced apoptosis . In addition , expression of inflammatory cytokines ( IL - 1β and IFN - γ ) , inducible nitric oxide synthase ( P35228 ) , kynurenine pathway enzymes indolamine 2 , 3 - dioxygenase ( P14902 ) and kynurenine monooxygenase ( O15229 ) , the microglial activation marker CD11b , and the neurotrophins P23560 and P01138 were quantified in the hippocampus using real - time PCR . Whilst clenbuterol treatment did not significantly alter KA - induced epileptic behavior it ameliorated KA - induced apoptosis , and this neuroprotective effect was accompanied by reduced inflammatory cytokine expression , reduced expression of P35228 , P14902 , O15229 and CD11b , coupled with increased P23560 and P01138 expression in KA - treated rats . In conclusion , the β ( 2 )- adrenoceptor agonist clenbuterol has anti - inflammatory and neurotrophic actions and elicits a neuroprotective effect in the KA model of neurodegeneration .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "P23219 behaves as a delayed response gene in PC12 cells differentiated by nerve growth factor . Treatment of PC12 cells with nerve growth factor ( P01138 ) results in a differentiation program characterized by expression of immediate early and delayed response genes . In this program , morphological changes such as neurite extension are accompanied by phenotypic changes in enzyme expression , including an increased capacity for prostaglandin synthesis . Cyclooxygenase ( P36551 ) , the enzyme responsible for prostanoid production , exists as two isoforms : constitutive P23219 and inducible P35354 . We report that P23219 behaves as a delayed response gene in PC12 cells exposed to P01138 . Six hours following P01138 treatment , P23219 mRNA levels were elevated in PC12 cells , reaching nearly 5 - fold above basal levels at 12 h . This increase was blocked by cycloheximide and was accompanied by concomitant increases in P23219 protein and enzyme activity . P23219 protein remained elevated for at least 10 days and localized to the cytoplasm and neurites of P01138 - differentiated PC12 cells . Moreover , basic fibroblast growth factor , but not epidermal growth factor , caused similar increases in P23219 , which is consistent with expression characteristics of other delayed response genes in PC12 cells . This is the first example of neurotrophic factor regulation of cyclooxygenase and may have important implications for determination of the differentiated phenotype in PC12 cells ." ]

[ "___MASK12___", "___MASK13___", "___MASK26___", "___MASK28___", "___MASK3___", "___MASK54___", "___MASK58___", "___MASK65___", "___MASK69___" ]

[ "Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK65___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK65___ .", "Combination of Lipitor and DB00482 inhibits prostate cancer VCaP cells in vitro and in vivo . BACKGROUND / AIM : Lipitor is a cholesterol - lowering drug and DB00482 is a P35354 inhibitor . We investigated the effects of Lipitor and DB00482 on human prostate cancer VCaP cells cultured in vitro and grown as orthotopic xenograft tumors in SCID mice . MATERIALS AND METHODS : Apoptosis was measured by morphological assessment and caspase - 3 assay . Nuclear factor - kappa B ( NF - κB ) activation was determined by luciferase reporter assay . B - cell lymphoma - 2 ( Bcl2 ) was measured by western blotting and immunohistochemistry . Orthotopic prostate tumors were monitored by the IVIS imaging system . RESULTS : the combination of Lipitor and DB00482 had stronger effects on the growth and apoptosis of VCaP cells than did either drug alone . The combination more potently inhibited activation of NFκB and expression of Bcl2 than either drug alone . The growth of orthotopic VCaP prostate tumors was strongly inhibited by treatment with the drug combination . CONCLUSION : Administration of Lipitor and DB00482 in combination may be an effective strategy for inhibiting the growth of prostate cancer .", "P35354 inhibitors -- IBC conference . 12 - 13 April 1999 , Coronado , CA , USA . The introduction of celecoxib ( DB00482 , Figure 1 ; GD Searle and Co ) as the first cyclooxygenase ( P36551 ) 2 selective inhibitor in the US and the expected introduction of rofecoxib ( Vioxx ; Merck and Co Inc ) as the first P35354 inhibitor with an acute pain indication , has prompted interest in this class of drugs as a possible therapeutic improvement on dual P23219 / P35354 inhibitor NSAIDs , currently on the market . Recognition that the P35354 enzyme may have a broader role than pain and inflammation has led to studies investigating the efficacy of P35354 inhibitors for Alzheimer ' s disease ( AD ) , stroke , cardiovascular disease and colon cancer . Speakers at the second annual conference sponsored by IBC , addressed issues ranging from the basic concepts of P35354 specificity versus selectivity , pathways and regulatory factors related to P35354 expression , the principles underlying the possible broad implications of the P35354 mechanisms , as well as summaries of recently completed clinical trials supporting the clinical efficacy and safety of P35354 inhibitors in humans . The timeliness of this meeting is emphasized by the recent approval of rofecoxib by the FDA Arthritis Advisory panel and the initial reports in the media of toxicity attributed to celecoxib . Preclinical and limited clinical data presented suggest possible therapeutic roles for selective P35354 inhibitors in neurodegeneration due to both AD and stroke , the prevention and treatment of colon cancer , prevention of premature labor , as well as pain and inflammation .", "[ A pop - up menu linked to a computerized drug prescribing system . Prescribing pattern ' s feedback via a simple and quick method ] . It takes time for a GP to acquire sufficient experience of a new drug to be able to prescribe competently . This article describes a project studying the use of computerized records to afford a group of GP ' s swift feedback on recently introduced drugs of special interest . In the south - east of Sweden a network of primary health care centers has been created in two neighboring counties . The pharmacies of the region are also taking part . When new drugs of particular interest are introduced , each participating GP will automatically see a pop - up menu , asking questions pertaining to each computer - assisted prescription . In the pharmacies , patients are given a questionnaire regarding their expectations with respect to the drug . In this way it will be possible to provide the individual GP swift feedback from a large number of colleagues and patients concerning the drug ' s effectiveness in clinical practice . We have now been studying the P35354 inhibitors rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) . Results show that a pop - up menu used in this way provides the general practitioner quick feed - back on prescribing behavior as well as drug effectiveness in clinical practice .", "P35354 inhibitors and cancer therapeutics : potential roles for inhibitors of P35354 in combination with cytotoxic therapy : reports from a symposium held in conjunction with the Radiation Therapy Oncology Group June 2001 Meeting . Tumor growth and angiogenesis are interdependent . Cyclooxygenase ( P36551 ) catalyzes the synthesis of prostaglandins ( PGs ) from arachidonic acid . Nonsteroidal antiinflammatory drugs ( NSAIDs ) inhibit P36551 - mediated synthesis of PGs . Although P23219 is constitutively expressed in a wide range of tissues , P35354 is cytokine inducible . Enhanced P35354 expression has been attributed a key role in the development of inflammation and related processes observed in pathologically altered disease states . Two specific P35354 inhibitors , namely , rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) , both oral agents and FDA approved , have been shown preclinically and clinically to have efficacy comparable to that of NSAIDs for relief of pain and inflammation in osteoarthritis , with decreased risk of gastrointestinal damage . Significant preclinical evidence strongly supports the potential role for these inhibitors for the treatment of cancer . On June 29 , 2001 , the Radiation Therapy Oncology Group ( www . rtog . org ) , a National Cancer Institute - sponsored cooperative group , held a 1 - day symposium focusing on the potential role of inhibitors of P35354 in the treatment of cancer . This issue of the American Journal of Clinical Oncology contains the summary of those presentations .", "Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .", "Modulation of pulmonary leukotriene B4 production by cyclooxygenase - 2 inhibitors and lipopolysaccharide . PURPOSE : Emerging data continue to link carcinogenesis to inflammatory events involving the eicosanoid metabolic pathways . We therefore evaluated the effects of cyclooxygenase ( P36551 ) - 2 inhibition on leukotriene ( LT ) B ( 4 ) synthesis in the lungs of active smokers , as part of a pilot lung cancer chemoprevention study with celecoxib ( DB00482 ) , an oral P35354 inhibitor . EXPERIMENTAL DESIGN : Bronchoalveolar lavage was performed before celecoxib treatment and after 1 month of celecoxib treatment to recover alveolar macrophages ( AMs ) and lining fluid for study . After harvest , AMs were immediately stimulated in vitro with the calcium ionophore A23187 . AMs obtained from smokers before treatment and from ex - smoker control subjects were also cultured overnight with SC58236 , a selective P35354 inhibitor , with or without lipopolysaccharide stimulation . RESULTS : Treatment with oral celecoxib only modestly increased Q06643 ( 4 ) levels in bronchoalveolar lavage , without increasing the mRNA transcription of P09917 ( 5 - P28300 ) or 5 - P28300 - activating protein in AMs , whereas the acute calcium ionophore - stimulated Q06643 ( 4 ) production from smokers ' AMs was markedly increased by 10 . 6 - fold . In addition , smokers ' AMs were twice as responsive in producing Q06643 ( 4 ) when exposed to lipopolysaccharide compared with ex - smokers ' AMs . Concomitant P35354 inhibition with SC58236 , however , did not significantly impact these changes , whereas the 5 - P28300 inhibitor Zileuton blocked the generation of Q06643 ( 4 ) in a dose - responsive manner . Finally , cycloheximide increased the production of Q06643 ( 4 ) under all conditions , suggesting a shunting phenomenon and / or the presence of pathway inhibitors . CONCLUSIONS : Our findings suggest that whereas oral celecoxib is capable of modulating Q06643 ( 4 ) production in the lung microenvironment , under physiologic conditions , this effect is probably not functionally significant .", "Acute generalized exanthematic pustulosis : a case and an overview of side effects affecting the skin caused by celecoxib and other P35354 inhibitors reported so far . A 55 - year - old woman who was treated for periarthritis humeroscapularis with celecoxib ( DB00482 ) developed a generalized pustular exanthema on the head and upper trunk , accompanied by fever , leukocytosis and increased erythrocyte sedimentation rate . The histological findings were subcorneal pustules , necrotic keratinocytes , edema in the upper dermis and polymorphic perivascular infiltrates . Four days after stopping celecoxib , the pustules disappeared without any treatment . Four weeks after disappearance of the skin lesions , celecoxib demonstrated a positive lymphocyte stimulation test . In this article , we present to our knowledge the first case of acute generalized exanthematic pustulosis caused by celecoxib , and we give an overview of the side effects affecting the skin caused by celecoxib and other cyclooxygenase type 2 inhibitors reported so far .", "Phospholipase A₂ activities in skin physiology and pathology . Skin inflammatory diseases are most commonly treated with corticosteroids , especially topical preparations , benefitting from high potency and unparalleled formulation flexibility . However , these benefits are limited due to side effects , especially under long - term use . Non - steroidal anti - inflammatory drugs ( NSAIDs ) which block the P36551 pathways have been used as safer alternatives to corticosteroids , and much effort and resources have been invested in developing P36551 inhibitors . However , synthetic NSAIDs are less potent than steroids , have limited formulation flexibility and have their own safety issues , thereby yielding unsatisfactory results , with some high - profile drugs ( e . g . , the P35354 inhibitors Vioxx , DB00482 ) being withdrawn from the market due to safety concerns . The potency and safety challenges of NSAIDs are related to inter - eicosanoid dynamics , pertaining to their pro - versus anti - inflammatory action , homeostatic functions and tissue - specific activities . Instead , the upstream control of phospholipase A2 ( P04054 ) enzymatic activity , which hydrolyzes cell membrane phospholipids to initiate the eicosanoid production , has been considered for inhibiting eicosanoid activation while maintaining the intricate balance needed for their homeostatic functions . Yet , PLA ( 2 ) inhibitors have hardly been tested for treating skin inflammatory / allergic conditions . In this article we review the involvement of PLA ( 2 ) s in skin physiology and pathology , and discuss the prospect of PLA ( 2 ) inhibition for the treatment of dermatological diseases .", "Expression of retinoic acid receptor beta in dermatofibrosarcoma protuberans . BACKGROUND : P10826 ( RAR beta ) has been shown to act as a tumor suppressor in many solid human tumors . To investigate the putative role of RAR beta in dermatofibrosarcoma protuberans ( DFSP ) , we examined the expression of RAR beta in DFSPs and analyzed the correlation of expression patterns between RAR beta and cyclooxygenase ( P36551 ) - 2 as well as clinicopathological variables . METHODS : Using tissue microarray and immunohistochemistry , we evaluated nuclear RAR beta staining and cytoplasm P35354 staining in 53 DFSPs . RESULTS : 48 DFSPs ( 90 . 58 % ) were immunopositive for RAR beta , while 32 DFSPs ( 60 . 38 % ) were immunopositive for P35354 . RAR beta staining was significantly inversely correlated with P35354 staining ( p < 0 . 001 ; r =- 0 . 668 ) . CONCLUSIONS : Our data indicated that RAR beta expressed in DFSPs and correlated with P35354 expression . RAR beta may be a potential therapeutic target for unresectable DFSP cases .", "P35354 inhibitors : do they have a role in emergency department prescribing ? P35354 selective inhibitors ( COXIB or CSI ) have been released with a fanfare as efficacious and safer alternatives to traditional non - steroidal anti - inflammatory drugs . They purport to offer equivalent degrees of analgesia and an improved safety profile . COXIB currently available in Australasia are celecoxib ( DB00482 ) , rofecoxib ( Vioxx ) and etoricoxib ( Arcoxia ) . This review discusses the pharmacology of these agents and reviews recent literature regarding their effectiveness and safety . It endeavours to answer the question ' Should we be using COXIB in emergency departments in Australasia ' ?", "Drug insight : cyclo - oxygenase 2 inhibitors and cardiovascular risk -- where are we now ? Cyclo - oxygenase ( P36551 ) 1 mediates the production of thromboxane A2 in platelets , leading to platelet aggregation and vasoconstriction . Conversely , P35354 catalyzes endothelial prostacyclin synthesis , which effectively counteracts thromboxane A2 , triggering vasodilation and platelet inhibition . Selective P35354 inhibitors decrease prostacyclin production , potentially disrupting homeostasis and creating a prothrombotic state . The VIGOR study findings of increased cardiovascular risk with rofecoxib were subsequently confirmed by large meta - analyses , observational studies and recent APPROVe trial publication . The P25054 trial findings of increased cardiovascular risk with DB00482 ( celecoxib ) conflict with those in the ADAPT trial , the upcoming PreSAP publication , a case - control study by Graham et al . and prior large clinical trials , meta - analyses and observational studies of this drug . Therefore , while an adverse class effect is a possibility for P35354 inhibitors , the published data are inconsistent . Baseline cardiovascular risk in patients might contribute significantly to these findings . In light of the negative Vioxx ( rofecoxib ) publicity , however , P35354 inhibitors might forever remain underinvestigated . The relative selectivity of these compounds for P35354 is extremely variable , casting significant doubt on the class - effect hypothesis . Improved endothelial function has also been reported with celecoxib , leading to endothelium - dependent vasodilation , and associated decreases in P02741 and LDL cholesterol . The addition of meloxicam to low - dose aspirin and heparin has improved clinical outcomes after acute coronary syndromes . These are the first studies suggesting improvement in endothelial function and reduction of inflammation with P35354 inhibition . Thus , more randomized controlled trials are needed to study the relative cardiovascular effects of different P35354 inhibitors , alone and in combination with aspirin .", "P35354 inhibitors and DB00482 : safe or suspect ?", "Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK23___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .", "Microscopic modes and free energies of 3 - phosphoinositide - dependent kinase - 1 ( PDK1 ) binding with celecoxib and other inhibitors . Celecoxib , also known as DB00482 ( approved by FDA in 1998 ) and remembered as the fastest - selling drug in history , was used as a cyclooxygenase - 2 ( P35354 ) selective inhibitor having both anti - inflammatory and anticancer activities . Most recent studies have revealed that the apoptotic activity of celecoxib ( and its derivatives ) is actually independent of the P35354 inhibitory activity and that celecoxib also inhibits the kinase activity of 3 - phosphoinositide - dependent protein kinase - 1 ( PDK1 ) , suggesting that the well - known anticancer activity of celecoxib is not due to the inhibition of P35354 , but possibly is due to the inhibition of PDK1 . It is highly desirable to develop new celecoxib derivatives as PDK1 - specifc inhibitors to avoid the side effects of P35354 inhibitors . To understand how PDK1 binds with celecoxib and its derivatives , we have performed extensive molecular docking and combined molecular dynamics ( MD ) simulations and molecular mechanics / Poisson - Boltzmann surface area ( MM - PBSA ) binding free energy calculations on eight representative PDK1 inhibitors , leading to the finding of a new , more favorable binding mode which is remarkably different from the previously proposed binding mode . Based on the determined most stable binding structures , the calculated binding free energies are all in good agreement with the corresponding experimental data , and the biological activity data available for celecoxib and its derivatives can be better interpreted . The obtained new insights , concerning both the binding mode and computational protocol , will be valuable not only for future rational design of novel , more potent PDK1 - specific inhibitors as promising anticancer therapeutics , but also for rational design of drugs targeting other proteins .", "Quantification and characterisation of cyclo - oxygenase and lipid peroxidation inhibitory anthocyanins in fruits of Amelanchier . The levels of bioactive anthocyanins in the fruits of Amelanchier alnifolia , A . arborea and A . canadensis have been determined by HPLC . Cyanidin 3 - galactoside ( 1 ) was present in the fresh fruit of the three species at concentrations of 155 , 390 and 165 mg / 100 g , respectively . Cyanidin 3 - glucoside ( 2 ) was present only in A . alnifolia and A . canadensis at concentrations of 54 and 48 mg / 100 g , respectively . The anthocyanins were confirmed by LC - P19957 / MS and NMR studies . At 100 ppm , anthocyanin mixtures from the three species inhibited cyclo - oxygenase ( P36551 ) - 1 and - 2 enzymes at 66 and 67 % , 60 and 72 % , and 51 and 76 % , respectively . The positive controls used in the P36551 assays were aspirin , DB00482 and Vioxx at 180 , 1 . 67 and 1 . 67 ppm , respectively , and showed 74 and 69 % , 5 and 82 % and 0 and 85 % P23219 and P35354 inhibition , respectively . Anthocyanins 1 and 2 and cyanidin ( 3 ) inhibited P23219 enzyme 50 . 5 , 45 . 62 and 96 . 36 % , respectively , at 100 ppm , whereas P35354 inhibition was the highest for 3 at 75 % . In the lipid peroxidation inhibitory assay , anthocyanin mixtures at 10 ppm from the three species showed activities of 72 , 73 and 68 % , respectively , compared with 89 , 87 and 98 % for commercial anti - oxidants butylated hydoxyanisole , butylated hydroxytoluene , and tert - butylhydroxyquinone at 1 . 67 , 2 . 2 and 1 . 67 ppm , respectively . At 10 ppm , compounds 1 - 3 inhibited lipid peroxidation by 70 , 75 and 78 % , respectively .", "Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK42___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .", "Chromosomal changes in high - and low - invasive mouse lung adenocarcinoma cell strains derived from early passage mouse lung adenocarcinoma cell strains . The incidence of adenocarcinoma of the lung is increasing in the United States , however , the difficulties in obtaining lung cancer families and representative samples of early to late stages of the disease have lead to the study of mouse models for lung cancer . We used Spectral Karyotyping ( Q06418 ) , mapping with fluorescently labeled genomic clones ( Q5TCZ1 ) , comparative genomic hybridization ( CGH ) arrays , gene expression arrays , Western immunoblot and real time polymerase chain reaction ( PCR ) to analyze nine pairs of high - invasive and low - invasive tumor cell strains derived from early passage mouse lung adenocarcinoma cells to detect molecular changes associated with tumor invasion . The duplication of chromosomes 1 and 15 and deletion of chromosome 8 were significantly associated with a high - invasive phenotype . The duplication of chromosome 1 at band C4 and E1 / 2 - H1 were the most significant chromosomal changes in the high - invasive cell strains . Mapping with Q5TCZ1 and CGH array further narrowed the minimum region of duplication of chromosome 1 to 71 - 82 centimorgans ( cM ) . Expression array analysis and confirmation by real time PCR demonstrated increased expression of P35354 , Q15631 ( TB - P02753 ) , O43781 , Q9H1E3 and Tubulin - alpha4 genes in the high - invasive cell strains . Elevated expression and copy number of these genes , which are involved in inflammation , cell movement , proliferation , inhibition of apoptosis and telomere elongation , were associated with an invasive phenotype . Similar linkage groups are altered in invasive human lung adenocarcinoma , implying that the mouse is a valid genetic model for the study of the progression of human lung adenocarcinoma .", "P35354 inhibition attenuates antibody responses against human papillomavirus - like particles . Vaccination to generate protective humoral immunity against infectious disease is becoming increasingly important due to emerging strains of virus , poorly immunogenic vaccines , and the threat of bioterrorism . We demonstrate that cyclooxygenase - 2 ( Cox - 2 ) is crucial for optimal Ab responses to a model vaccine , human papillomavirus type 16 virus - like particles ( HPV 16 VLPs ) . Cox - 2 - deficient mice produce 70 % less IgG , 50 % fewer Ab - secreting cells , and 10 - fold less neutralizing Ab to HPV 16 VLP vaccination compared with wild - type mice . The reduction in Ab production by Cox - 2 (-/-) mice was partially due to a decrease in class switching . SC - 58125 , a structural analog of the Cox - 2 - selective inhibitor DB00482 reduced by approximately 70 % human memory B cell differentiation to HPV 16 VLP IgG - secreting cells . The widespread use of nonsteroidal anti - inflammatory drugs and Cox - 2 - selective inhibitory drugs may therefore reduce vaccine efficacy , especially when vaccines are poorly immunogenic or the target population is poorly responsive to immunization .", "DB00482 offers a small protection from root resorption associated with orthodontic movement . Tooth movement results from alveolar bone resorption / deposition following application of orthodontic forces , and root resorption can be an undesirable complication associated with this process . No treatment for external root resorption is available to date . OBJECTIVE : To determine if P35354 inhibitors like DB00482 are effective in protecting root resorption associated with orthodontic forces . METHODS : A force of 80 grams was applied to the left maxillary first molars of 7 - week - old female Wistar rats using nickel titanium closed coil springs attached to the cervical area of the incisors with 0 . 010 stainless - steel ligature wires . Twenty animals were divided into three experimental groups : one receiving no treatment , the second receiving 25mg / kg , and the third receiving 50 mg / kg of celecoxib ( DB00482 ) in their drinking water . Rats were maintained on a soft diet and euthanized two weeks after initial placement of the force . Paraffin - embedded sections of the right ( control ) and left ( experimental ) maxillae were stained with H & E and the areas of root resorption were examined by counting the number of lacunaes in the roots . RESULTS : No difference in the distance of tooth movement ( 0 . 5 mm / two weeks ) was seen in all three groups . The rats that received the low dose of DB00482 showed no statistically significant difference in root resorption than that of the rats that received no dose . The rats that received the high dose of DB00482 showed a lower number of lacunaes ( mean = 3 . 5 ) than that of the control group ( mean 10 . 2 ; p = 0 . 02 ) . CONCLUSIONS : Administration of DB00482 during the application of orthodontic forces does not interfere with tooth movement and appears to offer some slight protection against root resorption .", "Dual carbonic anhydrase -- cyclooxygenase - 2 inhibitors . Cyclooxygenase is a key enzyme responsible for metabolisation of arachidonic acid into prostaglandins and thromboxane . This enzyme is the target of non steroidal anti - inflammatory drugs ( NSAIDs ) , used against inflammation and pain . The inducible P35354 was associated with inflammatory conditions , whereas the constitutive form ( P23219 ) was responsible for the beneficial effects of the PGs . This observation led to the development of P35354 inhibitors or \" coxibs \" of which rofecoxib ( Vioxx ) characterized by a methylsulfone moiety and the sulfonamides celecoxib ( DB00482 ) and valdecoxib ( Bextra ) . Initially described as P35354 \" selective \" inhibitors , recent reports revealed a nanomolar inhibition activity of the sulfonamide P35354 inhibitors for several carbonic anhydrase ( CA ) isoforms , confirmed by X - ray crystal structures for the adducts of celecoxib and valdecoxib with isozyme CA II . This dual activity may help to explain differences in clinical observation between sulfonamide and methylsulfone P35354 inhibitors . Moreover , the inhibition of CA isozymes , critical for the development and invasion of cancer cells , such as CA II , IX and XII , may constitute an important mechanism of antitumor action of such sulfonamide compounds .", "Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss - of - function mutations causing X - linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein - Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small - molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug - induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 - 32765 , recently renamed ___MASK99___ , has already entered several clinical trials for various forms of non - Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors .", "P35354 inhibitors in glioma therapy . The cyclooxygenase enzyme is a prostaglandin synthase that has two isoforms , cyclooxygenase - 1 ( P23219 ) and cyclooxygenase - 2 ( P35354 ) . Upregulation of the P35354 isoform in many cancers has led to investigation regarding the potential role of this enzyme in oncogenesis . The Food and Drug Administration has approved celecoxib ( DB00482 ) for patients with familial adenomatous polyposis ( FAP ) based on a study that showed a reduction in the number of polyps in such patients when treated with high doses of this drug . We are investigating the potential role of P35354 inhibitors in the treatment of recurrent malignant gliomas in combination with retinoids . In this article the rationale for using this combination therapy in patients with malignant gliomas is presented .", "[ Pharma - clinics . The drug of the month . Celecoxib ( DB00482 ) ] . Celecoxib ( DB00482 , Pharmacia ) is a potent and selective inhibitor of the P35354 isoform of cyclooxygenase which is used as nonsteroidal anti - inflammatory drug ( NSAID ) . Its current indications are osteoarthritis and rheumatoid arthritis . The usual recommended daily dosage of celecoxib is 200 mg ( in one or two intakes per day ) , to be increased up to 400 mg ( two intakes per day ) if necessary . Its clinical efficacy seems to be similar to that of other NSAIDs . However , its safety profile , especially gastro - intestinal tolerance and perhaps renal safety , is much better because of the P35354 selectivity .", "O76074 inhibitors enhance celecoxib killing in multiple tumor types . The present studies determined whether clinically relevant phosphodiesterase 5 ( O76074 ) inhibitors interacted with a clinically relevant NSAID , celecoxib , to kill tumor cells . Celecoxib and O76074 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types . Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia . Knock down of O76074 recapitulated the effects of O76074 inhibitor treatment ; the nitric oxide synthase inhibitor L - NAME suppressed drug combination toxicity . The effects of celecoxib were P35354 independent . Over - expression of O15519 - s or knock down of CD95 / Q13158 significantly reduced killing by the drug combination . CD95 activation was dependent on nitric oxide and ceramide signaling . CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing . The drug combination inactivated P42345 and increased the levels of autophagy and knock down of Beclin1 or Q9H1Y0 strongly suppressed killing by the drug combination . The drug combination caused an ER stress response ; knock down of IRE1α / P17861 enhanced killing whereas knock down of eIF2α / P18848 / P35638 suppressed killing . ___MASK40___ and celecoxib treatment suppressed the growth of mammary tumors in vivo . Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer .", "P35354 inhibitors : a story of greed , deception and death . In 1999 , drug manufacturers introduced a class of NSAIDs called P35354 inhibitors or coxibs . The drugs were avidly promoted directly to the consumers and became bestsellers from the start . Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain , bleeding and other side - effects . In the year after their introduction , doctors wrote over 100 million prescriptions for celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) . DB00482 is the sixth best - selling drug , with sales of more than US $ 4 billion since its debut in 1999 . Vioxx had sales of US $ 2 . 6 billion in 2001 . However , the coxibs increase the risk of heart attacks and strokes , and their price , in the USA , is obscene . The manufacturers faced a possibly complicit , toothless and bloodless FDA , and used every maneuvering to fleece the patients . We must now reflect on attitudes that we thought only belong to the tobacco industry . Fortunately , safe and active alternatives exist .", "P35354 inhibitors : better than traditional NSAIDs ? Vioxx and DB00482 may be no less risky than NSAIDs .", "Selective inhibition of P35354 is beneficial to mice infected intranasally with VSV . Cyclooxygenase ( P36551 ) is the key enzyme for prostaglandin ( PG ) synthesis . PGs are mediators of many critical physiological and inflammatory responses . There are two isoforms , P23219 and P35354 , both of which are constitutively expressed in the central nervous system ( CNS ) . Studies have shown that P23219 and P35354 are involved in physiological and pathological conditions of the brain . However , little is known about the role ( s ) of P36551 in the host defense system against a viral infection in the CNS . In this report , we used Vesicular Stomatitis Virus ( VSV ) induced acute encephalitis to distinguish between the contribution ( s ) of the two isoforms . P35354 activity was inhibited with a P35354 selective drug , celecoxib ( DB00482 ) , and P23219 was antagonized with SC560 . We found that inhibition of P35354 led to decreased viral titers , while P23219 antagonism did not have the same effect at day 1 post infection . 5 - lipooxygenase ( P09917 ) expression and neutrophil recruitment in the CNS were increased in celecoxib - inhibited mice . Furthermore , mice treated with celecoxib expressed more DB00435 Synthase - 1 ( Q8WY41 ) , a crucial component of the innate immune system in the restriction of VSV propagation . The expression of type 1 cytokines , P01579 and IL - 12 , were also increased in celecoxib - treated mice .", "Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .", "Lipoperoxidation and cyclooxygenases 1 and 2 inhibitory compounds from Iryanthera juruensis . Plants from Iryanthera genus have been traditionally used as food supplements by South American Indians . The MeOH extract of leaves of Iryanthera juruensis , one of the plants endemic to the Amazon region and consumed in Brazil , and the hexane extract from its seeds inhibited lipid peroxidation ( P22079 ) and cyclooxygenase ( P23219 and - 2 ) ) enzymes in in vitro assays . Further analyses of these extracts yielded 5 - deoxyflavones ( 1 - 5 ) from the leaf extract and sargachromenol ( 6 ) , sargaquinoic acid ( 7 ) , a novel juruenolic acid ( 8 ) , omega - arylalkanoic acids ( 9a - c ) , and the lignan guaiacin ( 10 ) from the seed extract . Compounds 3 - 5 inhibited P22079 by 86 % , 77 % , and 88 % at 10 ppm , respectively , and compounds 6 and 9a - c showed inhibition at 76 % and 78 % at 100 ppm , respectively . However , compounds 7 and 8 were inactive and lignan 10 exhibited P22079 inhibitory activity by 99 % at 100 ppm compared to commercial antioxidants butylated hydroxyanisole ( BHA ) , butylated hydroxytoluene ( BHT ) , and vitamin E . The flavones 1 - 5 also inhibited P23219 and - 2 enzymes by 50 - 65 % at 100 ppm . DB04088 showed high but nonselective inhibition of P23219 and P35354 enzymes , when compared to aspirin and DB00482 , a nonsteroidal anti - inflammatory drug ( NSAID ) . Compounds 7 and 10 inhibited P23219 by 60 % and 65 % and P35354 by 37 % and 18 % , respectively , whereas compounds 8 and 9a - c showed little or no activity against these enzymes .", "Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK50___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .", "Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis . Endometriosis displays some features that resemble malignant processes , including invasive growth , resistance to apoptosis and distant implantation . The objective of this study was to investigate whether gene alterations that are frequent in endometrial and / or ovarian cancers contribute to the pathogenesis of endometriosis . Biopsies were obtained from ectopic endometriosis lesions from 23 patients with revised American Fertility Score stage 1 ( n = 1 ) , 2 ( n = 10 ) , 3 ( n = 11 ) or 4 ( n = 1 ) endometriosis . Six genes ( P25054 , CDKN2A , Q9ULZ3 , P10826 , Q9NS23 and P03372 ) were analyzed for promoter hypermethylation using methylation - specific melting curve analysis , and 9 genes ( P15056 , P01112 , P01111 , P35222 , P11802 , P22607 , P42336 , P04637 and P60484 ) were analyzed for mutations using denaturing gradient gel electrophoresis and direct sequencing . An oncogenic mutation in P01116 ( c . 34G > T ; p . G12C ) was detected in a single lesion . No gene alterations were found in the remaining samples . Our data suggest that genetic and epigenetic events contributing to endometrial and ovarian cancers are rare in endometriosis . However , other proto - oncogenes and tumor suppressor genes should be tested for alterations in order to identify the molecular basis of the susceptibility of endometriosis to malignant transformation .", "Celecoxib - induced upper gastrointestinal hemorrhage and ulceration . P35354 inhibitors are a new class of nonsteroidal anti - inflammatory drugs with a reported benefit of less gastric and duodenal ulceration and hemorrhage . We describe a 67 - year - old man taking a higher than usual dose of celecoxib ( DB00482 ) for osteoarthritis with resultant gastric erosions , ulceration , and a significant gastrointestinal ( GI ) hemorrhage .", "Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK54___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .", "A triple combination of atorvastatin , celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors . Because K - Ras mutation and cyclooxygenase - 2 ( P35354 ) overexpression are hallmarks of majority of pancreatic cancer patients , an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets , should be considered . In the present study , we assessed the effects of atorvastatin ( Lipitor ) , celecoxib ( DB00482 ) and tipifarnib ( DB04960 ) on the growth of human pancreatic cancer . In the in vitro studies , we found that treatment of human pancreatic tumor cells with a combination of atorvastatin , celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs . We also found that treatment of Panc - 1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1 / 2 and Akt . In an animal model of xenograft tumors in severe combined immunodeficient ( SCID ) mice , we found that daily i . p . injections of a combination of atorvastatin , celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs . The results of our study indicate that a combination of atorvastatin , celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer .", "Combined preoperative use of celecoxib and gabapentin in the management of postoperative pain . BACKGROUND : In 2005 we reported a study on the efficacy of the preoperative use of the selective P35354 inhibitor celecoxib ( DB00482 ) for reducing both postoperative pain and opioid requirements in patients undergoing bilateral subpectoral breast augmentation . Our findings showed that patients who received 400 mg of celecoxib 30 min before surgery required significantly less postoperative opioid analgesics compared with those given a placebo . DB00996 ( DB00996 ) is an agent commonly used to control neuropathic pain . Here we describe a prospective study assessing the efficacy of preoperative gabapentin in combination with celecoxib for reducing postoperative pain and opioid requirements in elective subpectoral breast augmentation . METHODS : One hundred eighteen patients were given 1200 mg of gabapentin and 400 mg of celecoxib 30 - 60 min before surgery . From the day of surgery until postoperative day 5 , patients documented any use of analgesics and recorded their degree of pain . Results were then compared with those of our previous study in which only celecoxib was used . RESULTS : The combination of gabapentin and celecoxib was found to be significantly superior ( p < 0 . 001 ) in reducing postoperative pain and opioid requirements than celecoxib alone in the management of postoperative pain and opioid requirements . CONCLUSION : To decrease postoperative opioid requirements , we recommend 400 mg of celecoxib and 1200 mg of gabapentin taken 30 - 60 min before surgery by patients undergoing subpectoral breast augmentation or a comparable plastic surgery procedure .", "Inhibition of cyclooxygenases 1 and 2 by the phospholipase - blocker , arachidonyl trifluoromethyl ketone . BACKGROUND AND PURPOSE : Arachidonyl trifluoromethyl ketone ( Q06187 ) is widely used as an inhibitor of cytosolic group IV phospholipase A ( 2 ) ( cPLA ( 2 ) ) and calcium - independent group VI phospholipase A ( 2 ) ( iPLA ( 2 ) ) . Q06187 thus reduces arachidonic acid ( AA ) substrate for cyclooxygenase ( P36551 ; also known as prostaglandin H synthase ) and attenuates prostaglandin ( PG ) synthesis . It has been shown previously , that Q06187 blocks thromboxane B ( 2 ) production induced by exogenous AA in human platelets . It remains , however , unknown whether Q06187 also directly modulates the activity of cyclooxygenase ( P36551 ) . EXPERIMENTAL APPROACH : Time courses for inhibition of P36551 by Q06187 was obtained using osteoblast - like MC3T3 - E1 cells , with exogenous AA as substrate and the pure enzymes P23219 and P35354 . PGE ( 2 ) was measured by GC - MS . KEY RESULTS : Q06187 was a potent inhibitor of P23219 and P35354 with IC ( 50 ) values of 0 . 5 and 0 . 1 microM in MC3T3 - E1 cells and of 1 . 7 and 2 . 6 microM using the pure enzymes . Inhibition was reversible , with slow - and tight - binding characteristics . The arachidonyl carbon chain was essential , as the saturated palmitoyl analogue had no effect . CONCLUSIONS AND IMPLICATIONS : Attenuation of PG synthesis by Q06187 is taken to be the consequence of PLA ( 2 ) inhibition and the findings of many studies are interpreted on that basis . If there are , however , alternative routes for AA liberation ( such as phospholipase C / diacyl glycerol lipase or phospholipase D ) , this interpretation can lead to false conclusions . As Q06187 is a widely used and important pharmacological tool in eicosanoid research , knowledge of its interactions with other major enzymes of the cascade is of considerable importance .", "Docking studies on NSAID / P35354 isozyme complexes using contact statistics analysis . The selective inhibition of P35354 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects ; e . g . celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) . To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between P36551 isozymes - and NSAIDs . Although X - ray structures of P35354 complexed with a small number of ligands are available , experimental data are missing for two well - known selective P35354 inhibitors ( rofecoxib and nimesulide ) and docking results reported are controversial . We use a combination of a traditional docking procedure with a new computational tool ( Contact Statistics analysis ) that identifies the best orientation among a number of solutions to shed some light on this topic .", "Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK62___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .", "What ' s all the fuss ? Safety concerns about P35354 inhibitors rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) .", "DB00762 , cisplatin / carboplatin , and P35354 inhibition in small - cell lung cancer . Recent findings indicate significant prolongation of survival and time to disease progression with irinotecan ( CPT - 11 , Camptosar ) / cisplatin vs etoposide / cisplatin in extensive - stage small - cell lung cancer , and a larger - scale phase III trial has been planned to provide more definitive data on the benefits of the irinotecan / cisplatin combination in this setting . Early - phase studies indicate that the activity of carboplatin ( DB00958 ) in small - cell lung cancer is comparable to that of cisplatin , and that combining irinotecan on a day 1 and 8 schedule with split - dose carboplatin is feasible . Inhibition of the cyclooxygenase - 2 ( P35354 ) enzyme , which is active in tumorigenesis , may augment efficacy and reduce toxicity of platinum / irinotecan combinations . A phase II trial has been designed to compare irinotecan / carboplatin and irinotecan / cisplatin combinations with or without the P35354 inhibitor celecoxib ( DB00482 ) in patients with extensive - stage small - cell lung cancer . Results of these trials will help define the roles of platinum / irinotecan combinations and P35354 inhibition in treatment for small - cell lung cancer .", "[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( DB01050 ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .", "Celecoxib exhibits the greatest potency amongst cyclooxygenase ( P36551 ) inhibitors for growth inhibition of P35354 - negative hematopoietic and epithelial cell lines . P35354 ( P35354 ) is an important cellular target for both therapy and / or prevention of inflammatory disorders and cancer . The advent of selective P35354 inhibitors now allows a more precise and safer treatment approach . The screening of an array of cancer cell lines for growth inhibitory effects of P35354 - selective and - nonselective inhibitors , including celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) , produced two unanticipated findings . Firstly , the antiproliferative effects of celecoxib were noted to be of very similar magnitude for both hematopoietic and epithelial cancer cell lines . Most hematopoietic cell lines had no detectable P35354 expression by reverse transcription - PCR , and none expressed P35354 protein . In addition , P35354 - negative epithelial lines were found to have IC50s for celecoxib that were very similar to their P35354 + counterparts . Thus , important antiproliferative effects were observed that were independent of both the cell lineage and P35354 status . Secondly , it was also observed that P35354 inhibitor drugs , celecoxib and rofecoxib , with similar P35354 - selectivity and clinical efficacy for inflammatory indications , differed significantly in their in vitro antiproliferative effects on cancer cell lines . IC50s of 35 - 65 microM were observed for celecoxib across this entire panel of cell lines . Finally , no difference in the mode or degree of cytotoxicity was apparent between cell lines , because similar levels of apoptosis were observed in P35354 + and - negative cell lines after treatment with celecoxib , with correspondingly lower levels after rofecoxib treatment . These data are important in that they provide the first direct comparison of epithelial and hematopoietic cancer cell lines , as well as a direct comparison of the in vitro anticancer effects of the two clinically available P35354 inhibitors .", "Initial experience combining cyclooxygenase - 2 inhibition with chemoradiation for locally advanced pancreatic cancer . Pancreatic cancer is a lethal disease that is resistant to chemotherapy and radiotherapy . Gemcitabine has recently been shown to be an improvement over 5 - fluorouracil in patients with advanced disease . It is also a potent radiosensitizer , which has led to the investigation of gemcitabine with concurrent radiotherapy . However , preliminary results indicate that there are significant limitations to this approach in this challenging disease . Pancreatic cancer cells have alterations in many molecular signaling pathways that may be responsible for their resistance to cytotoxic therapy and aggressive behavior . P35354 ( P35354 ) is commonly overexpressed in pancreatic tumors , and preclinical evidence indicates that selective P35354 inhibition enhances both chemotherapy and radiotherapy response , without affecting normal tissue damage . We have initiated preclinical studies as well as a phase I clinical protocol evaluating the combination of gemcitabine and celecoxib ( DB00482 ) with radiotherapy . In preclinical studies , celecelecoxib strongly enhanced the antitumor efficacy of chemoradiation . However , preliminary observations from both the preclinical experiments as well as the clinical protocol have revealed more toxicity with this combination than with gemcitabine and radiotherapy alone . These observations require further study , but are cause for concern when combining gemcitabine , radiotherapy , and celecoxib .", "Regulation of male fertility by P13569 and implications in male infertility . BACKGROUND : The cystic fibrosis transmembrane conductance regulator ( P13569 ) is a DB02527 - activated Cl (-) and HCO ( 3 )(-) conducting channel , mutations of which are known to be associated with male infertility . However , the underlying mechanisms remain elusive . METHODS : Literature databases were searched for papers on the topics related to P13569 and male fertility and infertility with relevant keywords . Unpublished data from authors ' laboratory were also included for analysis . RESULTS : Clinical evidence shows increased mutation frequency or reduced P13569 expression in men with congenital bilateral absence of vas deferens ( CBAVD ) or sperm abnormalities , such as azoospermia teratospermia and oligoasthenospermia . Studies on primary rodent Sertoli cells and germ cells , as well as testes from P13569 knockout mice or a cryptorchidism model , yield findings indicating the involvement of P13569 in spermatogensis through the HCO ( 3 )(-)/ Q96PN6 / DB02527 / CREB ( Q03060 ) pathway and the NF - κB / P35354 / PGE ( 2 ) pathway . Evidence also reveals a critical role of P13569 in sperm capacitation by directly or indirectly mediating HCO ( 3 )(-) entry that is essential for capacitation . P13569 is emerging as a versatile player with roles in mediating different signaling pathways pertinent to various reproductive processes , in addition to its long - recognized role in electrolyte and fluid transport that regulates the luminal microenvironment of the male reproductive tract . CONCLUSIONS : P13569 is a key regulator of male fertility , a defect of which may result in different forms of male infertility other than CBAVD . It would be worthwhile to further investigate the potential of developing novel diagnostic and contraceptive methods targeting P13569 .", "Effects of selective P35354 and 5 - P28300 inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster . Selective inhibition of eicosanoid synthesis seems to decrease carcinogenesis , however , the effect on liver metastasis in pancreatic cancer is still unknown . Ductal pancreatic adenocarcinoma was chemically induced by weekly injection of N - nitrosobis - 2 - oxopropylamine ( BOP ) in Syrian hamster . Animals received selective inhibition of cyclooxygenase - 2 ( DB00482 ) and P09917 ( DB00744 ) . In week 33 , hamsters were sacrificed and incidence of pancreatic carcinomas as well as liver metastases were examined . Furthermore , size and number of liver metastases per animal were determined and concentration of PGF1alpha , DB00917 and leukotrienes was measured in hepatic and pancreatic tissue . Combined therapy ( DB00482 + DB00744 ) significantly decreased incidence , number and size of liver metastases . Furthermore extra - and intrametastatic concentration of DB00917 was reduced by this treatment in hepatic tissue . Single Cox - 2 - inhibition ( DB00482 ) decreased intrametastatic hepatic PGF1alpha and DB00917 concentration while PGF1alpha concentration was reduced in non - metastatic liver ( nml ) . Moreover 5 - P28300 - inhibition ( DB00744 ) decreased intrametastatic DB00917 concentration as well as PGF1alpha and DB00917 in nml . In pancreatic carcinomas highest LT - concentration was found after combined treatment and this therapy group was the only one revealing a significantly higher amount of LTs in carcinomas compared to tumour - free tissue . Hepatic LT - concentration was significantly lower in the control groups than in nml of the tumour groups . Combination of Cox - 2 - inhibition and 5 - Lox - inhibition might be a suitable adjuvant therapy to prevent liver metastasis in human ductal pancreatic adenocarcinoma .", "Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti - inflammatory drug ( NSAID ) - induced gastrointestinal injury ? Topical injury revisited . In this commentary , we take a critical look at the concept that the gastrointestinal ( GI ) side - effects of nonsteroidal anti - inflammatory drugs ( NSAIDs ) are due to the ability of these drugs to inhibit cyclooxygenase - 1 ( P23219 ) that is constitutively expressed in the GI mucosa . Indeed , development of the new \" super aspirins , \" such as DB00482 and Vioxx , that selectively inhibit the inducible P35354 , expressed in areas of inflammation , is a direct outgrowth of this concept . We discuss evidence from both the laboratory and the clinic that appears to be inconsistent with the above concept , and cite a number of examples where the depletion of mucosal prostaglandin levels and the development of GI injury can be dissociated . Instead , we revisit the possibility that NSAID - induced GI side - effects are mostly due to the ability of these drugs to topically injure the GI mucosa . We devote the remainder of the commentary to presenting evidence from our and other laboratories that NSAIDs can directly attenuate the surface hydrophobic barrier of the GI mucosa due to their ability to bind to zwitterionic phospholipids , and that even systemically administered NSAIDs that are secreted into the bile may induce GI ulceration and / or bleeding due to phospholipid interactions and the development of topical mucosal injury .", "P35354 - dependent and P35354 - independent mode of action of celecoxib in human liver cancer cells . Celecoxib ( DB00482 ( ( R ) ) , Pfizer ) is a selective cyclooxygenase - 2 ( P35354 ) inhibitor with chemopreventive and antitumor effects . However , it is now well known that celecoxib has several P35354 - independent activities . To better understand P35354 - independent molecular mechanisms underlying the antitumor activity of celecoxib , we investigated the expression profile of the celecoxib - treated P35354 - positive ( Huh7 ) and P35354 - negative ( HepG2 ) liver cancer cell lines , using microarray analysis . Celecoxib treatment resulted in significantly altered expression levels of 240 and 403 transcripts in Huh7 and HepG2 cells , respectively . Confirmation of the microarray results was performed for selected genes by semiquantitative RT - PCR . A pathway / functional analysis of celecoxib - affected transcripts , using ingenuity pathway analysis and exploring biological association networks , revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes , including cell death , cellular growth and proliferation , lipid metabolism , and energy turnover . Some of these processes were common for both HCC cell lines and seem to be coupled with NF - κB signaling , while others were cell - specific and possibly linked to the presence or the absence of P35354 activity in the corresponding cell line . Many novel genes emerged from our analyses that were not previously reported to be affected by celecoxib . Further studies on selected celecoxib - responsive genes will establish if they may serve as potential molecular targets for more effective therapeutic strategies in HCC .", "[ Selective inhibitors of type 2 cyclooxygenase : less renal effects than the classical non - steroidal anti - inflammatory agents ] . Prostaglandins play an important role in the regulation of renal hemodynamics and sodium excretion . Thus , the administration of non - steroidal anti - inflammatory drugs ( NSAIDs ) induces a renal vasoconstriction and sodium and potassium retention . In some high risk patients , this may lead to acute renal failure . The anti - inflammatory and renal effects of conventional NSAIDs are mediated by the non - selective inhibition of two cyclo - oxygenases , P23219 and P35354 . Recently , highly selective P35354 inhibitors have been developed such as celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) . These drugs were designed to preserve the analgesic and anti - inflammatory properties of NSAIDs while reducing their gastro - intestinal and renal side effects . Selective P35354 inhibitors have indeed less gastro - intestinal side - effects . However , their renal profile is comparable to that of non - selective inhibitors as they induce a decrease in glomerular filtration rate and a sodium and potassium retention . Thus , despite the good gastro - intestinal safety profile of selective P35354 , one should be careful with the use of these agents in high risk patients as they may induce similar renal complications as non - selective NSAIDs .", "Chronic anti - inflammatory drug therapy inhibits gel - forming mucin production in a murine xenograft model of human pseudomyxoma peritonei . BACKGROUND : Intraperitoneal accumulation of mucinous ascites in pseudomyxoma peritonei ( PMP ) promotes an inflammatory / fibrotic reaction that progresses to bowel obstruction and eventual patient demise . Cytokines and inflammation - associated transcription factor binding sites , such as glucocorticoid response elements and P35354 , regulate secretory mucin , specifically Q02817 , production . We hypothesized that anti - inflammatory drugs targeting inflammation - associated pathways may reduce mucin production and subsequent disease morbidity in PMP . METHODS : The effects of dexamethasone and DB00482 were assessed in mucin - secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo by serial parametric measurements , Q02817 transcripts via real - time RT - PCR , and Q02817 protein expression via immunofluorescence assays . RESULTS : Dexamethasone significantly inhibited basal Q02817 mRNA levels in LS174T cells , inhibited mucinous tumor accumulation in an intraperitoneal PMP xenograft model , and prolonged survival in a subcutaneous LS174T xenograft model . DB00482 significantly inhibited sodium butyrate - stimulated Q02817 mRNA levels in LS174T cells and demonstrated a statistically nonsignificant trend toward reduced mucinous tumor growth and prolonged survival in the xenograft models . Q02817 protein analysis by immunofluorescence demonstrated a dual effect of dexamethasone on mucin production and tumor cell count . CONCLUSIONS : Inflammatory mediators are known to regulate mucin production and may promote overexpression of Q02817 by neoplastic cells with goblet cell phenotype in PMP . Anti - inflammatory drugs , dexamethasone and DB00482 , could inhibit extracellular mucin production in PMP by targeting inflammatory cascades and , therefore , may decrease compressive symptoms , increase the disease - free interval , and reduce the extent or frequency of morbid cytoreductive surgeries .", "Mass spectrometry and hydrogen / deuterium exchange measurements of alcohol - induced structural changes in cellular retinol - binding protein type I . To bind and release its ligand , cellular retinol - binding protein type I ( P09455 ) needs to undergo conformational and dynamic changes to connect the inner , solvent - shielded cavity , where retinol is found to bind , and the outside medium . DB00162 dissociation in vitro is favoured by water / alcohol mixtures whose moderately low dielectric constants mimic a property characteristic of the membrane microenvironment where this process occurs in vivo . Apo - and holo - P09455 , in either water / methanol or water / trifluoroethanol ( TFE ) mixtures , were analyzed at equilibrium by electrospray ionization with orthogonal quadrupole time - of - flight mass spectrometry ( P19957 - Q - TOFMS ) to identify the alcohol - induced species . The questions were asked whether the presence of alcohols affects protein dynamics , as reflected by hydrogen / deuterium ( H / D ) exchange monitored by continuous - labelling experiments , and to which extent retinol dissociation influences the process . With increasing methanol , at pH near neutrality , apo - P09455 exhibits a progressively more compact conformation , resulting in reduced H / D exchange with respect to the native protein in water . DB00162 dissociation from the holo - protein did not promote hydrogen replacement . Similarly , in the presence of the low TFE concentration sufficient to cause retinol dissociation , the hydrogen exchange of the resulting apo - protein was not exalted . However , in contrast with the alkanol , higher TFE concentrations induced a transition of apo - P09455 to a new alpha - helix conformation capable of exchanging all available hydrogen atoms .", "Targeting angiogenic processes by combination rofecoxib and ionizing radiation . Tumor growth and angiogenesis are interdependent . Cyclooxygenase ( P36551 ) catalyzes the synthesis of prostaglandins from arachidonic acid . Nonsteroidal antiinflammatory drugs ( NSAIDs ) inhibit P36551 - mediated synthesis of prostaglandins . P23219 is constitutively expressed in a wide range of tissues , whereas P35354 is cytokine inducible . Enhanced P35354 expression has been attributed a key role in the development of inflammation and related processes observed in pathologically altered disease states . Two specific P35354 inhibitors , namely rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) , both oral agents and U . S . Food and Drug Administration approved , have been shown preclinically and clinically to have efficacy comparable to that of NSAIDs for relief of pain and inflammation in osteoarthritis , with decreased risk of gastrointestinal damage . Little is known about how angiogenesis is affected by the combination of rofecoxib and radiation . We have evaluated the combination of rofecoxib , at various concentrations , and radiation on cytokine - induced angiogenesis in vitro . We have found that rofecoxib inhibited endothelial cell proliferation , migration , and tube formation ( differentiation ) at clinically relevant doses . In combination with radiation , inhibition of endothelial cell function further increased twofold . The combination of rofecoxib and radiation suggests a complementary strategy with clinical ramifications to target angiogenesis - dependent malignancies .", "Celecoxib and radiation therapy in non - small - cell lung cancer . Overexpression of cyclooxygenase - 2 ( P35354 ) is frequently present in lung cancer and may play a significant role in carcinogenesis , invasion , and metastasis . It has been associated with shortened survival in patients with resected early - stage adenocarcinoma of the lung . P35354 inhibition decreases tumor cell proliferation in vivo and has been shown to enhance tumor radiosensitivity . Additionally , P35354 inhibition may protect normal pulmonary tissue from radiation fibrosis . Clinical studies are under way to assess the potential benefits and risks of P35354 inhibition in the treatment of lung cancer . The rationale for P35354 inhibitors in the treatment of lung cancer will be reviewed . The results of a phase II study assessing the acute toxicity of concurrent celecoxib ( DB00482 ) and thoracic irradiation in patients with non - small - cell lung cancer ( NSCLC ) are reported , and an ongoing Radiation Therapy Oncology Group study using celecoxib and concurrent radiation therapy for NSCLC in patients with intermediate prognostic factors is reviewed .", "Impairment of breast cancer cell invasion by P35354 - specific inhibitor NS398 : roles of P61073 and of uPA system . Inhibition of cyclooxygenase - 2 ( P35354 ) is known to impair cancer cell metastatic behaviour , but the mechanisms involved largely remain elusive . We aimed to analyse whether the antimetastatic effect of P35354 inhibition in breast cancer cells could be explained by variations in the expression levels of chemokine receptor P61073 , vascular endothelium growth factor ( P15692 ) and Q96NZ9 / Q03405 components of the urokinase plasminogen activator system ( Q03405 ) . Breast cancer cell line MDA - MB - 231 was exposed to P35354 - specific inhibitor NS398 . Experimental data were assessed using Matrigel invasion tests , qRT - PCR , ELISA , flow cytometry and MTT test . Exposure to NS398 had no major effect on cell viability , apoptosis or P15692 production . Cell invasion was significantly decreased with reductions ranging from of 3 . 6 % with 10 μM NS398 to 81 . 04 % with 100 μM NS398 . P61073 membrane expression was significantly reduced by 18 % ( P < 0 . 05 ) when cells were treated with 100 μM of NS398 for 72 h . Q96NZ9 mRNA levels were significantly reduced to 78 and 63 % after treatment with 10 μM NS398 for 48 and 72 h , respectively ( P < 0 . 05 ) . Q03405 mRNA levels also decreased with mild NS398 concentrations , reaching the lowest level of 56 % with 50 μM of NS398 for 48 h ( P < 0 . 05 ) . With NS398 higher concentrations , Q03405 and Q96NZ9 expression levels increased . According to our results , impairment of expression of P61073 , Q96NZ9 and Q03405 differentially contribute to the antimetastatic effect of P35354 inhibitors depending on drug concentration .", "Genetic tools to tailor cancer prevention by NSAIDs . It was shown that NSAIDs , such as aspirin or DB00482 , are effective cancer preventive agents when taken regularly . However , the long - term use of NSAIDs , the cyclooxygenase ( P36551 ) inhibitors , may have significant adverse effects - primarily on the gastrointestinal ( inhibiting P23219 ) and cardiovascular ( inhibiting P35354 ) systems . Genetic analysis of enzymes ( including P36551 ) involved in the prostaglandin synthesis should reveal and predict a person ' s benefits vs . toxicity resulting from the NSAID treatment .", "Antitumor properties of dimethyl - celecoxib , a derivative of celecoxib that does not inhibit cyclooxygenase - 2 : implications for glioma therapy . Celecoxib ( DB00482 ) appears to be unique among the class of selective P35354 inhibitors ( coxibs ) , because this particular compound exerts a second function that is independent of its celebrated ability to inhibit P35354 . This second function is the potential to inhibit cell proliferation and stimulate apoptotic cell death at much lower concentrations than any other coxibs . Intriguingly , these two functions are mediated by different moieties of the celecoxib molecule and can be separated . The author , as well as others , have generated and investigated analogs of celecoxib that retain only one of these two functions . One derivative , 2 , 5 - dimethyl - celecoxib ( Q6UXB2 ) , which retains the antiproliferative and apoptosis - inducing function , but completely lacks the P35354 inhibitory activity , is able to mimic faithfully all of the numerous antitumor effects of celecoxib that have been investigated so far , including reduction of neovascularization and inhibition of experimental tumor growth in various in vivo tumor models . In view of the controversy that has recently arisen regarding the life - threatening side effects of this class of coxibs , it may be worthwhile to pursue further the potential benefits of drugs such as Q6UXB2 for anticancer therapy . Because Q6UXB2 is not a coxib yet potently maintains celecoxib ' s antitumor potential , one may be inclined to speculate that this novel compound could potentially be advantageous in the management of P35354 - independent cancers . In this summary , the implications of recent findings with Q6UXB2 will be presented and discussed .", "P35354 ( P35354 ) in carcinogenesis and selective P35354 inhibitors for chemoprevention in gastrointestinal cancers . INTRODUCTION : Nonsteroidal anti - inflammatory drugs ( NSAIDs ) have been reported to have a property to inhibit tumor development in some cancers while it shows various side effects such as gastrointestinal bleeding and renal disorder . Selective cyclooxygenase ( P36551 ) - 2 inhibitors ( coxibs ) were originally developed as one of anti - inflammatory drugs to avoid side effect of NSAIDs . Fortunately , the coxibs was also proved to have an inhibiting effect on tumorigenesis by many experimental studies using cell lines and animal models like NSAIDs . DISCUSSION : Since a randomized study for polyp chemoprevention by celecoxib in familial adenomatous polyposis ( FAP ) patients demonstrated a significant reduction in the number of colorectal polyps , the clinical use of celecoxib was approved for FAP patients . Three large trials using celecoxib ( the Adenoma Prevention with DB00482 and the Prevention of Spontaneous Adenomatopus Polyps ) or refecoxib ( the Adenomatous Polyp Prevention on Vioxx ) for the recurrence of colorectal polyps in patients with a history of colorectal adenoma polypectomized confirmed chemopreventive effects on colorectal adenoma but two of three trails alerted us a hazard of cardiovascular ( CV ) events . Thereafter , some coxibs were withdrawn from the market because they showed to increase risk of serious CV events including heart attacks and strokes . But recent reports concluded that a merit of the reduction in gastrointestinal events by coxibs exceeded a demerit of the increase in serious CV events . In this review , a role of P35354 in carcinogenesis of gastrointestinal tract and a future of coxibs for chemoprevention are discussed .", "Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non - coxib analogue , 2 , 5 - dimethyl - celecoxib . The proteasome inhibitor bortezomib ( Velcade ) is known to trigger endoplasmic reticulum ( ER ) stress via the accumulation of obsolete and damaged proteins . The selective cyclooxygenase - 2 ( P35354 ) inhibitor celecoxib ( DB00482 ) causes ER stress through a different mechanism ( i . e . , by causing leakage of calcium from the ER into the cytosol ) . Each of these two mechanisms has been implicated in the anticancer effects of the respective drug . We therefore investigated whether the combination of these two drugs would lead to further increased ER stress and would enhance their antitumor efficacy . With the use of human glioblastoma cell lines , we show that this is indeed the case . When combined , bortezomib and celecoxib triggered elevated expression of the ER stress markers P11021 / P11021 and P35638 / P35638 , caused activation of c - Jun NH ( 2 )- terminal kinase and ER stress - associated caspase - 4 , and greatly increased apoptotic cell death . Small interfering RNA - mediated knockdown of the protective ER chaperone P11021 / P11021 further sensitized the tumor cells to killing by the drug combination . The contribution of celecoxib was independent of the inhibition of P35354 because a non - coxib analogue of this drug , 2 , 5 - dimethyl - celecoxib ( Q6UXB2 ) , faithfully and more potently mimicked these combination effects in vitro and in vivo . Taken together , our results show that combining bortezomib with celecoxib or Q6UXB2 very potently triggers the ER stress response and results in greatly increased glioblastoma cytotoxicity . We propose that this novel drug combination should receive further evaluation as a potentially effective anticancer therapy .", "Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .", "Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system . Evidence suggests that chronic inflammation , mitochondrial dysfunction , and oxidative stress play significant and perhaps synergistic roles in Parkinson ' s disease ( PD ) , where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra . The use of anti - inflammatory drugs for PD treatment has been proposed , and inhibition of cyclo - oxygenase - 2 ( P35354 ) or activation of peroxisome proliferator - activated receptor gamma ( P37231 ) yields neuroprotection in MPTP - induced PD . Lipopolysaccharide ( LPS ) induces inflammation - driven dopaminergic neurodegeneration . We tested the hypothesis that celecoxib ( DB00482 , P35354 inhibitor ) or pioglitazone ( Actos , P37231 agonist ) will reduce the LPS - induced inflammatory response , spare mitochondrial bioenergetics , and improve nigral dopaminergic neuronal survival . Rats were treated with vehicle , celecoxib , or pioglitazone and were intrastriatally injected with LPS . Inflammation , mitochondrial dysfunction , oxidative stress , decreased dopamine , and nigral dopaminergic neuronal loss were observed post - LPS . Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function . Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation . In summary , intrastriatal LPS served as a model for inflammation - induced dopaminergic neurodegeneration , anti - inflammatory drugs provided protective properties , and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro - inflammation and PD .", "Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK34___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided ." ]

[ "___MASK23___", "___MASK34___", "___MASK40___", "___MASK42___", "___MASK50___", "___MASK54___", "___MASK62___", "___MASK65___", "___MASK99___" ]

[ "The P04035 inhibitor rosuvastatin inhibits plasminogen activator inhibitor - 1 expression and secretion in human adipocytes . Human preadipocytes and adipocytes are known to produce the proatherogenic factor P05121 and proinflammatory cytokines , and obesity was found to be state of increased adipose production of these factors . In the present study , we investigated the effect of rosuvastatin on the regulation of P05121 gene expression in human adipocytes . Human preadipocytes , adipocytes in primary culture and the SGBS cell line were used as cell models . Cells were transfected using various constructs and promoter activity was measured as luciferase activity . P05121 expression was measured by quantitative RT - PCR and ELISA . ___MASK66___ inhibited P05121 mRNA expression and secretion of the protein in a concentration - dependent manner . This effect was reversed by isoprenoids . Addition of MEK - inhibitors and NFkappaB inhibitors also reduced P05121 expression and P05121 promoter luciferase activity . Further experiments revealed that rosuvastatin down - regulated the Q13233 - 1 mediated activation of the P05121 promoter . In conclusion our data suggest that rosuvastatin inhibits P05121 expression and release from human adipocytes via a Q13233 - 1 - dependent but not a NFkappaB - dependent mechanism .", "Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .", "New Q9H244 blockers . A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome ( ACS ) . This article reviews the pharmacology and clinical development of three of these agents : prasugrel , cangrelor , and ticagrelor . Prasugrel , a third - generation , oral thienopyridine , has been shown to be superior to clopidogrel , the current gold standard , in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention ( P05154 ) , although the bleeding rate was higher . DB06441 , a chemical analog of adenosine triphosphate , is a potent direct platelet Q9H244 antagonist . In development as an intravenous agent , cangrelor is currently being evaluated in two phase III studies in patients requiring P05154 . DB08816 is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by Q9H244 ; it is currently being studied in a phase III trial in patients with ACS .", "Transitioning patients from cangrelor to clopidogrel : pharmacodynamic evidence of a competitive effect . BACKGROUND : DB06441 is a direct , parenteral , and reversible inhibitor of the platelet Q9H244 receptor currently undergoing Phase III testing . As many individuals treated acutely with cangrelor will often be treated long - term with a thienopyridine , it is important to determine the effects of concurrent cangrelor and clopidogrel administration . METHODS AND RESULTS : Ten healthy volunteers received a 600 mg oral loading dose of clopidogrel and then underwent serial platelet function monitoring for 6 h . Two weeks later these same individuals received a 600 mg clopidogrel loading dose simultaneously with a cangrelor IV bolus ( 30 microg / kg ) and a 2 - hour infusion ( 4 microg / kg / min ) . A separate group of ten volunteers received a 600 mg clopidogrel loading dose after administration of a cangrelor bolus and a 1 - hour infusion . The effects on ADP - induced platelet activation and aggregation were evaluated by flow cytometry , whole - blood electrical impedance , and light - transmittance aggregometry . DB06441 and clopidogrel alone achieved the expected levels of platelet inhibition . However , the sustained platelet inhibition anticipated for clopidogrel treatment did not occur when cangrelor was initiated simultaneously . No such effect was found when clopidogrel was started upon completion of the cangrelor infusion . CONCLUSION : To achieve sustained platelet Q9H244 inhibition in patients treated with cangrelor , clopidogrel administration should be started when the cangrelor infusion is terminated .", "Q9H244 inhibitors : pharmacologic mechanism and clinical relevance . Platelets play a critical role in the pathogenesis of atherothrombotic processes and inhibition of platelet aggregation by antiplatelet therapy is essential and really important in the acute coronary syndromes or in the setting of percutaneous coronary intervention . The first family of adenosine diphosphate Q9H244 receptors inhibiting drug is represented by thienopyridines and among these ticlopidine was the first approved by Food and Drug Administration ; actually its use is discouraged because of its potential side effects ( neutropenia , anemia , gastrointestinal distress and thrombotic thrombocytopenic purpura ) . The second generation of thienopyridines is represented by clopidogrel that has replaced ticlopidine in the clinical practice ; clopidogrel has the largest clinical experience . Prasugrel represents the third generation . It inhibits platelet aggregation by irreversibly blocking the adenosine diphosphate Q9H244 receptor . DB08816 , DB06441 and Enilogrel represent the last generation of thienopyridines . This review is focused on the effects of adenosine diphosphate Q9H244 inhibitors .", "___MASK50___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK50___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK50___ is a promising pharmacological tool in the treatment of renal edema .", "DB06441 AstraZeneca . AstraZeneca is developing the P2T ( P2YADP ) purinoceptor antagonist and platelet aggregation inhibitor , cangrelor , for the potential treatment of unstable angina and as an ultrafast - acting intravenous antithrombotic agent . It is in phase IIb clinical trials [ 315723 ] . NDA and MAA applications are planned for after 2003 [ 275466 ] , [ 314472 ] . It superseded the earlier compound , ARL - 67085 , which also reached phase II trials [ 328760 ] . In ex vivo samples of angina patients ' blood , cangrelor inhibits platelet / monocyte conjugate development , which indicate the drug has some degree of disease - modifying activity [ 377418 ] . AstraZeneca is also developing derivatives of cangrelor . Removal of the triphosphate side chain , modification of the ribose to a carbocycle and the purine to a triazolopyridine resulted in a potent ( IC50 = 4 nM ) orally - active P2T / Q9H244 receptor antagonist . A lead compound was scheduled to enter trials as an antithrombotic agent in July 2000 [ 377666 ] . In March 1999 , Lehman Brothers predicted a 30 % probability that the drug would reach world markets and would be launched in 2002 [ 336599 ] .", "___MASK11___ unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . ___MASK11___ ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .", "Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .", "DB06441 for treatment during percutaneous coronary intervention . Dual antiplatelet therapy consisting of aspirin and a Q9H244 - receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention ( P05154 ) . The current Q9H244 - receptor antagonists are only available for oral administration and exhibit a delayed onset of action . Furthermore , several days are required for platelet function to return to normal following cessation of therapy . DB06441 is an intravenous DB00171 analog that directly , selectively and reversibly inhibits Q9H244 receptors on platelets . A 30 - μg / kg bolus dose followed by a 4 - μg / kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration . DB06441 also demonstrates a fast offset as normal platelet function is restored 1 - 2 h after cessation of the infusion . Three large , double - blind , randomized trials - CHAMPION PLATFORM , CHAMPION P05154 and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel ( during or immediately after P05154 ) or placebo in the setting of P05154 . In the most recent CHAMPION PHOENIX trial , cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding . Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset , cangrelor may provide benefit in certain patients undergoing P05154 .", "Potentiation of platelet aggregation by heparin in human whole blood is attenuated by Q9H244 and P47900 antagonists but not aspirin . INTRODUCTION : DB01109 ( UFH ) potentiates platelet aggregation induced by some agonists . Q9H244 and P47900 receptors play a major role in amplifying platelet aggregation . We assessed the ability of cangrelor , a selective Q9H244 antagonist , A2P5P , a selective P47900 antagonist , and aspirin to block the potentiating effects of heparin . MATERIALS AND METHODS : Whole blood from healthy human volunteers was anticoagulated with either hirudin or UFH 10 IU / ml . Some tubes anticoagulated with hirudin also contained UFH 1 or 10 IU / ml . The low - molecular - weight heparin dalteparin was also assessed . Platelet aggregation was performed using whole blood single - platelet counting . Dense granule release was assessed using 14C - 5HT - labelled platelets . RESULTS : UFH and , to a lesser extent , dalteparin potentiated platelet aggregation induced by ADP , Q15004 , 5HT , U46619 , epinephrine and TRAP in a concentration - dependent manner but inhibited aggregation induced by collagen . DB06441 effectively opposed the potentiating effects of heparins on sustained aggregation induced by ADP , Q15004 , 5HT , U46619 and TRAP but had less effect on epinephrine - induced aggregation , whereas A2P5P was more effective at blocking both the initial phase of ADP - induced aggregation and the aggregation response to epinephrine , reflecting the differences in G protein coupling between the agonist receptors . DB00945 had no effect on potentiation by heparin . Heparins did not increase ADP - or TRAP - induced 14C - 5HT release . CONCLUSIONS : Heparins potentiate platelet responses to ADP and numerous other agonists . This potentiation is attenuated by cangrelor and A2P5P , and is not mediated by increased dense granule release . ADP receptor antagonists but not aspirin may have potential therapeutic benefits in counteracting the pro - thrombotic effects of heparins .", "Efficacy and safety of cangrelor for patients with coronary artery disease : a meta - analysis of four randomized trials . BACKGROUND : The efficacy and safety of new intravenous Q9H244 inhibitor ( cangrelor ) for patients with coronary artery disease ( CAD ) remain unclear . METHODS AND RESULTS : Trials were identified in PubMed , Web of Science , Embase , and Cochrane Database searches . We included four randomized , placebo - controlled reports in the meta - analysis . The database consisted of 36 , 081 patients on cangrelor compared with clopidogrel or placebo . Major adverse cardiac events ( MACE ) were defined as the primary efficacy endpoint and major or severe bleeding at 48 hours was defined as the primary safety endpoint . DB06441 significantly decreased risk of MACE ( OR : 0 . 87 , P = 0 . 002 ) and stent thrombosis ( OR : 0 . 53 , P < 0 . 001 ) . However , at the same time , an increase in TIMI minor bleeding ( OR : 1 . 49 , P = 0 . 04 ) and in GUSTO moderate bleeding ( OR : 1 . 43 , P = 0 . 04 ) were observed by cangrelor . CONCLUSIONS : Intravenous administration of cangrelor is benefit to reduce risk of MACE and stent thrombosis in patients with CAD excepting for increased minor bleeding events .", "Clinical effects and outcomes with new Q9H244 inhibitors in ACS . Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses . Newly developed Q9H244 inhibitors are more potent , more predictable , and have a faster onset of action than clopidogrel , characteristics that make them particularly attractive for high - risk percutaneous coronary intervention ( P05154 ) . Four new Q9H244 inhibitors have been tested each of them having particular individual properties . Prasugrel is an oral pro - drug leading to irreversible blockade of the Q9H244 receptor and is approved worldwide for ACS P05154 . DB08816 is a direct - acting and reversible inhibitor of the Q9H244 receptor with potentially more pleiotropic effects . DB06441 is an intravenous direct and reversible inhibitor of the Q9H244 receptor providing the highest level of inhibition , and elinogrel is an intravenous and oral Q9H244 antagonist with a direct and reversible action . Both prasugrel and ticagrelor , opposed to clopidogrel , have shown that stronger Q9H244 inhibition led respectively to significant 19 and 16 % relative risk reduction of a similar primary end point combining cardiovascular death , non - fatal myocardial infarction , or non - fatal stroke . Both drugs showed a significant 0 . 6 % absolute excess of TIMI major bleeding not related to CABG surgery . Because in clinical trials , patients perceived to be at higher risk of bleeding usually are excluded , the risk of major and even fatal bleeding might even be higher in a ' real - world ' setting , i . e . in the elderly patient with comorbidities . On the other hand , these newly developed Q9H244 inhibitors decrease mortality after P05154 compared with clopidogrel . The risk / benefit ratio is particularly favorable in P05154 for patients with STEMI .", "Clinical overview of promising nonthienopyridine antiplatelet agents . Three novel nonthienopyridine antiplatelet agents -- cangrelor , ticagrelor ( AZD6140 ) , and P35240 530348 -- are in advanced clinical testing in patients with coronary artery disease . DB06441 and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5 '- diphosphate Q9H244 receptor , whereas P35240 530348 is a thrombin receptor antagonist . Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention . We review the clinical features of these new platelet inhibition therapies .", "[ Anti - cholesterol agents , new therapeutic approaches ] . Statins and fibrates constitute the two major families of lipid - lowering agents . Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia . Both drugs are also used for the treatment of mixed dyslipidemia . Some fibrates efficiently lower serum LDL - cholesterol . Statins inhibit P04035 and decrease cellular cholesterol synthesis . The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the P01130 gene . This over expression of the P01130 in the liver increases the clearance of circulating LDL thus decreasing the LDL - cholesterol plasma levels . The effects of fibrates on lipid metabolism are entirely due to their capacity to activate Q07869 and to induce the over expression of genes containing a PPRE in their promoter . Fibrates decrease triglyceride concentrations by increasing the beta - oxidation of fatty acids in the liver and by decreasing triglyceride - VLDL synthesis . Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C - III transcription , respectively . Fibrates could decrease triglycerides partly by inducing apo A - V over - expression . These molecules increase HDL - cholesterol by increasing apo A - I and apo A - II transcription . Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism .", "[ Recent advances on the studies of the platelet ' s inhibition and aggregation . State of the art of new Q9H244 antagonists ] . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : i ) it is a pro - drug that needs to be metabolized to its active metabolite ; ii ) it has a delayed onset and offset of action ; iii ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG ( Coronary Artery Bypass Grafting ) related bleeding complications . Two direct and reversible Q9H244 antagonists , cangrelor and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 did not prove superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . DB08816 proved to be superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but was , like prasugrel , was associated with higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery was necessary in ticagrelor - treated patients compared to clopidogrel - treated patients to limit the severity of post - surgical bleeding .", "DB06441 : review of the drug and the CHAMPION programme ( including PHOENIX ) . Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions ( P05154 ) . Thienopyridines and ticagrelor are oral drugs developed for this purpose . DB06441 is an intravenous , non - thienopyridine antagonist of the Q9H244 receptor with a rapid , potent , predictable , and quickly reversible effect . DB06441 has been studied in a broad population intended to receive P05154 in the CHAMPION program , where it was compared with different clopidogrel regimens . The first two trials , CHAMPION P05154 and PLATFORM , failed their primary objective , likely for challenges in the adjudication of P05154 - related myocardial infarction . In a third trial that implemented the universal definition of MI , CHAMPION PHOENIX , a reduction of thrombotic events , including stent thrombosis , was observed . In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery . DB06441 appears a promising agent in patients who require P05154 or when a rapid reversal is needed .", "A field synopsis and meta - analysis of genetic association studies in peripheral arterial disease : The CUMAGAS - PAD database . In an electronic search of the literature , the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease ( PAD ) . They created a comprehensive database of all eligible studies , collecting detailed genetic and bioinformatics data on each polymorphism . Data from eligible studies were synthesized using meta - analysis techniques . Gene variants were classified into distinct pathophysiologic pathways , and their potential involvement in PAD pathogenesis was determined . Forty - one publications that examined 44 gene polymorphisms were included . For 37 polymorphisms , the variant form had a functional effect . Twenty - three polymorphisms in 22 potential PAD candidate genes ( F2 , P02675 , P42898 , P05106 , P12821 , AGT , P05231 , P13500 , P05362 , P16581 , P14780 , P37231 , P03956 , P35611 , Q9H244 , P11150 , Q13093 , Q8WTV0 , P08254 , P55157 , P08519 , P32297 ) showed a significant association in individual studies . Eighty - eight percent of the studies had statistical power of less than 50 % , and in 15 studies the genotype distribution in the control group did not conform to Hardy - Weinberg equilibrium . Data on 12 polymorphisms ( P12259 1691 G / A , P42898 677C / T , F2 20210 G / A , P05106 1565 T / C , P12821 I / D , AGT 704C / T , AGT - 6G / A , AGT 733C / T , P05231 - 174 G / C , P14780 - 1562C / T , P05362 1462A / G , P32297 831C / T ) were synthesized , and a positive association was found for 3 ( P05231 - 174 G / C , P05362 1462A / G , P32297 831C / T ) .", "DB06441 in percutaneous coronary intervention . DB06441 is a novel , intravenous Q9H244 receptor antagonist in development for use in percutaneous coronary intervention . Currently in Phase III testing , the reversible platelet inhibitor provides several inherent advantages over other Q9H244 receptor antagonists in this setting for the prevention of adverse cardiac events . Unlike the class of thienopyridines ( ticlopidine , clopidogrel and potentially soon to be available , prasugrel ) , cangrelor has nearly immediate onset after a bolus dose and a short half - life , and achieves maximal inhibition of ADP - mediated platelet function . DB06441 ' s distinct mechanism of action allows for intravenous administration and avoids both hepatic and renal metabolism . These unique characteristics make cangrelor a promising agent for use in cardiovascular patients undergoing percutaneous coronary intervention .", "Pharmacological effects of lipid - lowering drugs recapitulate with a larger amplitude the phenotypic effects of common variants within their target genes . BACKGROUND : A major expectation underlying the search for novel susceptibility genes for common diseases using genome - wide association studies ( GWAS ) is that these discoveries will lead to new drug targets . This claim has not been verified yet . Here , we tested the hypothesis that common single nucleotide polymorphisms ( SNPs ) within drug target genes are associated with the corresponding phenotypes , using a population - based GWAS dataset and lipid - lowering drugs as a test case . METHODS : We examined the association between 36 genotyped and 193 imputed SNPs within four lipid - lowering drug target genes ( P04035 , Q07869 , Q8TDS4 / Q8TDS4 and P11597 ) and four non - lipid drug target genes ( P12821 , P30556 , Q9H244 , and P51164 ) and lipid phenotypes , blood pressure , and coronary artery disease in 5635 adult participants of the Lausanne , Switzerland , CoLaus study , genotyped using the Affymetrix 500K SNP chip technology . RESULTS : The phenotypes associated with SNPs within drug target genes recapitulated to a certain extent the pharmacological effects of the drug . The amplitude of the SNP effect was about 10 times smaller than the pharmacological effect of the corresponding drug . In particular , several P11597 SNPs were associated with an elevation in HDL - cholesterol levels , yet a lower diastolic blood pressure , providing evidence that the blood pressure elevation induced by the P11597 inhibitor torcetrapib is more likely compound specific than class specific . CONCLUSION : Pharmacological modulation of lipid - lowering drug targets recapitulates , and markedly amplifies , the phenotypic effects of common SNPs within these target genes . This data provides indirect evidence that , with certain limitations , large - scale GWAS represent a new tool for the discovery and the development of innovative drugs .", "Echicetin coated polystyrene beads : a novel tool to investigate GPIb - specific platelet activation and aggregation . P04275 / ristocetin ( P04275 / R ) induces GPIb - dependent platelet agglutination and activation of αIIbβ3 integrin , which also binds P04275 . These conditions make it difficult to investigate GPIb - specific signaling pathways in washed platelets . Here , we investigated the specific mechanisms of GPIb signaling using echicetin - coated polystyrene beads , which specifically activate GPIb . We compared platelet activation induced by echicetin beads to P04275 / R . Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling . Echicetin beads induced αIIbβ3 - dependent aggregation of washed platelets , while under the same conditions P04275 / R treatment led only to αIIbβ3 - independent platelet agglutination . The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation , while the total amount of echicetin used for activation is not critical . Echicetin beads induced strong phosphorylation of several proteins including p38 , P29323 and P31749 . Synergistic signaling via Q9H244 and thromboxane receptor through secreted ADP and TxA2 , respectively , were important for echicetin bead triggered platelet activation . Activation of PKG by the NO / sGC / cGMP pathway inhibited echicetin bead - induced platelet aggregation . Echicetin - coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb - triggered pathways .", "New frontiers in the management of acute coronary syndromes : cangrelor and elinogrel . The activation and aggregation of platelets at sites of vascular injury or near to implanted stent are pivotal in the development of thrombotic events during and after an acute coronary syndrome ( ACS ) or a percutaneous coronary intervention ( P05154 ) . For that reason , an exclusively oral dual antiplatelet treatment regimen with platelet Q9H244 receptor antagonists in addition to the cyclooxygenase inhibitor aspirin has become the cornerstone of treatment in that contest . However , every trial underlines the same problem : if maximizing antiplatelet therapy significantly attenuates ischemic events in patients with coronary artery disease , on the other side it may also increase bleeding phenomena . These limitations have prompted a search for novel antiplatelet agents with a more favorable risk - benefit ratio . Moreover , an early onset of action is desirable during P05154 and an early offset after bleeding events . Two novel antiplatelet agents , DB06441 and Elinogrel , are available in intravenous form ( Elinogrel also in oral form ) and expand this context . Recent trials have tested them against DB00758 regarding efficacy and safety outcomes . This review aimed at providing an overview on intravenous emerging compounds and recent patents in the setting of ACS and P05154 .", "Nucleotide receptors stimulation by extracellular DB00171 controls Hsp90 expression through P27695 / Ref - 1 in thyroid cancer cells : a novel tumorigenic pathway . Nucleotide receptors signaling affects cell proliferation , with possible implications on tumorigenic processes . However , molecular targets and action mechanisms of the extracellular nucleotides are still poorly elucidated . We have previously shown in ARO cells that P27695 / Ref - 1 , a transcriptional coactivator responsible for the maintenance of the cellular proliferative rate , is functionally controlled by P2 - mediated signaling . Here , we demonstrate that extracellular DB00171 has a mitogenic effect on ARO cells , increasing P29323 phosphorylation , P05412 activation , and cyclin D1 expression . Using the DB00171 / ADPase apyrase and the P2 receptor antagonist suramin , we show that the extracellular DB00171 , physiologically released by ARO cells , exerts mitogenic effects . A differential proteomic approach was used to identify molecular events associated with the DB00171 - induced cell proliferation . Among other proteins , Hsp90 was found upregulated upon DB00171 stimulation . Pretreatment with suramin completely blocked the DB00171 - induced Hsp90 activation , confirming the involvement of cell - surface P2 nucleotide receptors in the DB00171 - mediated activation of ARO cells . Treatment of proliferating ARO cells with suramin and apyrase significantly reduced the intracellular levels of Hsp90 , suggesting an autocrine / paracrine mechanism of control on Hsp90 expression by extracellular DB00171 . The influence of Hsp90 on DB00171 - induced cell proliferation was also demonstrated by its specific inhibition with 17 - P29372 . The molecular pathway by which DB00171 stimulates cell proliferation was further investigated by siRNA strategies showing that Hsp90 is a target of P27695 / Ref - 1 functional activation . Stimulation of ARO cells with specific nucleotide receptors agonists evidenced a major involvement of P47900 and P41231 receptors in controlling the Hsp90 activation . Accordingly , these two receptors resulted significantly upregulated in sample biopsies from different thyroid tumors .", "Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .", "A critical appraisal of the functional evolution of Q9H244 antagonists as antiplatelet drugs . Q9H244 receptor mediated inhibition of platelet aggregation is one of the most explored and exploited pathways in antiplatelet drug therapy to prevent ischemic events in patients undergoing percutaneous coronary intervention ( P05154 ) for the treatment of the acute coronary syndrome ( ACS ) . DB00208 , DB00758 , Prasugrel , DB08816 , DB06441 and Elinogrel are the Q9H244 inhibitors that act as antiplatelet drugs . In this review , the features of these drugs and the factors reported to be responsible for drug resistance or drug ineffectiveness were described . The features like drug metabolism , reversible or irreversible binding of drugs to their target protein and the mode of administration were observed to evolve along with the antiplatelet drugs . These features also include the drug - drug interactions , the pharmacogenetics and pharmacodynamics of Q9H244 inhibitors . We attempted to critically analyze how the desirable features were met by the Q9H244 inhibitors in the course of time . This review provides an overview of the evolution of Q9H244 inhibitors and may guide the researchers to develop better antiplatelet drugs in the future .", "Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( ___MASK49___ ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( DB00293 ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with ___MASK49___ , DB01629 , FUdR , DB00432 , AG331 , AG337 , DB00293 , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .", "State of the art of new Q9H244 antagonists . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : ( a ) it is a pro - drug that needs to be metabolized to its active metabolite ; ( b ) it has a delayed onset and offset of action and ( c ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG - related bleeding complications . Two direct and reversible Q9H244 antagonists , DB06441 and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 is not superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . DB08816 is superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but , like prasugrel , is associated with a higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery is necessary in ticagrelor - treated patients compared to clopiodgrel - treated patients to limit the severity of post - surgical bleeding .", "DB06441 for patients undergoing percutaneous coronary intervention : evidence from a meta - analysis of randomized trials . DB06441 is a new parenteral adenosine diphosphate Q9H244 receptor inhibitor with rapid , profound and reversible inhibition of platelet activity . The aim of this meta - analysis was to evaluate efficacy and safety of this new agent in patients undergoing percutaneous coronary intervention ( P05154 ) . We searched PubMed , Cochrane Library , EMBASE , Web of Science and CINAHL databases from the inception through April 2013 . Randomized controlled trials ( RCTs ) comparing cangrelor with control ( clopidogrel / placebo ) were selected . We used the random - effects models to calculate the risk ratio . The primary efficacy outcome was risk of myocardial infarction , and the primary safety outcome was TIMI major bleeding at 48 h . Three RCTs included a total of 25 , 107 participants . Effects of DB06441 were not different against comparators for myocardial infarction ( MI ) ( Risk ratio [ RR ] 0 . 94 , 95 % confidence interval [ CI ] 0 . 78 - 1 . 13 ) and all - cause mortality ( RR 0 . 72 , 95 % CI 0 . 36 - 1 . 43 ) . However , cangrelor significantly reduced the risk of ischemia - driven revascularization ( RR 0 . 72 , 95 % CI 0 . 52 - 0 . 98 ) , stent thrombosis ( RR 0 . 60 , 95 % CI 0 . 44 - 0 . 82 ) and Q wave MI ( RR 0 . 53 , 95 % CI 0 . 30 - 0 . 92 ) without causing extra major bleeding ( Thrombolysis in Myocardial infarction criteria ) and severe or life - threatening bleeding ( Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries criteria ) . Separate analysis against only clopidogrel also showed similar findings except Q wave MI outcome . Use of cangrelor during P05154 might reduce the risk of ischemia - driven revascularization and stent thrombosis , without causing extra major bleeding .", "P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , DB08816 and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas DB08816 is in clinical development as an orally active agent .", "Natriuretic peptide / natriuretic peptide receptor - A ( P16066 ) system has inhibitory effects in renal fibrosis in mice . OBJECT : This study was designed to examine whether natriuretic peptide / natriuretic peptide receptor - A ( P16066 ) system attenuates renal fibrosis in a unilateral ureteral obstruction ( UUO ) model and also examined the mechanism involved . METHODS : Three groups were studied : untreated UUO in wild - type mice ; untreated UUO in P16066 KO mice ; and P01160 treated ( 0 . 05 microg / kg / min ) UUO in wild - type mice . We measured histological and immunohistochemical findings ( alpha - SMA and F4 / 80 ) , tissue cGMP levels , various mRNA expression levels by real - time PCR analysis , and transcription factor levels ( AP - 1 and NF - kappaB ) in renal tissue . RESULTS : Compared with wild - type UUO mice , NPRA - KO UUO mice had abnormal morphological findings ( fibrous area : + 26 % , alpha - SMA expression : + 30 % ) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF - beta , collagen I , collagen III , P05121 , renin and angiotensinogen , whereas there were no differences in F4 / 80 positive cells or the mRNA expression levels of P05362 , osteopontin , or P13500 between the two groups . In contrast , P01160 pre - treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF - beta , collagen I , collagen III , P05121 , P05362 , osteopontin , P13500 , renin , and angiotensinogen . NPRA - KO UUO mice had higher AP - 1 levels than wild - type UUO mice and P01160 pre - treatment reduced AP - 1 and NF - kappaB activity . CONCLUSION : The endogenous natriuretic peptide / P16066 system may inhibit renal fibrosis partly via inhibition of the angiotensin / AP - 1 / TGF - beta / collagen pathway and exogenous P01160 pre - treatment may inhibit it partly via both the angiotensin / AP - 1 / TGF - beta / collagen and NF - kappaB / inflammatory pathways .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK59___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK59___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK59___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK59___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "___MASK11___ induces the TGFbeta1 / Smad signaling cascade in renal mesangial cells upstream of P42345 . The P42345 kinase inhibitor rapamycin ( sirolimus ) is a drug with potent immunosuppressive and antiproliferative properties . We found that rapamycin induces the TGFbeta / Smad signaling cascade in rat mesangial cells ( MC ) as depicted by the nuclear translocation of phospho - Smads 2 , - 3 and Smad - 4 , respectively . Concomitantly , rapamycin increases the nuclear DNA binding of receptor ( R ) - and co - Smad proteins to a cognate Smad - binding element ( SBE ) which in turn causes an increase in profibrotic gene expression as exemplified by the connective tissue growth factor ( P29279 ) and plasminogen activator inhibitor 1 ( P05121 ) . Using small interfering ( si ) RNA we demonstrate that Smad 2 / 3 activation by rapamycin depends on its endogenous receptor FK binding protein 12 ( P62942 ) . Mechanistically , Smad induction by rapamycin is initiated by an increase in active TGFbeta ( 1 ) as shown by ELISA and by the inhibitory effects of a neutralizing TGFbeta antibody . Using an activin receptor - like kinase ( Q9UM73 ) - 5 inhibitor and by siRNA against the TGFbeta type II receptor ( TGFbeta - RII ) we furthermore demonstrate a functional involvement of both types of TGFbeta receptors . However , rapamycin did not compete with TGFbeta for TGFbeta - receptor binding as found in radioligand - binding assay . Besides SB203580 , a specific inhibitor of the p38 MAPK , the reactive oxygen species ( ROS ) scavenger N - acetyl - cysteine ( Q9C000 ) and a cell - permeable superoxide dismutase ( SOD ) mimetic strongly abrogated the stimulatory effects of rapamycin on Smad 2 and 3 phosphorylation . Furthermore , the rapid increase in dichlorofluorescein ( DCF ) formation implies that rapamycin mainly acts through ROS . In conclusion , activation of the profibrotic TGFbeta / Smad signaling cascade accompanies the immunosuppressive and antiproliferative actions of rapamycin .", "Emerging Q9H244 receptor antagonists : role in coronary artery disease . The use of oral antiplatelet therapy in reducing vascular events has been extensively studied . Currently available oral antiplatelet agents include aspirin and the thienopyridine Q9H244 receptor antagonists . These classes are combined frequently in the setting of acute coronary syndrome and percutaneous coronary intervention ( P05154 ) . Resistance to either or both of these agents is a major concern , as antiplatelet resistance has been linked to an increase in thrombotic events and worse clinical outcomes . As a result , there is a need for newer , more effective antiplatelet agents to address the limitations of currently available therapy . Prasugrel , a third generation thienopyridine , has been approved by both the FDA and European Commission . Two additional Q9H244 agents , ticagrelor and cangrelor are in advanced stages of development . The possible advantages of prasugrel over clopidogrel include a faster onset of action , reduced inter - patient variability and more potent platelet inhibition . DB08816 is an oral reversible Q9H244 antagonist with greater platelet inhibition compared with clopidogrel . DB06441 is being developed as an intravenous Q9H244 antagonist with a very fast onset and offset , which may offer advantages particularly in the setting of coronary intervention . These emerging antiplatelet agents may offer advantages such as faster onset of action , greater potency and reversibility of platelet inhibition . This article summarizes the available clinical data on the upcoming Q9H244 antiplatelet agents in the treatment of coronary artery disease .", "Localisation of P47900 and P51582 receptors in dorsal root , nodose and trigeminal ganglia of the rat . The presence and distribution of P2Y ( nucleotide ) receptor subtypes in rat sensory neurons has been investigated . RT - PCR showed that P2Y ( 1 ) , P2Y ( 2 ) , P2Y ( 4 ) and P2Y ( 6 ) receptor mRNA is expressed in sensory ganglia [ dorsal root ganglion ( Q86YR7 ) , nodose ganglion ( NG ) and trigeminal ganglion ( TG ) ] . The regional and cellular distribution of P2Y ( 1 ) and P2Y ( 4 ) receptor proteins in these ganglia was investigated using immunohistochemistry . P2Y ( 1 ) polyclonal antibodies stained over 80 % of the sensory neurons , particularly the small - diameter ( neurofilament - negative ) neurons . The P2Y ( 4 ) receptor antibody stained more medium - and large - ( neurofilament - positive ) diameter neurons than small - diameter neurons . P2Y ( 1 ) and P2Y ( 4 ) receptor immunoreactivity ( P2Y ( 1 )- IR and P2Y ( 4 )- IR ) was often coexpressed with P2X ( 3 ) receptor immunoreactivity ( P2X ( 3 )- IR ) in subpopulations of neurons . Double immunohistochemistry showed that 73 - 84 % of P2X ( 3 ) receptor - positive neurons also stained for the P2Y ( 1 ) receptor in Q86YR7 , TG and NG while only 25 - 35 % also stained for the P2Y ( 4 ) receptor . Subpopulations of P2Y ( 1 )- IR neurons were coexpressed with NF200 , P80511 and IB ( 4 ) ; most P2Y ( 4 )- IR neurons were coexpressed with NF200 , while only a few neurons were coexpressed with P80511 ( 10 - 20 % ) or with IB ( 4 ) ( 1 - 2 % ) . The results suggest that P2Y as well as P2X receptor subtypes contribute to purinergic signalling in sensory ganglia .", "DB06441 for treatment of arterial thrombosis . INTRODUCTION : Percutaneous coronary intervention ( P05154 ) is a highly effective treatment for obstructive coronary artery disease . Oral platelet Q9H244 receptor antagonists reduce ischemic events in patients treated with P05154 . However , there are several limitations to their use , including variable pharmacodynamics , a slow onset and offset , and in those patients who are pretreated but subsequently require cardiac surgery , increased bleeding . DB06441 is an intravenous agent that provides rapid and intensive inhibition of the Q9H244 receptor that quickly dissipates after discontinuation . A recent , Phase III randomized clinical trial of P05154 patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding . AREAS COVERED : This review outlines the pharmacodynamics , pharmacokinetics , and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned P05154 . EXPERT OPINION : DB06441 is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients , without increasing major bleeding or the need for transfusion . DB06441 will have particular benefit in clopidogrel - naïve patients with high anatomical complexity and / or increased clinical risk ( where the absolute risk for thrombotic and ischemic complications of P05154 is greatest ) .", "Differential effects of P47900 and Q9H244 nucleotide receptors on P27361 / P28482 and phosphatidylinositol 3 - kinase signalling and cell proliferation in serum - deprived and nonstarved glioma P13671 cells . We have previously shown that , in glioma P13671 cells , two nucleotide ADP - sensitive receptors coexist : P47900 , coupled to P98160 and responsible for Ca2 + release , and Q9H244 , negatively coupled to adenylate cyclase . In the present study , we examined the effects of the stimulation of these two receptors on P27361 / 2 and P19957 - K activation , and cell proliferation in either serum - deprived or nonstarved P13671 cells . In response to ADP and its analogues , in serum - starved cells , both Q8TCB0 P27361 and Q8NFH3 P28482 were activated in a time - dependent manner , as monitored by Western blot analysis using an antiphospho - Q8NFH3 / Q8TCB0 MAPK antibody . The phosphorylation was reduced both by removal of the extracellular Ca2 + and partially or almost completely by MRS2179 or AR - C69931MX , specific antagonists of the P47900 and Q9H244 receptors , respectively . The inhibitory effect of antagonists was additive . These data indicate the involvement of both receptors , P47900 and Q9H244 , in the P27361 / 2 activation , but the Q9H244 receptor contribution predominates . P27361 / 2 activity was positively correlated with cell proliferation of cultured glioma P13671 cells . In nonstarved cells , ADP markedly decreased the P19957 - K activity . In contrast , in serum - starved cells , ADP evoked an increase in the P19957 - K activity . Blocking of the P47900 receptor by MRS2179 additionally increased this ADP response . These results suggest that the P47900 receptor has an inhibitory and the Q9H244 receptor a stimulatory effect on P19957 - K signalling pathway . RT - PCR analysis revealed different mRNA expression of both receptors in starved and nonstarved cells . In nonstarved cells , the P47900 receptor mRNA predominates , whereas in serum - deprived cells the expression of Q9H244 mRNA becomes more pronounced . British Journal of Pharmacology ( 2004 ) 141 , 497 - 507 . doi : 10 . 1038 / sj . bjp . 0705639", "P06401 membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine - induced matrix metalloproteinase 9 activity in vitro . Progesterone ( P4 ) and the progestin , 17α - hydroxyprogesterone caproate , are clinically used to prevent preterm births ( PTBs ) ; however , their mechanism of action remains unclear . Cytokine - induced matrix metalloproteinase 9 ( P14780 ) activity plays a key role in preterm premature rupture of the membranes and PTB . We demonstrated that the primary chorion cells and the HTR8 / SVneo cells ( cytotrophoblast cell line ) do not express the classical progesterone receptor ( P06401 ) but instead a novel progesterone receptor , progesterone receptor membrane component 1 ( O00264 ) , whose role remains unclear . Using HTR8 / SVneo cells in culture , we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate ( ___MASK59___ ) and dexamethasone ( DB00514 ) but not P4 or 17α - hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor α - induced P14780 activity after a 24 - hour incubation period . The inhibitory effect of ___MASK59___ , but not DB00514 , was attenuated when O00264 expression was successfully reduced by O00264 small interfering RNA . Our findings highlight a possible novel role of O00264 in mediating the effects of ___MASK59___ and in modulating cytokine - induced P14780 activity in cytotrophoblast cells in vitro .", "DB06441 : a novel Q9H244 receptor antagonist . Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions . Current antiplatelet agents ( aspirin , clopidogrel and glycoprotein IIb / IIIa antagonists ) have demonstrated the capacity to reduce major adverse cardiac events . However , these agents have limitations that compromise their clinical utility . The platelet Q9H244 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies . DB06441 is a potent , competitive inhibitor of the Q9H244 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP - induced platelet aggregation . This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis .", "Involvement of P21453 receptor pathway in angiogenic effects of a novel adenosine - like nucleic acid analog COA - Cl in cultured human vascular endothelial cells . COA - Cl ( 2Cl - C . P01178 - A ) is a recently developed adenosine - like nucleic acid analog that promotes angiogenesis via the mitogen - activated protein ( Q96HU1 ) kinases P27361 / 2 . Endothelial P21453 receptor plays indispensable roles in developmental angiogenesis . In this study , we examined the functions of P21453 in COA - Cl - induced angiogenic responses . Antagonists for P21453 , W146 , and VPC23019 , substantially but still partly inhibited the effects of COA - Cl with regard to P27361 / 2 activation and tube formation in cultured human umbilical vein endothelial cells ( HUVEC ) . Antagonists for adenosine A1 receptor and purinergic P47900 receptor were without effect . Genetic knockdown of P21453 with siRNA , but not that of Q99500 , attenuated COA - Cl - elicited P27361 / 2 responses . The signaling properties of COA - Cl showed significant similarities to those of sphingosine 1 - phosphate , an endogenous P21453 ligand , in that both induced responses sensitive to pertussis toxin ( Gα i / o inhibitor ) , 1 , 2 - bis ( 2 - aminophenoxy ) ethane - N , N , N ', N '- tetraacetic acid tetrakis ( acetoxymethyl ester ) ( BAPTA - AM ) , ( calcium chelator ) , and Q99463 ( c - Src tyrosine kinase inhibitor ) . COA - Cl elevated intracellular Ca ( 2 +) concentration and induced tyrosine phosphorylation of p130Cas , a substrate of c - Src , in HUVEC . COA - Cl displaced [( 3 ) H ] Q14703 in a radioligand - binding competition assay in chem - 1 cells overexpressing P21453 . However , COA - Cl activated P27361 / 2 in CHO - P04264 cells that lack functional P21453 receptor , suggesting the presence of additional yet - to - be - defined COA - Cl target in these cells . The results thus suggest the major contribution of P21453 in the angiogenic effects of COA - Cl . However , other mechanism such as that seen in CHO - P04264 cells may also be partly involved . Collectively , these findings may lead to refinement of the design of this nucleic acid analog and ultimately to development of small molecule - based therapeutic angiogenesis .", "Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK78___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .", "Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor : a direct , parenteral Q9H244 receptor antagonist . The purpose of this study is to evaluate the safety , tolerability , pharmacokinetics , and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers . Twenty - two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens : a 15 - microg / kg bolus followed by a 2 - microg / kg / min infusion or a 30 - microg / kg bolus followed by a 4 - microg / kg / min infusion . The infusion is continued for 60 minutes , and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters . Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes . Moreover , extensive platelet inhibition is maintained throughout the infusion period with near - full recovery of platelet function within 60 to 90 minutes of terminating the infusion . The effect of high - dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate - induced P16109 expression ; how ever , no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function . DB06441 administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function .", "Pharmacodynamic effects during the transition between cangrelor and ticagrelor . OBJECTIVES : This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor . BACKGROUND : DB06441 is an intravenous antagonist of Q9H244 and its use will require transition to and from oral agents . METHODS : Patients ( n = 12 ) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited . On study day 1 , they received a bolus plus 2 - h infusion of cangrelor plus a 180 - mg dose of ticagrelor at either 0 . 5 h ( n = 6 ) or 1 . 25 h ( n = 6 ) . Pharmacodynamic effects ( light transmission platelet aggregation in response to 20 and 5 μmol / l adenosine diphosphate , VerifyNow , Q9H244 assay ( Accumetrics , San Diego , California ) , vasodilator - stimulated phosphoprotein index , and flow cytometry ) were assessed during and after the cangrelor infusion . Patients took 90 mg of ticagrelor twice daily for either 6 ( n = 6 ) or 7 ( n = 6 ) doses . On study day 5 , pharmacodynamic effects were assessed before and during a bolus plus 2 - h infusion of cangrelor . RESULTS : During cangrelor infusion , extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent . After cangrelor was stopped , the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity . CONCLUSIONS : DB08816 given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor . The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor . Consistent with the reversible binding of ticagrelor , this oral Q9H244 antagonist can be administered before , during , or after treatment with cangrelor .", "DB06441 : a review on pharmacology and clinical trial development . Dual antiplatelet therapy with aspirin and an oral ADP Q9H244 receptor antagonist is the standard - of - care for the prevention of ischemic events in patients with acute coronary syndrome or undergoing percutaneous coronary intervention ( P05154 ) . However , currently available ADP Q9H244 receptor antagonists have several limitations , such as interindividual response variability , drug - drug interactions , slow onset / offset and only oral availability . DB06441 is a reversible , potent , intravenous , competitive inhibitor of the ADP Q9H244 receptor that rapidly achieves near complete and predictable platelet inhibition . Along with reversible binding to the receptor cangrelor also has a very short half - life ( 3 - 5 min ) , which in turn results in a rapid offset of action . These properties make cangrelor a promising drug for clinical use in patients undergoing P05154 or patients waiting for major surgery but still require antiplatelet protection . This manuscript provides an update of the current status of knowledge on cangrelor , focusing on its pharmacologic properties and clinical trial development , including the BRIDGE and CHAMPION - PHOENIX trials .", "Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK93___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .", "Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .", "Contribution of the Q9H244 receptor - mediated pathway to platelet hyperreactivity in hypercholesterolemia . BACKGROUND : In hypercholesterolemia , platelets demonstrate increased reactivity and promote the development of cardiovascular disease . OBJECTIVE : This study was carried out to investigate the contribution of the ADP receptor Q9H244 - mediated pathway to platelet hyperreactivity due to hypercholesterolemia . METHODS : P01130 - deficient mice and C57Bl / 6 wild - type mice were fed on normal chow and high - fat ( Western or Paigen ) diets for 8 weeks to generate differently elevated cholesterol levels . Q9H244 receptor - induced functional responses via G ( i ) signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin . Platelet aggregation and secretion , α ( IIb ) β ( 3 ) receptor activation and the phosphorylation of extracellular signal - regulated protein kinase ( P29323 ) and Akt were analyzed . RESULTS : Plasma cholesterol levels ranged from 69 ± 10 to 1011 ± 185 mg dL (- 1 ) depending on diet in mice with different genotypes . Agonist - dependent aggregation , dense and α - granule secretion and JON / A binding were gradually and significantly ( P < 0 . 05 ) augmented at low agonist concentration in correlation with the increasing plasma cholesterol levels , even if elevated thromboxane generation was blocked . These functional responses were induced via increased levels of G ( i ) - mediated P29323 and Akt phosphorylation in hypercholesterolemic mice vs . normocholesterolemic animals . In addition , blocking of the Q9H244 receptor by AR - C69931MX ( DB06441 ) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls . CONCLUSIONS : These data revealed that the Q9H244 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia .", "Gq - mediated Akt translocation to the membrane : a novel PIP3 - independent mechanism in platelets . Akt is an important signaling molecule regulating platelet aggregation . Akt is phosphorylated after translocation to the membrane through Gi signaling pathways by a phosphatidylinositol - 3 , 4 , 5 - trisphosphate ( PIP3 ) - dependent mechanism . However , Akt is more robustly phosphorylated by thrombin compared with adenosine 5 '- diphosphate in platelets . This study investigated the mechanisms of Akt translocation as a possible explanation for this difference . Stimulation of washed human platelets with protease - activated receptor agonists caused translocation of Akt to the membrane rapidly , whereas phosphorylation occurred later . The translocation of Akt was abolished in the presence of a Gq - selective inhibitor or in Gq - deficient murine platelets , indicating that Akt translocation is regulated downstream of Gq pathways . Interestingly , phosphatidylinositol 3 - kinase ( PI3K ) inhibitors or Q9H244 antagonist abolished Akt phosphorylation without affecting Akt translocation to the membrane , suggesting that Akt translocation occurs through a PI3K / PIP3 / Gi - independent mechanism . An Akt scaffolding protein , P38936 - activated kinase ( PAK ) , translocates to the membrane after stimulation with protease - activated receptor agonists in a Gq - dependent manner , with the kinetics of translocation similar to that of Akt . Coimmunoprecipitation studies showed constitutive association of PAK and Akt , suggesting a possible role of PAK in Akt translocation . These results show , for the first time , an important role of the Gq pathway in mediating Akt translocation to the membrane in a novel Gi / PI3K / PIP3 - independent mechanism .", "Electrocardiographic safety of cangrelor , a new intravenous antiplatelet agent : a randomized , double - blind , placebo - and moxifloxacin - controlled thorough QT study . DB06441 is an intravenous Q9H244 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes . To determine the electrophysiologic safety of parenteral cangrelor , cardiac repolarization effects were measured in 67 healthy volunteers ( aged 18 - 45 years ) in a randomized crossover design , including 4 treatment sequences of therapeutic cangrelor , supratherapeutic cangrelor , placebo , and moxifloxacin ( positive control ) . Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and 9 time points postdose on day 1 . For both cangrelor and moxifloxacin , time - matched , placebo - adjusted change in QT from baseline was evaluated using an individual ( QTcI ) heart rate correction . After cangrelor dosing , change in QTcI was < 5 ms at all times points and all corresponding upper 2 - sided 90 % confidence intervals ( CIs ) were < 10 ms . Although moxifloxacin failed to show a lower CI > 5 ms , expected time trends and lower CI > 4 . 0 ms demonstrate assay sensitivity . QTcI was not affected by plasma concentrations of cangrelor metabolites , and cangrelor had no other adverse effects on electrocardiographic parameters . Clinically , cangrelor exposure was well tolerated . Thus , this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers ( clinicaltrials . gov ; identifier NCT00699504 ) .", "Antitumor activity of Triolimus : a novel multidrug - loaded micelle containing Paclitaxel , ___MASK11___ , and 17 - P29372 . Triolimus is a first - in - class , multidrug - loaded micelle containing paclitaxel , rapamycin , and 17 - P29372 . In this study , we examine the antitumor mechanisms of action , efficacy , and toxicity of Triolimus in vitro and in vivo . In vitro cytotoxicity testing of Triolimus was conducted using two aggressive adenocarcinomas including the lung cancer cell line , A549 , and breast cancer cell line , MDA - MB - 231 . The three - drug combination of paclitaxel , rapamycin , and 17 - P29372 displayed potent cytotoxic synergy in both A549 and MDA - MB - 231 cell lines . Mechanistically , the drug combination inhibited both the Ras / Raf / mitogen - activated protein kinase and PI3K / Akt / P42345 pathways . Triolimus was advanced into tumor xenograft models for assessment of efficacy , toxicity , and mechanisms of action . In vivo , a three - infusion schedule of Triolimus inhibited A549 and MDA - MB - 231 tumor growth far more potently than paclitaxel - containing micelles and effected tumor cures in MDA - MB - 231 tumor - bearing animals . Tumor growth delays resulted from a doubling in tumor cell apoptosis and a 50 % reduction in tumor cell proliferation compared with paclitaxel - containing micelles . Enhanced antitumor efficacy was achieved without clinically significant increases in acute toxicity . Thus , Triolimus displays potent synergistic activity in vitro and antitumor activity in vivo with comparable toxicity to paclitaxel . These observations provide strong support for further development of Triolimus and an important proof of concept for safe , effective nanoparticle - based delivery of three complementary anticancer agents .", "Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered .", "Purinergic receptors involved in the immunomodulatory effects of DB00171 in human blood . We recently showed that the physiological compound DB00171 simultaneously inhibited P01375 and stimulated P22301 release in LPS - PHA stimulated blood . The purpose of the present study was to determine the mechanism involved in the concerted modulatory effect of DB00171 on P01375 and P22301 . Incubation of blood with DB00171 in the presence of selective P2 receptor antagonists showed that the stimulatory effect of DB00171 on P22301 release was completely annihilated by both 2 - MeSAMP ( a Q9H244 / 13 receptor antagonist ) and PSB - 0413 ( a Q9H244 receptor antagonist ) . On the other hand , the inhibitory effect of DB00171 on P01375 release was completely reversed by 5 '- P30566 ( a Q96G91 receptor antagonist ) as well as by H - 89 , an inhibitor of DB02527 - activated PKA . The concerted inhibition by DB00171 of P01375 release via Q96G91 activation and stimulation of P22301 release via Q9H244 activation implicates a novel approach towards immunomodulation by altering the balance among pro - and anti - inflammatory cytokines .", "___MASK93___ induces plasminogen activator inhibitor - 1 gene expression in a O15516 - dependent circadian manner . A functional interaction between peroxisome proliferator - activated receptor alpha ( PPARalpha ) and components of the circadian clock has been suggested , but whether these transcriptional factors interact to regulate the expression of their target genes remains obscure . Here we used a PPARalpha ligand , bezafibrate , to search for PPARalpha - regulated genes that are expressed in a O15516 - dependent circadian manner . Microarray analyses using hepatic RNA isolated from bezafibrate treated - wild type , Clock mutant ( Clk / Clk ) , and PPARalpha - null mice revealed that 136 genes are transcriptionally regulated by PPARalpha in a O15516 - dependent manner . Among them , we focused on the plasminogen activator inhibitor - 1 ( P05121 ) gene , because its expression typically shows circadian variation , and it has transcriptional response elements for both Q07869 and O15516 . The bezafibrate - induced expression of P05121 mRNA was attenuated in Clk / Clk mice and in PPARalpha - null mice . The protein levels of PPARalpha were reduced in Clk / Clk hepatocytes . However , the overexpression of PPARalpha could not rescue bezafibrate - induced P05121 expression in Clk / Clk hepatocytes , suggesting that impaired bezafibrate - induced P05121 expression in Clk / Clk mice is not due to reduced PPARalpha expression . Luciferase reporter and chromatin immunoprecipitation analyses using primary hepatocytes demonstrated that DNA binding of both PPARalpha and O15516 is essential for bezafibrate - induced P05121 gene expression . Pull - down assays in vitro showed that both PPARalpha and its heterodimerized partner retinoic acid receptor - alpha can serve as potential interaction targets of O15516 . The present findings revealed that molecular interaction between the circadian clock and the lipid metabolism regulator affects the bezafibrate - induced gene expression .", "Emerging antithrombotic drugs for acute coronary syndrome . INTRODUCTION : Acute coronary syndrome ( ACS ) encompasses acute myocardial infarction ( MI ) and unstable angina . Activation of platelets and coagulation cascade plays a central role in the development of ACS . Over the past decade , there have been substantial improvements in the strategies for secondary prevention of ACS , including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor . However , therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable . AREAS COVERED : This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents ; cangrelor ( an intravenous Q9H244 receptor antagonist ) , vorapaxar ( protease - activated receptor - 1 inhibitor ) and rivaroxaban ( an oral factor Xa inhibitor ) . EXPERT OPINION : DB06441 appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed . DB09030 in addition to standard oral antiplatelet therapy was effective in patients with prior MI , but was not safe in patients with a prior stroke . Low dose rivaroxaban decreased cardiovascular events and mortality in patients post - ACS compared to placebo , although bleeding was increased .", "Q8NFH3 / Q8TCB0 mitogen - activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 - mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 - mediated cardiomyocyte hypertrophy , and the involved mitogen - activated protein kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) mol / L ) . MTT was used to analyze the viability and RT - PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose - and time - dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 - mediated hypertrophic ventricular myocytes .", "Comparison of three GPCR structural templates for modeling of the Q9H244 nucleotide receptor . The P2Y ( 12 ) receptor ( P2Y ( 12 ) R ) is an ADP - activated G protein - coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y ( 12 ) R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A ( 2A ) adenosine receptor ( A ( 2A ) AR ) , and human P61073 ( P61073 ) . By criteria of sequence analysis ( 25 . 6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly - binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N - terminus , the P61073 - based model appeared to be the most consistent with known characteristics of P2Y ( 12 ) R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB - 0739 in the binding pocket of P2Y ( 12 ) R - CXC agree with previously published site - directed mutagenesis studies of Arg256 and Lys280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174 ( EL2 ) side chain . The docking poses of the irreversibly - binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist DB00758 were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~ 4 . 7 Å ) to the sulfur atom of a disulfide bridge involving Cys175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 - based model of the P2Y ( 12 ) R predicted poses of both reversibly and irreversibly - binding small molecules , consistent with observed pharmacology and mutagenesis studies .", "Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK92___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .", "P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK59___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK59___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK59___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK59___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .", "Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .", "The influence of variation in the Q9H244 receptor gene on in vitro platelet inhibition with the direct Q9H244 antagonist cangrelor . Novel Q9H244 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used Q9H244 inhibitor clopidogrel . DB06441 is an intravenously administered Q9H244 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action , and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel . It was the objective of this study to determine the contribution of variation in the Q9H244 receptor gene to platelet aggregation after in vitro partial Q9H244 receptor blockade with the direct antagonist cangrelor . Optical aggregometry was performed at baseline and after in vitro addition of 0 . 05 and 0 . 25 microM cangrelor to the platelet - rich plasma of 254 healthy subjects . Five haplotype - tagging ( ht )- SNPs covering the entire Q9H244 receptor gene were genotyped ( rs6798347C > t , rs6787801T > c , rs9859552C > a , rs6801273A > g and rs2046934T > c [ T744C ] ) and haplotypes were inferred . The minor c allele of SNP rs6787801 was associated with a 5 % lower 20 microM ADP - induced peak platelet aggregation ( 0 . 05 microM cangrelor , p < 0 . 05 ) . Aa homozygotes for SNP rs9859552 showed 20 % and 17 % less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes ( 0 . 05 and 0 . 25 microM cangrelor respectively ; p < 0 . 05 ) . Results of the haplotype analyses were consistent with those of the single SNPs . Polymorphisms of the Q9H244 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the Q9H244 antagonist cangrelor .", "___MASK88___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK88___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .", "___MASK66___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK66___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .", "Stimulation of purinergic receptors modulates chemokine expression in human keratinocytes . DB00171 is abundantly released from stressed or damaged cells in response to mechanical stimulation , bacteria , or noxious agents . In this study , we have investigated the possible involvement of P2 receptors ( receptor for extracellular nucleotides ) in the expression and release of inflammatory mediators by human keratinocytes . Notably , extracellular DB00171 displayed a complex regulation of P01579 - stimulated chemokine expression , with upregulation of CC chemokine ligand 2 ( P13500 ) , P13501 and CXC chemokine ligand 8 ( P10145 ) , and suppression of the receptor CXC chemokine receptor 3 ( P49682 ) , Q07325 , P02778 , and O14625 . The effect of DB00171 was mimicked by ADP and adenosine - 5 '- O - 3 - thiotriphosphate , whereas 2 ', 3 '- O -( 4 - benzoylbenzoyl ) DB00171 ( BzATP ) downmodulated all chemokines investigated . UTP had no effect on P01579 - stimulated chemokine secretion . The broad - spectrum P2 receptor antagonist suramin and the selective P47900 inhibitor adenosine 3 '- phosphate 5 '- phosphosulfate counteracted the effect of DB00171 on secretion of all the chemokines examined , whereas pyridoxal phosphate 6 - azophenyl 2 ', 4 '- disulfonic acid and KN62 ( 1 - [ N , O - bis ( 5 - isoquinoline sulfonyl ) - N - methyl - L - tyrosyl ] 4 phenylpiperazine ) partially prevented the inhibitory effect of DB00171 on P02778 secretion , but on the other hand potentiated the DB00171 - stimulatory effect on P13501 , P13500 , and P10145 release . In lesional skin of psoriasis and atopic dermatitis patients , intense Q99572 reactivity was confined to the cell membrane of the basal layer , whereas diffuse P47900 immunostaining was found throughout the epidermis . Collectively , our data suggest that the orchestrated activation of distinct P2Y and P2X receptors modulates skin inflammation .", "DB06441 for treatment of coronary thrombosis . OBJECTIVE : To review and assess available literature on the chemistry , pharmacology , pharmacodynamics , pharmacokinetics , clinical studies , adverse events , drug interactions , special populations , and dosing and administration for cangrelor , a product in late stage Phase II clinical trials . DATA SOURCES : A literature search of MEDLINE ( 1966 - March 2006 ) , International Pharmaceutical Abstracts ( 1970 - February 2006 ) , and Cochrane database ( first quarter 2006 ) was conducted using key terms of cangrelor , AR - C69931MX , and Q9H244 receptor antagonist . Bibliographies of relevant articles were reviewed for additional references . The Medicines Company Web site was reviewed , and a company representative was contacted . STUDY SELECTION AND DATA EXTRACTION : Available English - language literature , including abstracts , preclinical studies , clinical trials , and review articles , was reviewed . DATA SYNTHESIS : DB06441 is a Q9H244 antagonist under development for treatment of acute coronary syndrome . DB06441 has been studied as an intravenous infusion in doses of 2 or 4 microg / kg / min . It inhibits platelet aggregation with rapid onset and offset and does not require metabolism for therapeutic activity . Published Phase II trials have demonstrated safety and inhibition of platelet aggregation . CONCLUSIONS : DB06441 is a promising investigational medication for inhibition of platelet aggregation in acute arterial coronary events . Phase II trials have shown safety and a greater inhibition of platelet aggregation over clopidogrel . Phase III trials will provide more definitive information on clinical efficacy and safety . Until then , the role of cangrelor is uncertain .", "Mechanism of purinergic activation of endothelial nitric oxide synthase in endothelial cells . BACKGROUND : Decreased endothelial nitric oxide ( NO ) synthase ( P29474 ) activity and NO production are critical contributors to the endothelial dysfunction and vascular complications observed in many diseases , including diabetes mellitus . Extracellular nucleotides activate P29474 and increase NO generation ; however , the mechanism of this observation is not fully clarified . METHODS AND RESULTS : To elucidate the signaling pathway ( s ) leading to nucleotide - mediated P29474 phosphorylation at DB00133 - 1177 , human umbilical vein endothelial cells were treated with several nucleotides , including DB00171 , UTP , and ADP , in the presence or absence of selective inhibitors . These experiments identified P47900 , P41231 , and possibly P51582 as the purinergic receptors involved in P29474 phosphorylation and demonstrated that this process was adenosine independent . Nucleotide - induced P29474 phosphorylation and activity were inhibited by BAPTA - AM ( an intracellular free calcium chelator ) , rottlerin ( a protein kinase Cdelta inhibitor ) , and protein kinase Cdelta siRNA . In contrast , blockade of AMP - activated protein kinase , calcium / calmodulin - dependent kinase II , calcium / calmodulin - dependent kinase kinase , serine / threonine protein kinase B , protein kinase A , extracellular signal - regulated kinase 1 / 2 , and p38 mitogen - activated protein kinase did not affect nucleotide - mediated P29474 phosphorylation . CONCLUSIONS : The present study indicates that extracellular nucleotide - mediated P29474 phosphorylation is calcium and protein kinase Cdelta dependent . This newly identified signaling pathway opens new therapeutic avenues for the treatment of endothelial dysfunction ." ]

[ "___MASK11___", "___MASK49___", "___MASK50___", "___MASK59___", "___MASK66___", "___MASK78___", "___MASK88___", "___MASK92___", "___MASK93___" ]

[ "Circulating undercarboxylated osteocalcin and gingival crevicular fluid tumour necrosis factor - α in children . BACKGROUND : P02818 , a protein secreted by osteoblasts during bone formation , is negatively associated with adult periodontal disease . Little is known about this association in children . AIM : To examine the extent to which plasma undercarboxylated osteocalcin ( ucOC ) is associated with gingival crevicular fluid tumour necrosis factor - alpha ( P16383 P01375 - α ) - a potential marker of gingival inflammation - in children . METHODS : We used data from the Quebec Adipose and Lifestyle InvesTigation in Youth cohort , an ongoing longitudinal study on the natural history of obesity among Caucasian children with a family history of obesity in Quebec , Canada . This cross - sectional analysis from the baseline visit includes 120 children aged 8 - 10 years . Plasma ucOC and P16383 P01375 - α levels were determined by enzyme - linked immunosorbent assay . Linear regression analyses , adjusting for age , gender , family income , sexual maturity stage , daily physical activity , obesity , and fasting glucose were conducted , with P01375 - α level as the dependent variable . RESULTS : A 1 - ng / ml increase in ucOC was associated with a 0 . 96 % decrease ( 95 % confidence interval ( CI ) : - 1 . 69 , - 0 . 23 ) in P16383 P01375 - α level . CONCLUSION : A negative association between a marker of bone formation and a marker of gingival inflammation was observed as early as childhood among Caucasian children with a family history of obesity .", "___MASK43___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .", "Serial changes in serum vitamin P04264 , triglyceride , cholesterol , osteocalcin and 25 - hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis . Serum vitamin P04264 concentrations were measured at presentation ( just before surgery ) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur ( FON , n = 13 ) or total hip replacement for osteoarthritis of the hip ( OA , n = 16 ) . In comparison with healthy elderly volunteers ( n = 25 ) , serum vitamin P04264 concentrations were significantly lower in both groups at presentation , and fell significantly within 24 h after surgery to concentrations approaching non - detectable , subsequently returning to pre - operative values within 3 weeks . Serum vitamin P04264 tended to be lower in the fracture group both before and after operation , although calculation of a vitamin P04264 - triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group . P02818 concentrations were similar and fell significantly after operation in both groups , returning to pre - operative levels within 7 days . No differences in the two forms of osteocalcin ( carboxylated and undercarboxylated ) were observed either before or after operation in either group . DB00146 concentrations were not significantly different between the two groups at any time . DB01022 status may be lower than desirable in certain groups of the elderly population , and supplementation should be considered as prophylactic therapy .", "A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulfide isomerase . The assembly of triglyceride - rich lipoproteins requires the formation in the endoplasmic reticulum of a complex between apolipoprotein B ( apoB ) , a microsomal triglyceride transfer protein ( P55157 ) , and protein disulfide isomerase ( P07237 ) . In the P55157 complex , the amino - terminal region of P55157 ( residues 22 - 303 ) interacts with the amino - terminal region of apoB ( residues 1 - 264 ) . Here , we report the identification and characterization of a site on apoB between residues 512 and 721 , which interacts with residues 517 - 603 of P55157 . P07237 binds in close proximity to this apoB binding site on P55157 . The proximity of these binding sites on P55157 for P07237 and amino acids 512 - 721 of apoB was evident from studies carried out in a yeast two - hybrid system and by co - immunoprecipitation . The expression of P07237 with P55157 and apoB16 ( residues 1 - 721 ) in the baculovirus expression system reduced the amount of P55157 co - immunoprecipitated with apoB by 73 % . The interaction of residues 512 - 721 of apoB with P55157 facilitates lipoprotein production . Mutations of apoB that markedly reduced this interaction also reduced the level of apoB - containing lipoprotein secretion .", "___MASK41___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .", "[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK40___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .", "Paradoxical effects of resveratrol on the two prostaglandin H synthases . Prostaglandin H synthase ( PGHS ) is the primary enzyme responsible for the biosynthesis of prostaglandins and thromboxanes . Of the two isoenzymes of PGHS , P23219 is constitutively expressed and P35354 is inducible by mitogens or other inflammatory stimuli . Constitutive expression of P35354 in neoplastic tissues has been implicated in carcinogenesis . DB02709 , a lignan , was recently shown to be an anticarcinogen that selectively inhibits P23219 . In vitro experiments to resolve these seemingly paradoxical observations revealed that resveratrol is not only an inhibitor of P23219 but also is an activator of P35354 . DB02709 non - competitively inhibited P23219 with a P04264 of 26 +/- 2 microM but enhanced the P35354 activity nearly twofold . Additionally , resveratrol did not serve as a reducing co - substrate for the peroxidase activities of either enzyme despite being an easily oxidizable phenolic compound . DB02709 inhibited the peroxidase activity of P23219 ( IC50 = 15 microM ) better than that of P35354 ( IC50 = > 200 microM ) . Inhibition of the perxidase activity but not the cyclooxygenase activity of P35354 resulted in the production of PGG2 from arachidonic acid . A plausible relationship between these observation and the anticarcinogenic activity of resveratrol is discussed .", "___MASK11___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK11___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK11___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK11___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK11___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK11___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .", "Creating a genotype - based dosing algorithm for acenocoumarol steady dose . ___MASK62___ is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol . The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2 , 683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R² = 0 . 15 ( estimation ´ s standard error = 4 . 5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation ´ s standard error = 4 . 6 ) . Again , the best model combined clinical and genetic factors ( R² = 0 . 48 ; estimation ´ s standard error = 4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg / week ) or higher ( ≥ 25 mg / week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication .", "P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK75___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .", "Direct binding of recombinant plasminogen kringle 1 - 3 to angiogenin inhibits angiogenin - induced angiogenesis in the chick embryo P62158 . P03950 is one of the most potent angiogenesis - inducing proteins . Angiostatin is one of the most potent angiogenesis inhibitors , and it contains the first four kringle domains of plasminogen ( P04264 - 4 ) . Recombinant human plasminogen kringle 1 - 3 ( rK1 - 3 ) was expressed in Escherichia coli and purified to homogeneity . The binding of t - 4 - aminomethylcyclohexanecarboxylic acid with the purified kringle 1 - 3 was determined by changes in intrinsic fluorescence . rK1 - 3 exhibits comparable ligand - binding properties as native human plasminogen kringle 1 - 3 . The purified rK1 - 3 inhibits neovascularization in the chick embryo chorioallantoic membrane ( P62158 ) assay . Interaction of angiogenin with rK1 - 3 was examined by immunological binding assay and surface plasmon resonance kinetic analysis , and the equilibrium dissociation constants for the complex , Kd , are 0 . 89 and 0 . 18 microM , respectively . rK1 - 3 inhibits angiogenin - induced angiogenesis in the chick embryo P62158 in a concentration - dependent manner . These results indicate that rK1 - 3 directly binds to angiogenin and thus rK1 - 3 inhibits the angiogenic activity of angiogenin .", "The revised human liver cytochrome P450 \" Pie \" : absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics . The CYP4F subfamily of enzymes has been identified recently to be involved in the metabolism of endogenous compounds ( arachidonic acid and leukotriene B4 ) , nutrients ( vitamins P04264 and E ) , and xenobiotics ( pafuramidine and fingolimod ) . P78329 and CYP4F3B are reported to be expressed in the human liver . However , absolute concentrations of these enzymes in human liver microsomes ( HLMs ) and their interindividual variability have yet to be determined because of the lack of specific antibodies . Here , an liquid chromatography with tandem mass spectrometry ( LC - MS / MS ) - based targeted quantitative proteomic approach was employed to determine the absolute protein concentrations of P78329 and CYP4F3B compared with CYP3A in two panels of HLMs ( n = 31 ) . As a result , the human hepatic cytochrome P450 ( P450 ) \" pie \" has been revised to include the contribution of CYP4F enzymes , which amounts to 15 % of the total hepatic cytochrome P450 enzymes . CYP4F3B displayed low interindividual variability ( 3 . 3 - fold ) in the HLM panels whereas P78329 displayed large variability ( 21 - fold ) . However , P78329 variability decreased to 3 . 4 - fold if the two donors with the lowest expression were excluded . In contrast , CYP3A exhibited 29 - fold interindividual variability in the same HLM panels . The proposed marker reaction for CYP4F enzymes pafuramidine / DB289 M1 formation did not correlate with CYP4F protein content , suggesting alternate metabolic pathways for DB289 M1 formation in HLMs . In conclusion , CYP4F enzymes are highly expressed in the human liver and their physiologic and pharmacologic roles warrant further investigation .", "Disulfide - dependent protein folding is linked to operation of the vitamin K cycle in the endoplasmic reticulum . A protein disulfide isomerase - Q9BQB6 redox enzyme complex appears to be responsible for vitamin P04264 2 , 3 - epoxide reduction . Gamma - carboxylation of vitamin K - dependent proteins is dependent on formation of reduced vitamin P04264 ( Vit . K1H2 ) in the endoplasmic reticulum ( ER ) , where it works as an essential cofactor for gamma - carboxylase in post - translational gamma - carboxylation of vitamin K - dependent proteins . Vit . K1H2 is produced by the warfarin - sensitive enzyme vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) of the vitamin K cycle that has been shown to harbor a thioredoxin - like CXXC center involved in reduction of vitamin P04264 2 , 3 - epoxide ( Vit . K > O ) . However , the cellular system providing electrons to the center is unknown . Here data are presented that demonstrate that reduction is linked to dithiol - dependent oxidative folding of proteins in the ER by protein disulfide isomerase ( P07237 ) . Oxidative folding of reduced RNase is shown to trigger reduction of Vit . K > O and gamma - carboxylation of the synthetic gamma - carboxylase peptide substrate FLEEL . In liver microsomes , reduced RNase - triggered gamma - carboxylation is inhibited by the P07237 inhibitor bacitracin and also by small interfering RNA silencing of P07237 in P29320 293 cells . Immunoprecipitation and two - dimensional SDS - PAGE of microsomal membrane proteins demonstrate the existence of a Q9BQB6 enzyme complex where P07237 and Q9BQB6 appear to be tightly associated subunits . We propose that the P07237 subunit of the complex provides electrons for reduction of the thioredoxin - like CXXC center in Q9BQB6 . We can conclude that the energy required for gamma - carboxylation of proteins is provided by dithiol - dependent oxidative protein folding in the ER and thus is linked to de novo protein synthesis .", "Novel biologically active bibenzyls from Bauhinia saccocalyx Pierre . Four new bibenzyls , bauhinols A - D ( 1 - 4 ) , together with the two known bibenzyls 5 and 6 , were isolated from the roots of Bauhinia saccocalyx , and their structures were elucidated by analyses of spectroscopic data . Bauhinol A ( 1 ) exhibits significant cytotoxicity towards NCI - H187 ( small - cell lung cancer ) , BC ( breast cancer ) , and KB ( oral - cavity cancer ) cell lines , with IC50 values of 2 . 7 - 4 . 5 microg / ml . Bauhinol B ( 2 ) is cytotoxic against NCI - H187 ( IC50 = 1 . 1 microg / ml ) and BC ( IC50 = 9 . 7 microg / ml ) cell lines , but inactive toward the KB cell line ( at 20 microg / ml ) . Compound 2 also is mildly antifungal towards Candia albicans ( IC50 = 28 . 9 microg / ml ) . Bibenzyl 6 is active against NCI - H187 ( IC50 = 14 . 1 microg / ml ) and BC ( IC50 = 4 . 0 microg / ml ) cells , but inactive ( at 20 microg / ml ) toward the KB cell line . Compounds 1 , 2 , and 6 show mild antimycobacterial activities , with MIC values of 25 - 50 microg / ml , but are inactive at 20 microg / ml against the P04264 malarial parasite strain ( Plasmodium falciparum ) . While bauhinol A ( 1 ) is inactive against cyclooxygenase 1 ( P23219 ) and cyclooxygenase 2 ( P35354 ) , compounds 2 and 6 inhibit both P23219 and P35354 , with IC50 values comparable to those of the standard drug , aspirin ( Table 3 ) .", "___MASK81___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .", "Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK68___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .", "Expression of two variants of the human mu opioid receptor mRNA in SK - N - SH cells and human brain . A partial mu opioid receptor gene was isolated from a human genomic library using a mouse delta opioid receptor cDNA as a probe . Using information from this genomic clone and the published human mu receptor , P35372 , a cDNA was isolated from SK - N - SH mRNA that codes for a variant of the P35372 mRNA , MOR1A . The presence of MOR1A is also shown in human brain using RT - PCR . MOR1A differs from P35372 in that the 3 ' terminal intron has not been removed . An in - frame termination codon is found four amino acids after the 5 ' consensus splice site , making MOR1A eight amino acids shorter than P35372 . Both receptors show similar ligand binding and coupling to DB02527 in CHO - P04264 cells . The C - terminal differences between P35372 and MOR1A could have effects on receptor coupling or receptor transport and localization .", "The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin - dependent kinase inhibitors . We examined the effect of suboptimal concentrations of cyclin - dependent kinase inhibitors , which do not interfere with cell proliferation , on retinoblastoma expression in hamster ( Chinese hamster ovary P04264 ) and human ( K562 and HeLa ) cells . To achieve this , we used the chemical inhibitors roscovitine and olomoucine ( which inhibit P24941 preferentially ) , P55089 - 01 ( which also inhibits P11802 / 6 ) and P38936 ( as an intrinsic inhibitor ) . All chemical inhibitors and overexpression of P38936 strongly induced retinoblastoma protein expression . P55089 - 01 - mediated retinoblastoma expression was caused by an increase in both the levels of retinoblastoma mRNA and the stability of the protein . The expression of the transcription factor Sp1 , a retinoblastoma - interacting protein , was also enhanced by all the cyclin - dependent kinase inhibitors tested . However , Sp1 expression was caused by an increase in the levels of Sp1 mRNA without modification in the stability of the protein . By using luciferase experiments , the transcriptional activation of both retinoblastoma and Sp1 promoters by P55089 - 01 was confirmed . Bisindolylmaleimide I , at concentrations causing a similar or higher inhibition of protein kinase C than P55089 - 01 , provoked a lower activation of retinoblastoma and Sp1 expression . Finally , the effects of cyclin - dependent kinase inhibitors on dihydrofolate reductase gene expression were evaluated . Treatment with P55089 - 01 increased cellular dihydrofolate reductase mRNA levels , and dihydrofolate reductase enzymatic activity was enhanced by P55089 - 01 , roscovitine , olomoucine and P38936 , in transient transfection experiments . These results support a mechanism for the self - regulation of retinoblastoma expression , and point to the need to establish the appropriate dose of cyclin - dependent kinase inhibitors as antiproliferative agents in anticancer treatments .", "[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK73___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .", "Titration of KATP channel expression in mammalian cells utilizing recombinant baculovirus transduction . A variety of transfection approaches have been used to deliver plasmids encoding ion channel genes into cells . We have used the baculovirus transduction system , BacMam , to demonstrate transient expression of multi - subunit KATP channels in CHO - P04264 and P29320 - 293 EBNA cells using sulfonylurea receptor 1 ( Q09428 ) , SUR2A , SUR2B , and P55040 6 . 2 genes . [ 3H ] - glyburide binding , patch clamp , and DiBAC4 ( 3 ) measurements of membrane potential changes were used to monitor channel expression . BacMam delivery of each Q09428 isoform with KIR6 . 2 was demonstrated based on its pharmacological profiles . Expression levels of Q09428 and KIR6 . 2 were titrated by varying the viral concentration or time of virus addition , with functional activity measured in as little as 4 - 6 hours posttransduction . Further increases in BacMam virus induced sufficient KATP expression to dominate membrane potential without pharmacological opening of the channel . Independently altering treatment with virus containing either the Q09428 or KIR6 . 2 gene revealed interactions among subunits during formation of functional channels in the plasma membrane . This study demonstrates the utility and versatility of BacMam as a valuable gene delivery tool for the study of ion channel function ." ]

[ "___MASK11___", "___MASK40___", "___MASK41___", "___MASK43___", "___MASK62___", "___MASK68___", "___MASK73___", "___MASK75___", "___MASK81___" ]

[ "Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK44___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .", "Adverse reactions during biological drug therapy in psoriasis : clinical series and a review of the literature . AIM : Psoriasis is a chronic , inflammatory skin disorder , histologically characterized by epidermal hyperplasia , anomalous keratinocyte differentiation , angiogenesis , and by inflammatory cell infiltrate . Psoriasis has a significant impact on quality of life and is often associated with serious psychological effects . The use of biological agents is expanding worldwide as alternative treatment for chronic inflammatory diseases including psoriasis . The European Medicines Agency ( EMEA ) approved the use of DB00095 , DB00005 , DB00065 and DB00051 in the treatment of psoriasis on the basis of the positive findings obtained from well - designed clinical trials . The ongoing monitoring of tolerability and possible side - effects of these drugs has , however , recently lead to the EMEA suspending DB00095 on the grounds that the possible risks of its use outweighed the benefits . METHODS : Fifty - four patients treated with the two classes of biological drug ( DB00095 and anti - P01375 - α ) were studied . The choice of biological drug therapy was conditioned by the extent and seriousness of the disease and by the presence of concomitant pathologies . RESULTS : Nineteen patients presented adverse reactions , of which 9 necessitated interruption in treatment ( 6 DB00095 and 3 anti - P01375 - α ) . CONCLUSION : This work reports the adverse reactions to these biological therapies found in our patients along with a review of the literature concerning adverse reactions in psoriasis treatment . From our experience and basing ourselves on the literature reporting studies conducted in large centres , we feel that it is indispensable to continue monitoring any reactions during biological drug treatment . In this way , there is more likelihood of preventing , where possible , or better managing any reactions linked to the use of these drugs .", "DB00051 : new indication . Ankylosing spondylitis : just another P01375 alpha antagonist . No comparisons with other P01375 alpha antagonists .", "Anti - P01375 treatments and obstructive symptoms in Crohn ' s disease : a prospective study . BACKGROUND : The development of symptomatic strictures in Crohn ' s Disease after anti - Tumour Necrosis Factor - α antibodies is undefined . AIM : To assess , in a prospective longitudinal study , the frequency of sub / obstructions in Crohn ' s Disease patients after treatment with DB00065 or DB00051 . Changes of small bowel lesions after these biological therapies were searched by ultrasonography . MATERIALS AND METHODS : From January 2007 to October 2008 , 36 Crohn ' s Disease patients with no previous sub / obstructions were treated with either DB00065 ( n = 13 ) or DB00051 ( n = 23 ) for ≥ 12months ( mean follow - up duration after the first treatment 23 . 2 ± 6 . 8months ) . Small Intestine Contrast Ultrasonography was performed before and after treatment in 19 / 36 patients . Sonographic parameters included : bowel wall thickness , lumen diameter , bowel dilation and lesion extent . RESULTS : Sub / obstructions developed in 3 / 36 patients treated with DB00065 ( n = 1 ) or DB00051 ( n = 2 ) , all with fibrostricturing Crohn ' s Disease . Sonographic parameters did not significantly change after treatment . CONCLUSIONS : Sub / obstructive symptoms may develop in one tenth of Crohn ' s Disease patients treated with anti - Tumour Necrosis Factor - α antibodies , with no significant sonographic changes of the small bowel lesions .", "Alopecia areata universalis elicited during treatment with adalimumab . DB00051 is a fully humanized recombinant anti - tumour - necrosis - factor ( P01375 ) monoclonal antibody which has been approved for rheumatoid arthritis , active ankylosing spondylitis , psoriatic arthritis and Crohn ' s disease . We report a case of alopecia areata ( AA ) universalis occurring 6 months after administration of adalimumab monotherapy in a patient with a long - standing history of psoriatic arthritis and psoriasis . The diagnosis was confirmed by a scalp biopsy which showed a peribulbar infiltrate of both P01730 + and CD8 + T cells , CD1a + dendritic cells as well as P34810 + and Q86VB7 + macrophages . In addition , immunofluorescence staining for P01375 was found in the mononuclear cell infiltrate . This case suggests a complex role of P01375 in the induction of AA .", "Cordycepin suppresses P01375 - α - induced NF - κB activation by reducing p65 transcriptional activity , inhibiting IκBα phosphorylation , and blocking IKKγ ubiquitination . Cordycepin is reported to participate in multiple pharmacological activities including anti - tumor and anti - inflammation , and is involved in the regulation of NF - κB signaling pathway . However , the detailed molecular mechanism of cordycepin in suppression of NF - κB signaling pathway remains ambiguous . In this study , we first analyzed the effect of cordycepin on NF - κB activity in P29320 - 293T cells , and found that cordycepin resulted in a dose - dependent reduction in P01375 - α - induced NF - κB activation . Although cordycepin did not block P01375 - α - induced nuclear translocation of p65 , high concentration of cordycepin reduced the DNA - binding and transcriptional activities of NF - κB . Moreover , cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα . Further investigation revealed that cordycepin suppressed IKKs - mediated NF - κB activation and inhibited the ubiquitination of IKKγ . In conclusion , cordycepin effectively inhibits NF - κB signaling through suppressing the activities of NF - κB , IκB and IKK . Thus , cordycepin may provide some potential therapeutic application in inflammation - associated disorders and cancer .", "Efficacy and complications of adalimumab treatment for medically - refractory Crohn ' s disease : analysis of nationwide experience in Scotland ( 2004 - 2008 ) . BACKGROUND : DB00051 is a second generation humanized anti - tumour necrosis factor ( P01375 ) monoclonal antibody with established efficacy in Crohn ' s disease ( CD ) . AIMS : To evaluate the efficacy and safety of adalimumab on a nationwide clinical setting . METHODS : We used the Scottish Society of Gastroenterology network to identify and follow up the clinical outcomes of patients with CD treated with adalimumab over a 4 - year period ( 2004 - 2008 ) . RESULTS : A total of 98 patients received adalimumab - 100 . 5 patient follow - up years were recorded ( 64 . 3 % females ; median age at diagnosis of 20 . 7 years ; 88 . 8 % treated with 80 / 40 mg induction regimen . Eighty eight ( 89 . 8 % ) had previous infliximab with 29 ( 32 . 9 % ) primary nonresponders ; 32 ( 32 . 6 % ) were corticosteroid - dependent ; 47 ( 47 . 9 % ) were intolerant / resistant to most immunosuppressive therapies ( two or more ) . In all , 60 % of patients were in clinical remission at 1 - year follow - up , with 30 % and 55 % requiring dose escalation to weekly therapy at 1 - and 2 - year follow - up respectively . Overall , 29 ( 29 . 6 % ) patients developed complications with eight nonfatal serious ( 8 . 2 % ) adverse events and 2 ( 2 . 0 % ) case fatalities ( sepsis following perforation and disseminated colorectal cancer , respectively ) . CONCLUSIONS : DB00051 is efficacious in severe and refractory CD in the clinical setting , although there remain significant therapy - and disease - related risks of serious complications .", "Effect of adalimumab on sleep parameters in patients with psoriasis and obstructive sleep apnea : a randomized controlled trial . INTRODUCTION : Obstructive sleep apnea ( OSA ) is frequently seen in patients with psoriasis vulgaris . The effect of adalimumab , a P01375 - α antagonist , on OSA is unknown . METHODS : Patients with at least 5 % of their body surface area covered with psoriasis and a sleep apnea defined as an apnea / hypopnea index ( AHI ) of at least 15 were recruited . They were randomized to either adalimumab 80 mg followed by adalimumab 40 mg every other week for 7 weeks or placebo . Patients were evaluated by polysomnography at baseline and day 56 . The objective of this trial was to study the efficacy of adalimumab on sleep parameters in patients with psoriasis and OSA . The primary end point of this double - blind study was the change in AHI between baseline and day 56 . RESULTS : A total of 20 patients who were randomized completed the trial . There was no significant difference ( p = 0 . 485 ) ( 95 % CI = - 21 . 07 - 42 . 73 ) at day 56 in the change from baseline in AHI between groups . CONCLUSIONS : DB00051 used for 8 weeks at 40 mg every other week for the treatment of psoriasis did not improve OSA in this 20 - patient study .", "Role of novel biological therapies in psoriatic arthritis : effects on joints and skin . Psoriatic arthritis ( PsA ) is a partly debilitating disease that may affect small and large joints and the spine . Patients with PsA are divided into different subgroups according to joint involvement and their disease may be classified as part of the spectrum of spondyloarthritides or seronegative rheumatoid arthritis . Traditional treatment comprises nonsteroidal anti - inflammatory drugs , systemic and intra - articular corticosteroids and disease - modifying antirheumatic drugs such as sulfasalazine , methotrexate and cyclosporin . On the basis of the very recent studies performed in the US and Germany , patients with severe disease can be treated with anti - tumour necrosis factor ( P01375 ) therapy . Biologicals such as etanercept and infliximab have been used successfully to treat PsA . While etanercept is a 75kD P01375 receptor fusion protein that binds to TNFalpha and TNFbeta , infliximab is a chimeric monoclonal antibody that binds to TNFalpha both in its soluble form in the serum and on the cell membrane . DB00051 is a fully humanised antibody recognising TNFalpha that has not been tested in PsA to date . Another biological agent , alefacept , is directed against the adhesion molecule lymphocyte function - associated antigen ( LFA ) - 2 , which is known to interfere with T - cell activation . DB00092 has been shown to be efficacious in a limited number of patients with PsA . Taken together , there has been definite recent progress in the treatment of PsA . Severely affected patients may especially have substantial benefit from therapy with biologicals directed against TNFalpha and other targets .", "Drug focus : adalimumab in the treatment of moderate to severe psoriasis . DB00051 is a fully human IgG1 monoclonal antibody that specifically binds to tumor necrosis factor ( P01375 ) - alpha , and is administered by subcutaneous injection . The mechanism of action is based on both the neutralization of P01375 bioactivity and the induction of apoptosis of P01375 - expressing mononuclear cells . The drug is approved for the treatment of rheumatoid arthritis , ankylosing spondylitis , and psoriatic arthritis ( PsA ) , and recently also for the treatment of Crohn ' s disease . The effectiveness of adalimumab in psoriasis was previously suggested by the subset analysis of patients enrolled in PsA trials who were affected by concomitant psoriasis , and recently confirmed by a phase II trial and the preliminary results from phase III trials in moderate to severe psoriasis . These results demonstrate that adalimumab is effective in improving psoriasis and quality of life , with sustained effects over >/= 1 - year treatment period . The safety data from psoriasis studies were similar to those of previous studies in other diseases . The risk of adverse events did not appear to increase with continuous long - term exposure to adalimumab .", "A SPECIAL MEETING REVIEW EDITION : Highlights in Anti - Tumor Necrosis Factor Monitoring and Antibody Monitoring From the 2014 DDW Meeting : Digestive Disease Week 2014 May 3 - 6 , 2014 • Chicago , Illinois : Special Reporting on :• Therapeutic Monitoring of Anti - P01375 Levels and Antibodies to Predict Response and Achieve Mucosal Healing • Prospective Therapeutic Drug Monitoring and Optimization of DB00065 Maintenance Therapy in IBD • Classification of Non - Q9UKU7 , Crohn ' s Disease and Ulcerative Colitis in a Young Patient Population Using a Multi - Marker Diagnostic Panel • Persistence of Antibodies to DB00065 for More Than Two Months Predicts Loss of Response to DB00065 in Inflammatory Bowel Diseases • Pre - Operative Serological Markers May Predict Postoperative Crohn ' s Disease Recurrence : Results From a Prospective Mono - Centric Trial • Antibodies and Levels of Biologies - Reactive vs Proactive Measurements • Higher DB00352 Nucleotide Concentrations Are Associated With Higher Trough Levels of DB00065 in Patients on Combination Therapy • The Clinical and Immunological Significance of Low Levels of DB00065 in the Absence of Anti - lnfliximab Antibodies in Patients With IBD • Antibodies to DB00051 Predict Inflammation in Crohn ' s Patients on Maintenance DB00051 Therapy • Q676U5 Genotype Is Associated With Response to Anti - TNFWith Expert Commentary by : William J . Sandborn , MDProfessor and Chief , Division of Gastroenterology Director , UCSD Q9UKU7 CenterUC San Diego Health SystemLa Jolla , California .", "[ Pharmacology of biologic medications ] . Two major types of inflammatory bowel diseases ( Q9UKU7 ) are Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) . Insights into their pathophysiology and inflammatory cascade have lead to the discovery of medications that can have a selective effect on a particular molecule or signal pathway and correct an imbalance in pro - and anti - inflammatory mediators . The first to be developed were the P01375 antagonists , soluble receptors like etanercept and monoclonal antibodies . DB00065 has been approved worldwide for treatment of moderate to severe and active fistulizing forms of Crohn ' s disease , as well as for severe forms of ulcerative colitis in adults who do not react to full and adequate corticosteroid and / or immunosuppressive therapy , i . e . for patients who have problems with or medical contraindications to such therapy and for treatments of severe forms of active disease in children . DB00051 can be applied in cases when antibodies develop as a reaction to infliximab , leading to reduced drug efficacy and allergic reactions . According to the available data from preclinical tests and earlier phases of clinical tests , potential candidates for new biological medications in treating IBDs are another P01375 antagonist ( certolizumab ) , inhibitors of Th1 polarisation ( fontolizumab , ustekinumab ) and selective adhesion - molecule inhibitors ( natalizumab ) .", "DB00051 for the treatment of ankylosing spondylitis . Ankylosing spondylitis is a chronic inflammatory disease , with a prevalence of approximately 0 . 5 % , which starts in the third decade of life . Treatment was , until recently , limited . Conventional disease - modifying drugs are not effective for the spinal manifestations , and NSAIDs and physical therapy were the standard treatment , without any other options for patients who did not respond to this treatment . Therefore , the high efficacy of the new group of P01375 - blockers for the treatment of active ankylosing spondylitis represents a breakthrough for NSAID - refractory patients . Following the introduction of the two P01375 - blockers , infliximab and etanercept , the fully humanized , anti - P01375 monoclonal antibody adalimumab is now the third product that has been approved for the treatment of ankylosing spondylitis . DB00051 is given subcutaneously every 2 weeks at a dose of 40 mg . In open and placebo - controlled trials , the drug was shown to be safe and effective in ankylosing spondylitis patients . Long - term treatment data of up to 2 years are now available , confirming efficacy and acceptable safety .", "DB00051 ( HUMIRA ) : a review . DB00051 ( HUMIRA , Abbott Laboratories ) is a new fully human P01375 monoclonal antibody recently approved for the treatment of rheumatoid arthritis and undergoing trials for use in treating other conditions , including psoriasis and psoriatic arthritis . This article reviews its mechanisms of action , clinical trial results , and related discussion .", "DB00051 specifically induces CD3 (+) P01730 (+) CD25 ( high ) Foxp3 (+) CD127 (-) T - regulatory cells and decreases vascular endothelial growth factor plasma levels in refractory immuno - mediated uveitis : a non - randomized pilot intervention study . AIM : To explore immunoregulatory and anti - inflammatory pathways specifically targeted by a subcutaneous anti - TNFαdrug - adalimumab - which might be relevant for controlling refractory uveitis . DESIGN : Non - randomized pilot intervention study on the effects of adalimumab on Treg populations and plasma P15692 levels in refractory uveitis patients . Inflammatory and immunological parameters were measured in 12 patients before therapy , and 1 and 6 months after therapy , and analyzed in the context of ophthalmological outcomes . The results were compared with those obtained in 10 systemic prednisone - treated uveitis patients . RESULTS : After 1 month of treatment , all patients responded , with 67 % of adalimumab group and 80 % of the corticosteroid group achieving inactivity ( P = 0 . 5 ) . Unlike steroid - treated patients , a significant increase in T - regulatory P01730 (+) CD25 ( high ) Foxp3 (+) CD127 (-) cells was observed in adalimumab patients after 1 month of treatment , and maintained after 6 months ( P = 0 . 003 ) . A significant adalimumab - specific drop in plasma P15692 was observed after 1 and 6 months of treatment ( P = 0 . 019 ) . In every single patient , Tregs but not P15692 correlated with disease activity . CONCLUSIONS : In refractory uveitis patients treated with adalimumab , clinical efficacy may be mediated through upregulation of Tregs in addition to modulation of P15692 - mediated inflammatory pathways . These biological properties , which were not observed in patients treated with corticosteroids , may reflect the specificity of P01375 - αtargeting .", "DB00051 : a review of its use in adult patients with rheumatoid arthritis . DB00051 ( Humira ) is a recombinant , fully human anti - tumor necrosis factor ( P01375 ) monoclonal antibody approved in the US and Europe for the treatment of adult patients with moderate to severe , active rheumatoid arthritis ( RA ) . In combination with methotrexate or standard antirheumatic therapy or as monotherapy , adalimumab effectively reduced signs and symptoms of RA , induced remission , improved physical function and inhibited the progression of structural damage in several randomized , double - blind , placebo - controlled phase III trials . The drug was generally well tolerated , with most adverse events being mild to moderate , and the serious adverse events profile being similar to that generally seen in patients with RA not receiving anti - P01375 agents . DB00051 was at least as cost effective as other anti - P01375 agents used in the therapy of RA , and provided significant improvements in patients ' health - related quality of life . Overall , adalimumab in combination with methotrexate or standard antirheumatic therapy is valuable as a first - line therapeutic option in patients with early , aggressive RA , and a second - line therapeutic option in patients with long - standing , moderate to severe RA . For the latter indication , adalimumab may also be used as monotherapy .", "Usefulness of DB00051 for Treating a Case of Intestinal Behçet ' s Disease With Trisomy 8 Myelodysplastic Syndrome . Behçet ' s disease ( BD ) is a systemic vasculitis , while myelodysplastic syndrome ( P43034 ) is a heterogeneous group of clonal hematologic disorders characterized by ineffective hematopoiesis . Some studies suggest a relationship between P43034 and BD , especially intestinal BD , and trisomy 8 seems to play an important role in both diseases . There are several reports on patients with BD comorbid with P43034 involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapies . P01375 ( P01375 ) - α is strongly involved in the pathophysiology of several autoimmune diseases such as rheumatoid arthritis , inflammatory bowel disease , and BD . In addition , P01375 - α plays an important role in the pathophysiology of P43034 by inhibiting normal hematopoiesis and inducing the programmed cell death of normal total bone marrow cells and normal P28906 + cells . Recent clinical reports demonstrate the favorable effect of P01375 - α antagonists in patients with refractory intestinal BD and in those with P43034 . We present the case of a patient with intestinal BD and P43034 involving trisomy 8 who was successfully treated with adalimumab .", "Anterior optic neuropathy associated with adalimumab . PURPOSE : Our purpose was to report a case of anterior optic neuropathy with pupillary edema in a patient treated with the P01375 - antagonist adalimumab . METHODS : We report the case of a 60 - year - old woman with optic neuropathy in 1 eye after 6 months of treatment with adalimumab . RESULTS : The patient developed decreased visual acuity of the left eye . The ocular findings were left optic disc swelling and bleeding at the rim , superior visual field depression in both eyes and left afferent pupillary defect . DB00051 was discontinued and the visual acuity recovered slowly . CONCLUSIONS : Like infliximab , the modern P01375 antagonist adalimumab is associated with optic neuropathy . Ophthalmologists should thus be alert when seeing patients treated with adalimumab .", "Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases . BACKGROUND : Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases ( Q9UKU7 ) . To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis , we investigated their effects on endotoxin - induced tumour necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 1 beta and P05231 release by elutriation - purified human monocytes in vitro . METHODS : Drugs tested were dexamethasone , DB00244 , sulphapyridine and zileuton ( a P09917 inhibitor ) . Monocytes were isolated and stimulated with endotoxin , and P01375 , IL - 1 and P05231 levels were determined using an enzyme - linked immunosorbent assay . RESULTS : Monocyte stimulation with endotoxin resulted in an average P01375 release of 2464 +/- 64 pg / 10 ( 6 ) cells , IL - 1 release of 616 +/- 47 pg / 10 ( 6 ) cells and P05231 release of 2259 +/- 148 pg / 10 ( 6 ) cells . Addition of dexamethasone resulted in a reduction of P01375 , IL - 1 and P05231 release to below background levels . DB00891 significantly reduced P01375 and induced IL - 1 release in a dose - dependent fashion , but had no significant effect on P05231 release . 5 - ___MASK4___ did not modulate P05231 synthesis , but significantly reduced IL - 1 and enhanced P01375 synthesis . Zileuton reduced P01375 and P05231 release , but enhanced IL - 1 release . CONCLUSION : We conclude that these anti - inflammatory drugs are able to modulate cytokine release by human monocytes . Further studies are needed to determine whether these effects are related to their therapeutic efficacy in Q9UKU7 .", "DB00051 for treatment of moderate to severe psoriasis and psoriatic arthritis . Psoriasis and psoriatic arthritis are common diseases associated with considerable morbidity and disability . Their pathophysiology comprises similar processes leading to inflammation of skin , entheses , and joints . Although traditional systemic agents can be effective , their use may be limited by lack of efficacy and concerns regarding adverse effects . The objective of this study was to assess the efficacy and safety of adalimumab , a fully human antitumor necrosis factor ( anti - P01375 ) monoclonal antibody , over 16 weeks . The present authors report their personal experience in 15 patients with severe plaque psoriasis and psoriatic arthritis , refractory to other treatments , in which a decisive regression of joint / skin involvement was obtained . Psoriasis and psoriatic arthritis are chronic inflammatory disorders resulting from a combination of genetic and environmental factors .", "DB00051 ameliorates abdominal aorta cross clamping which induced liver injury in rats . The aim of this study was to investigate the possible protective effects of adalimumab ( P00813 ) on cell damage in rat liver tissue during ischemia / reperfusion ( I / R ) injury of infrarenal abdominal aorta . Thirty male Wistar - albino rats were divided into three groups : control , I / R , and I / R + P00813 , each group containing 10 animals . Laparotomy without I / R injury was performed in the control group animals . Laparotomy in the I / R group was followed by two hours of infrarenal abdominal aortic cross ligation and then two hours of reperfusion . P00813 ( 50 mg / kg ) was administered intraperitoneally as a single dose , to the I / R + P00813 group , five days before I / R . The tumor necrosis factor - alpha ( P01375 - α ) ( pg / mg protein ) and nitric oxide ( NO ) ( µmol / g protein ) levels in the I / R group ( 430 . 8 ± 70 . 1 , 8 . 0 ± 1 . 1 , resp . ) were significantly higher than those in the I / R + P00813 group ( 338 . 0 ± 71 . 6 , P = 0 . 006 ; 6 . 3 ± 1 . 2 , P = 0 . 008 ) and the control group ( 345 . 5 ± 53 . 3 , P = 0 . 008 ; 6 . 5 ± 1 . 5 , P = 0 . 010 , resp . ) . I / R causes severe histopathological injury to the liver tissue , but P00813 leads to much less histopathological changes . P00813 treatment significantly decreased the severity of liver I / R injury . P00813 pretreatment may have protective effects on experimental liver injury .", "Influenza H1N1 infection in a patient with psoriatic arthritis in treatment with DB00051 : a case report . In March 2009 was the beginning of an epidemic flue caused by avian influenza A virus H1N1 . The disease varies from mild to serious and fatal cases . There are many hypotheses explaining why this virus infection would be fatal . One of these is the impaired immune response of the infected patient . The use of tumor necrosis factor - alpha inhibitors may cause decreased immune response and greater susceptibility to infections . We presented a case of a patient using adalimumab that have developed H1N1 without complications . This is the first case of H1N1 in a patient using adalimumab reported in Brazil . We discuss the possibility that anti - P01375 may not predisposes to a serious form of the disease or fatal complications .", "Circulating apoptotic proteins are increased in long - term disease - free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis - related proteins and inflammation markers are increased in long - term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF - receptor ( sTNF - R ) 1 and 2 , sFas , sFas ligand , sTNF - related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High - sensitivity P02741 ( HS - CRP ) , fibrinogen , plasma B - type and N - terminal atrial natriuretic peptide ( NT - P01160 and DB04899 ) were also determined . Thirty - four patients with median 6 . 0 years follow - up and 12 healthy age - matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high - dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high - dose than in the standard - dose group . In conclusion , we observed increased circulating apoptotic protein levels in long - term disease - free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .", "DB00051 treatment for life threatening pulmonary artery aneurysm in Behçet disease : a case report . Behçet ' s disease ( BD ) is a multisystem disorder characterized by vasculitis . Pulmonary vascular problems such as pulmonary artery aneurysms ( PAA ) are reported to indicate poor prognosis and high mortality . We describe a 43 - year - old man who presented with life threatening bilateral PAA and thromboembolic disease due to BD . He was treated with prednisone and pulse cyclophosphamide and was poorly responsive to the conventional immunosuppression . The introduction of adalimumab therapy stabilized his PAA . We report that the inhibition of P01375 using the neutralizing monoclonal antibody adalimumab has the potential to induce rapid , complete , and long - lasting remission in a life - threatening manifestation of BD .", "DB00051 - induced noncaseating granuloma in the bone marrow of a patient being treated for rheumatoid arthritis . Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous infiltration , primarily of the lungs and lymphatic system . While reports of the efficacy of adalimumab in the treatment of refractory sarcoidosis have been mixed , the more widely used infliximab has demonstrated clear efficacy in this disease . The association between tumor necrosis factor ( P01375 ) - inhibitors and noncaseating granulomas in the lung has been reported in literature . With the exception of one patient treated with adalimumab , who developed pulmonary granuloma , the remaining patients described in literature were treated with etanercept . The current case study is , to our knowledge , the first to describe adalimumab - induced noncaseating granulomas in the bone marrow of a patient being treated for rheumatoid arthritis and suggests that although P01375 - inhibitors are used in the treatment of granulomatous disorders , their use should be carefully monitored as , in rare cases , P01375 - inhibitors may leave sufficient cytokine activation to support granuloma formation .", "DB00051 ( P01375 α Inhibitor ) Therapy Exacerbates IgA Glomerulonephritis Acute Renal Injury and Induces Lupus Autoantibodies in a Psoriasis Patient . DB00051 ( Humira ) is a tumour necrosis factor α ( P01375 α ) inhibitor that is approved for the treatment of rheumatoid arthritis , psoriasis , psoriatic arthritis , Crohn ' s disease , ankylosing spondylitis , and juvenile idiopathic arthritis ( Sullivan and Preda ( 2009 ) , Klinkhoff ( 2004 ) , and Medicare Australia ) . Use of P01375 α inhibitors is associated with the induction of autoimmunity ( systemic lupus erythematosus , vasculitis , and sarcoidosis or sarcoid - like granulomas ) ( Ramos - Casals et al . ( 2010 ) ) . We report a patient with extensive psoriasis presenting with renal failure and seropositive lupus markers without classical lupus nephritis after 18 months treatment with adalimumab . He has renal biopsy proven IgA nephritis instead . Renal biopsy is the key diagnostic tool in patients presenting with adalimumab induced nephritis and renal failure . He made a remarkable recovery after adalimumab cessation and steroid treatment . To our knowledge , this is a unique case of a psoriasis patient presenting with seropositive lupus markers without classical lupus nephritis renal failure and had renal biopsy proven IgA glomerulonephritis after receiving adalimumab .", "Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .", "Redo Ileal pouch - anal anastomosis combined with anti - P01375 - α maintenance therapy for Crohn ' s disease with pelvic fistula : report of two cases . Pouch failure has been reported to occur after ileal pouch - anal anastomosis for Crohn ' s disease . We report two cases of patients with Crohn ' s disease , who underwent redo ileal pouch - anal anastomosis ( redo - IPAA ) combined with anti - P01375 - α maintenance therapy , with good functional results . The first patient , a man with presumed ulcerative colitis , suffered pelvic fistula recurrence and anastomotic dehiscence . He underwent redo - IPAA , at which time longitudinal ulcers were found . DB00065 was started 4 days postoperatively and continued . The second patient , a woman treated for ulcerative colitis , underwent laparoscopic IPAA 8 years later . After the development of a pelvic fistula , twisted mesentery of the ileal pouch was found intraoperatively and Crohn ' s disease was diagnosed . DB00051 therapy resulted in fistula closure . Redo - IPAA was performed to normalize the twisted mesentery of the ileal pouch . No complications have been observed in either patient , both of whom have experienced good functional results after closure of the covering stomas .", "DB00051 in the treatment of rheumatoid arthritis . DB00051 ( P00813 ) , a fully human monoclonal antibody against P01375 - α is indicated for the treatment of rheumatoid arthritis ( RA ) , psoriatic arthritis , ankylosing spondylitis , juvenile idiopathic arthritis , Crohn ' s disease , ulcerative colitis and psoriasis . In RA , it may be prescribed in combination with methotrexate or other disease - modifying antirheumatic drugs or as monotherapy . Studies comparing P00813 with other P01375 - α inhibitors are limited and are based mainly on meta - analyses of randomised controlled trials and large observational cohorts . In this study , the effectiveness and safety of P00813 is compared with that of etanercept and infliximab .", "The efficacy and safety of a third anti - P01375 monoclonal antibody in Crohn ' s disease after failure of two other anti - P01375 antibodies . BACKGROUND : DB00051 ( P00813 ) and certolizumab pegol ( CZP ) have demonstrated efficacy in Crohn ' s disease ( CD ) patients previously treated with infliximab ( IFX ) . AIM : To assess the efficacy and tolerability of a third anti - P01375 in CD after failure of and / or intolerance to two different anti - P01375 antibodies . METHODS : Crohn ' s disease patients who received P00813 or CZP after loss of response and / or intolerance to two anti - P01375 agent were included in this retrospective study . Data were collected using a standardized questionnaire . Clinical response , duration , safety and reasons for discontinuation were assessed . RESULTS : Sixty - seven patients treated with CZP ( n = 40 ) or P00813 ( n = 27 ) were included . A clinical response was observed in 41 ( 61 % ) at week 6 and 34 patients ( 51 % ) at week 20 . The probability of remaining under treatment at 3 months , 6 months and 9 months was 68 % , 60 % and 45 % , respectively . At the end of follow - up , the third anti - P01375 had been stopped in 36 patients for intolerance ( n = 13 ) , or failure ( n = 23 ) . Two deaths were observed . CONCLUSIONS : The treatment with a third anti - P01375 ( CZP or P00813 ) agent of CD patients , who have experienced loss of response and / or intolerance to two anti - P01375 antibodies , has favourable short - term and long - term efficacy . It is an option to be considered in patients with no other therapeutic options .", "P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK17___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .", "DB00051 in Crohn ' s disease . Although the advent of infliximab has changed the treatment paradigm and goals in inflammatory bowel diseases ( Q9UKU7 ) , it does not provide a cure for Q9UKU7 and recent evidence has demonstrated that the immunogenicity of this chimeric anti - P01375 antibody is associated with secondary loss of response and intolerance . In ulcerative colitis ( UC ) the efficacy of infliximab was demonstrated in two large clinical trials , but long - term maintenance efficacy data are lacking . Novel biological agents have entered clinical development and pioneering trials have been reported in the last two years . For Crohn ' s disease ( CD ) two anti - P01375 agents , the fully human IgG1 anti - P01375 monoclonal adalimumab and the humanized pegylated Fab - fragment certolizumab - pegol and the humanized anti alpha4 integrin IgG4 antibody both have demonstrated efficacy as maintenance agents . DB00051 has been approved to treat active rheumatoid arthritis , psoriatric arthritis , and ankylosing spondylitis , and recently moderate - to - severe luminal CD has been added as an indication for this agent both by the FDA and EMEA . Further evidence is needed to establish the therapeutic potential of adalimumab in fistulizing CD and in UC . The benefit to risk ratio of anti - P01375 agents in refractory Q9UKU7 is clearly positive and since most of the toxicity is class specific , adalimumab is expected to have a safety profile similar to that of infliximab except for adverse events related to infusions .", "DB00051 prevents barrier dysfunction and antagonizes distinct effects of P01375 - α on tight junction proteins and signaling pathways in intestinal epithelial cells . Intestinal barrier dysfunction is pivotal in the etiology of inflammatory bowel diseases . Combined clinical and endoscopic remission ( \" mucosal healing \" ) in patients who received anti - P01375 - α therapies suggests restitution of the intestinal barrier , but the mechanisms involved are largely unknown . We therefore investigated the impact of the anti - P01375 - α antibody adalimumab on barrier function in two in vitro models . Combined stimulation of Caco - 2 and T - 84 cells with interferon - γ and P01375 - α resulted in a significant decrease of transepithelial electrical resistance ( TEER ) within 6 h that was prevented by adalimumab in concentrations down to 100 ng / ml . DB00051 furthermore antagonized the appearance of irregular membrane undulations and prevented internalization of tight junction proteins upon cytokine exposure . In addition , P01375 - α induced a downregulation of claudin - 1 , claudin - 2 , claudin - 4 , and occludin as well as activation of phosphatidylinositol 3 - kinase signaling in T - 84 but not Caco - 2 cells , which was reversed by adalimumab . At the signaling level , adalimumab prevented increased phosphorylation of myosin light chain as well as activation of p38 MAPK and NF - κB accompanying the decline in TEER in both model systems . Pharmacological inhibition of NF - κB signaling partially prevented the P01375 - α - induced TEER loss , whereas inhibition of p38 worsened barrier dysfunction in Caco - 2 but not T - 84 cells . Taken together , these data demonstrate that adalimumab prevents barrier dysfunction induced by P01375 - α both functionally and structurally as well as at the level of signal transduction . Barrier protection might therefore constitute a novel mechanism how anti - P01375 - α therapy contributes to epithelial restitution and tissue repair in inflammatory bowel diseases .", "___MASK12___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK12___ , in the USA in 2003 .", "DB00051 for the treatment of psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic inflammatory joint disease occurring in 6 - 39 % of patients with psoriasis . Standard therapy of PsA includes nonsteroidal anti - inflammatory drugs , intra - articular steroids and disease - modifying antirheumatic drugs . Failure of standard therapy is an indication for anti - P01375 therapy . DB00051 - a fully human monoclonal antibody against P01375 - is an effective and generally reasonably well - tolerated drug for treating signs and symptoms of PsA . In placebo - controlled clinical trials , adalimumab showed American College of Rheumatology ( P10323 ) 20 response rates of 39 - 58 % and ACR50 response rates of 25 - 39 % in patients with active PsA who had failed previous standard therapy . Significant improvement of psoriatic skin changes and disease - related quality of life were also noted . The response of joints and skin and quality of life improvement was sustained over 2 years of therapy . In addition , adalimumab suppressed structural joint damage and retards radiographic progression of PsA .", "Refractory dissecting Cellulitis of the Scalp Successfully controlled with DB00051 . Dissecting cellulitis of the scalp ( DB00260 ) is an uncommon inflammatory disease that often results in scarring alopecia . Numerous therapies have either proved ineffective or only temporarily effective in the management of this condition . Recent reports show adequate responses to tumor necrosis factor ( P01375 ) inhibitors in cases of DB00260 . We report a case of severe recalcitrant DB00260 successfully treated with adalimumab .", "DB00051 therapy : clinical findings and implications for integration into clinical guidelines for rheumatoid arthritis . DB00051 ( Humira ) is the first fully human monoclonal anti - tumor necrosis factor ( P01375 ) antibody available . Similar to the other P01375 blockers , adalimumab has been shown to effectively reduce the symptoms and signs of rheumatoid arthritis and prevent the progression of erosive joint changes seen on radiological examination , which would lead to disabling joint damage . Clinical guidelines recommend the use of P01375 blockers , specifically etanercept and infliximab ( the only two available when the guidelines were issued ) as treatment options for adults with rheumatoid arthritis who continue to have clinically active disease that has not responded adequately to two conventional disease - modifying antirheumatic drugs ( DMARDs ) . The clinical results available using adalimumab , and summarized in this review , reveal a clinical profile similar to etanercept and infliximab , achieving similarly high response rates , suppression of joint damage , and improvements in quality of life and disability , together with a good safety profile . Being a fully human monoclonal antibody , adalimumab may induce less antigenicity than these other agents , which might also be advantageous in maintaining the level of effectiveness . However , direct comparisons in controlled , long - term trials are needed to draw conclusions about which agent to try first in the sequence of DMARDs considered for patients .", "DB00051 for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis - a five - year update . INTRODUCTION : Following its marketing authorization for the treatment of ankylosing spondylitis ( AS ) in 2006 in the United States und in the European Union , adalimumab became one of the most frequently prescribed tumor necrosis factor ( P01375 ) α blockers available for this indication . Recently , the label for adalimumab was extended to nonradiographic axial spondyloarthritis ( nr - axSpA ) , which might be considered as an early stage of AS . The increasing number of patients with AS being treated with adalimumab raises issues concerning long - term safety , efficacy in the prevention of structural damage in the spine and high treatment costs . AREAS COVERED : Herein , we summarize data on efficacy and safety of adalimumab treatment in AS and nr - axSpA obtained over the past 5 years . EXPERT OPINION : DB00051 is clinically effective and reasonably safe in the short - term and long - term treatment of patients with AS who do not respond to standard therapy . Recent data indicate good efficacy of adalimumab also in patients with nr - axSpA but only in the presence of objective signs of active inflammation . Yet unresolved questions relate to the ability of adalimumab to stop or retard structural damage development in the spine in patients with AS and nr - axSpA . The introduction of biosimilar drugs in the near future may potentially reduce the currently very high treatment costs associated with adalimumab treatment .", "Oral tuberculosis associated with a treatment with anti - rheumatic drugs . BACKGROUND : The use of immunosuppressive medication is a dominant risk factor for infection in patients with rheumatoid arthritis ( RA ) . DB00563 ( MTX ) is one of the traditional disease - modifying antirheumatic drugs . DB00051 [ a human anti - tumor necrosis factor - alpha ( anti - P01375 ) monoclonal antibody ] represent an important advance in the treatment of RA and has been recently come in use . P01375 plays a role in the host defense against Mycobacterium tuberculosis and notably in granuloma formation . Infections occur at a high rate among those who use one or the combination of the two medications . METHOD : We examined a female patient that was referred to our department for evaluation and treatment of a granular lesion on the soft palate and uvula , complaining of mild dysphagia . The patient was treated for 4 months with MTX and adalimumab for RA before the oral lesion appeared . RESULTS : The histopathological examination of a specimen of the oral lesion , taken by biopsy , showed a chronic inflammation characterized by tuberculous granulomas . Polymerase chain reaction test and culture of a new specimen was positive for M . tuberculosis . CONCLUSIONS : The therapeutic use of MTX or / and adalimumab for the treatment of RA or few others diseases , can cause oral tuberculosis .", "DB00051 , a human anti - P01375 monoclonal antibody , outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis : the HOPEFUL 1 study . OBJECTIVES : To evaluate the efficacy and safety of adalimumab + methotrexate ( MTX ) in Japanese patients with early rheumatoid arthritis ( RA ) who had not previously received MTX or biologics . METHODS : This randomised , double - blind , placebo - controlled , multicentre study evaluated adalimumab 40 mg every other week + MTX 6 - 8 mg every week versus MTX 6 - 8 mg every week alone for 26 weeks in patients with RA ( ≤ 2 - year duration ) . The primary endpoint was inhibition of radiographic progression ( change ( Δ ) from baseline in modified total Sharp score ( mTSS ) ) at week 26 . RESULTS : A total of 171 patients received adalimumab + MTX ( mean dose , 6 . 2 ± 0 . 8 mg / week ) and 163 patients received MTX alone ( mean dose , 6 . 6 ± 0 . 6 mg / week , p < 0 . 001 ) . The mean RA duration was 0 . 3 years and 315 ( 94 . 3 % ) had high disease activity ( DAS28 > 5 . 1 ) . DB00051 + MTX significantly inhibited radiographic progression at week 26 versus MTX alone ( ΔmTSS , 1 . 5 ± 6 . 1 vs 2 . 4 ± 3 . 2 , respectively ; p < 0 . 001 ) . Significantly more patients in the adalimumab + MTX group ( 62 . 0 % ) did not show radiographic progression ( ΔmTSS ≤ 0 . 5 ) versus the MTX alone group ( 35 . 4 % ; p < 0 . 001 ) . Patients treated with adalimumab + MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission , using various definitions , at 26 weeks versus MTX alone . Combination therapy was well tolerated , and no new safety signals were observed . CONCLUSIONS : DB00051 in combination with low - dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity .", "Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway . OBJECTIVE : Inducible costimulator ( Q9Y6W8 ) is a member of the P10747 family . Although inflammation is an essential pathological feature of myocarditis , the role of Q9Y6W8 in myocarditis remains unclear . METHODS AND RESULTS : Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish experimental autoimmune myocarditis ( EAM ) . Flow cytometry was used to examine expression of Q9Y6W8 on myocardial infiltrating cells . Anti - Q9Y6W8 antibody or Q9Y6W8 - immunoglobulin ( ICOSIg ) was administered intravenously , and rats were killed on day 14 or 21 to study effects of Q9Y6W8 / Q9Y6W8 - ligand ( O75144 ) pathway blockade during the antigen priming phase ( days 0 - 14 ) or immune response phase ( days 14 - 21 ) , respectively . The heart weight to body weight ratio was determined , and histological examination and echocardiogram were performed to evaluate the severity of the disease . Cytokine expression in the heart and T cell proliferation against cardiac myosin were analyzed . Flow cytometry revealed that the majority of infiltrating cells , especially P01730 - positive cells , expressed Q9Y6W8 . Blockade of the Q9Y6W8 / O75144 pathway during the immune response phase attenuated EAM development . However , blockade of the Q9Y6W8 / O75144 pathway during the antigen priming phase did not attenuate and exacerbate EAM . Blockade of T cell activation through Q9Y6W8 suppressed expression of cytokines including P27352 - gamma , P05112 , P05231 , P22301 , P01584 , and P01375 and inhibited T cell proliferation in vitro . CONCLUSIONS : Blockade of T cell activation through Q9Y6W8 during the immune response phase regulates development of EAM , and therefore , Q9Y6W8 may be an effective target for treating myocarditis .", "[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK36___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK36___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .", "Signaling by proinflammatory cytokines : oligomerization of TRAF2 and Q9Y4K3 is sufficient for JNK and IKK activation and target gene induction via an amino - terminal effector domain . Interleukin - 1 ( IL - 1 ) and tumor necrosis factor ( P01375 ) stimulate transcription factors AP - 1 and NF - kappaB through activation of the Q96HU1 kinases JNK and p38 and the O15111 ( IKK ) , respectively . The P01375 and IL - 1 signals are transduced through TRAF2 and Q9Y4K3 , respectively . Overexpressed TRAF2 or Q9Y4K3 activate JNK , p38 , or IKK in the absence of extracellular stimulation . By replacing the carboxy - terminal TRAF domain of TRAF2 and Q9Y4K3 with repeats of the immunophilin P62942 , we demonstrate that their effector domains are composed of their amino - terminal Zn and RING fingers . Oligomerization of the TRAF2 effector domain results in specific binding to Q13233 , a protein kinase capable of JNK , p38 , and IKK activation , and induction of P01375 and IL - 1 responsive genes . P01375 also enhances the binding of native TRAF2 to Q13233 and stimulates the kinase activity of the latter . Thus , P01375 and IL - 1 signaling is based on oligomerization of TRAF2 and Q9Y4K3 leading to activation of effector kinases .", "Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .", "Efficacy of adalimumab in plaque psoriasis : experience on 28 patients . Psoriasis is a common , chronic inflammatory skin disease with arthritis that may occur in a percentage of patients that varies between 5 % and 42 % . Many systemic agents as cyclosporine , methotrexate , acitretin , and photochemotherapy have been used for the treatment of patients affected by moderate - to - severe plaque psoriasis although they present side effects ( ie , cumulative organ toxicity and lack of efficacy over time ) that limit long - term use . Significant therapeutical improvement has been obtained introducing biological therapies , designed to modify and regulate immunological processes by targeting specific molecules involved in the immunopathogenesis of psoriasis . DB00051 is a fully human recombinant antibody against tumor necrosis factor - alpha ( P01375 ) . To date , there is not much data available on the efficacy and safety of adalimumab in patients affected by moderate - to - severe plaque psoriasis . The authors report our first experience on the efficacy and safety of adalimumab in monotherapy at a dose of 40 mg every - other - week for the treatment of plaque psoriasis in patients with or without arthritis . Twenty - eight patients were treated for a period of 48 months . It was observed an improvement of the psoriasis condition as well as of patients ' quality of life and mood state .", "___MASK10___ antagonizes P01375 induction of P19320 on endothelial cells by inhibiting mTORC2 . Recruitment of circulating leukocytes into inflamed tissues depends on adhesion molecules expressed by endothelial cells ( ECs ) . Here we report that rapamycin pretreatment reduced the ability of P01375 - treated ECs to capture T cells under conditions of venular flow . This functional change was caused by inhibition of P01375 - induced expression of vascular cell adhesion molecule - 1 ( P19320 ) and could be mimicked by knockdown of mammalian target of rapamycin ( P42345 ) or rictor , but not raptor , implicating mTORC2 as the target of rapamycin for this effect . Mechanistically , mTORC2 acts through Akt to repress Raf1 - Q02750 / 2 - P27361 / 2 signaling , and inhibition of mTORC2 consequently results in hyperactivation of P27361 / 2 . Increased P27361 / 2 activity antagonizes P19320 expression by repressing P01375 induction of the transcription factor P10914 . Preventing activation of P27361 / 2 reduced the ability of rapamycin to inhibit P01375 - induced P19320 expression . In vivo , rapamycin inhibited mTORC2 activity and potentiated activation of P27361 / 2 . These changes correlated with reduced endothelial expression of P01375 - induced P19320 , which was restored via pharmacological inhibition of P27361 / 2 . Functionally , rapamycin reduced infiltration of leukocytes into renal glomeruli , an effect which was partially reversed by inhibition of P27361 / 2 . These data demonstrate a novel mechanism by which rapamycin modulates the ability of vascular endothelium to mediate inflammation and identifies endothelial mTORC2 as a potential therapeutic target .", "[ Mesalazine - related interstitial lung disease : an under - diagnosed effect ? ] . We report the case of a woman treated with adalimumab and mesalazine for a Crohn ' s disease who presented 9 years after the beginning of the treatments an interstitial lung disease ( ILD ) discovered by chance during a routine medical examination . Several hypotheses were evocated : progression of the Crohn ' s disease with a pulmonary involvement then the role of adalimumab was finally suspected . DB00051 treatment was stopped , but several months later , the pulmonary disease persisted . Six months after the initial medical consult , mesalazine treatment was suspected and stopped . The ILD improved and finally completely resolved with no recurrence after one year . Interstitial lung disease is a rare side effect of mesalazine probably underdiagnosed by physicians especially in patients treated with P01375 alpha inhibitors .", "Onset of palmoplantar pustular psoriasis while on adalimumab for psoriatic arthritis : a ' class effect ' of P01375 antagonists or simply an anti - psoriatic treatment adverse reaction ? DB00051 is a human , recombinant IgG1 monoclonal antibody that specifically blocks the interaction of tumour necrosis factor ( P01375 ) - alpha with the p55 and the p75 P01375 cell surface receptors . We report the appearance of palmoplantar pustular psoriasis in a patient after 6 months of successful adalimumab administration for psoriatic arthritis . The development or worsening of psoriatic skin lesions is a known side effect of adalimumab and other P01375 antagonists increasingly reported in the literature . Although it has been reported as a ' class - effect ' of P01375 antagonists , we believe that the deterioration or new onset of psoriasis is an adverse reaction seen mainly with drugs used for the treatment of psoriasis and not solely with anti - P01375 agents . The latter is probably implying an existing gap in the understanding of the pathophysiology of psoriasis or of the anti - psoriatic drugs ' mechanisms of action .", "Human anti - tumor necrosis factor monoclonal antibody ( adalimumab ) in Crohn ' s disease : the CLASSIC - I trial . BACKGROUND & AIMS : P01375 blockade has been shown to be an effective treatment strategy in Crohn ' s disease ( CD ) . DB00051 is a human immunoglobulin P55008 ( IgG ( 1 ) ) monoclonal antibody targeting tumor necrosis factor ( P01375 ) . A randomized , double - blind , placebo - controlled , dose - ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD . METHODS : A total of 299 patients with moderate to severe CD naive to anti - P01375 therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg / 20 mg , 80 mg / 40 mg , or 160 mg / 80 mg or placebo . The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 ( defined as a Crohn ' s Disease Activity Index score < 150 points ) among the 80 mg / 40 mg , 160 mg / 80 mg , and placebo groups . RESULTS : The rates of remission at week 4 in the adalimumab 40 mg / 20 mg , 80 mg / 40 mg , and 160 mg / 80 mg groups were 18 % ( P = . 36 ) , 24 % ( P = . 06 ) , and 36 % ( P = . 001 ) , respectively , and 12 % in the placebo group . Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions , which were more common in adalimumab - treated patients . CONCLUSIONS : DB00051 was superior to placebo for induction of remission in patients with moderate to severe Crohn ' s disease naive to anti - P01375 therapy . The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2 . DB00051 was well tolerated .", "[ Autoimmune aspects of treatment with P01375 inhibitors ] . P01375 - alpha ( P01375 ) plays an important role in the pathogenesis of such diseases as rheumatoid arthritis , Crohn ' s disease , ankylosing spondylitis , psoriatic arthritis , and juvenile chronic arthritis . Recent years have brought improvement in the understanding of the pathogeneses of these diseases , resulting in the production of new groups of biological drugs , including , among others , anti - P01375 antibodies . The use of P01375 inhibitors has been a great advance in the treatment of patients with these inflammatory diseases . DB00065 and adalimumab are monoclonal antibodies that bind to and neutralize the activity of P01375 . DB00065 is a mouse / human chimera that joins the variable regions of a mouse antibody to the constant region of human IgG1 . DB00051 is a fully human IgG1 antibody . DB00005 is a dimeric fusion protein that joins the human p75 P01375 receptor to the Fc domain of human IgG1 . The beneficial effects of the anti - P01375 monoclonal antibodies infliximab and adalimumab and the soluble receptor fusion protein etanercept in the treatment of rheumatoid arthritis , especially in patients resistant to other disease - modifying antirheumatic drugs ( DMARDs ) , are discussed . We observe stoppage of articular destruction during treatment with P01375 inhibitors . Soon after the introduction of this therapy it was found that these agents have a propensity for stimulating the production of autoantibodies and antibodies against themselves . In this review , recent studies analyzing the effect of P01375 blockade ( infliximab , etanercept , and adalimumab ) on the Q14201 , anti - dsDNA , and anticardiolipin antibody profiles in autoimmune diseases are discussed .", "[ Anti - P01375 - α in the treatment of uveitis in the Besançon Hospital ] . BACKGROUND : Noninfectious chronic uveitis is a difficult - to - treat situation in which corticosteroids , immunosuppressive agents , and more recently , anti - tumor necrosis factor ( P01375 ) - α are used to prevent and / or reverse severe visual impairment . This single - center retrospective study was designed to assess the use ( indications , efficacy , and side effects ) of anti - P01375 - α agents in noninfectious uveitis . PATIENTS AND METHODS : Eight patients were analyzed : three children ( age , 7 - 15 years ) and five adults ( age , 27 - 44 years ) . Anti - P01375 - α agents were etanercept ( three patients ) , adalimumab ( four patients ) , and infliximab ( four patients ) . Diagnoses were Behçet ' s diseases ( n = 3 ) , sarcoidosis ( n = 1 ) , juvenile chronic arthritis ( n = 2 ) , spondyloarthropathy ( n = 2 ) , one of the latter two combined with Crohn disease . In all cases , anti - P01375 - α therapies were prescribed because uveitis and / or associated disease were not under control . RESULTS : DB00051 and infliximab were effective for all patients . One patient with infliximab needed to add corticosteroids and immunosuppressive agents because of relapse . DB00005 was stopped in all cases due to a lack of effectiveness or a change in indication . In all patients , anti - P01375 - α agents improved uveitis and the underlying systemic disease . In children , their use improved quality of life by corticosteroid weaning . Prescriptions did not comply with regulations for three children , because of age limits ( etanercept , one ; adalimumab , two ) . No adverse event was recorded . CONCLUSION : In this short case series , anti - P01375 - α agents were effective both on uveitis and the underlying systemic disease and were well tolerated in patients with noninfectious chronic uveitis .", "Efficacy of DB00051 as a long term maintenance therapy in ulcerative colitis . INTRODUCTION : DB00051 is a recombinant human IgG1 monoclonal antibody to P01375 . There are limited data with regard to its efficacy in ulcerative colitis . We report experience of adalimumab in ulcerative colitis in a single centre with a focus on the ability of this agent to maintain response and avoid colectomy in the medium to long - term . METHODS : Twenty - three ulcerative colitis patients ( mean age 32 years ; 7 female ) who received adalimumab were identified from a prospectively maintained database of over 2700 Q9UKU7 patients . The primary study endpoint was treatment failure defined as discontinuation of adalimumab due to lack of efficacy , as defined by requiring an alternative maintenance therapy or colectomy , or intolerance . Colectomy rate was recorded as a secondary endpoint . RESULTS : Most patients ( 96 % ) had received immunosuppressants prior to adalimumab therapy ( infliximab 20 / 23 87 % ) . Sixteen of 23 patients ( 70 % ) discontinued adalimumab . Six primary failures , 8 secondary loss of response , one had unacceptable side effects and one discontinued treatment after 6 months but remains in remission . Overall estimated cumulative treatment failure rates at 6 , 12 and 24 months were 50 % , 65 % and 72 % respectively . Median follow - up in patients continuing adalimumab is 23 months ( IQR 17 - 31 months ) . Treatment failure was unrelated to patient age , gender , disease extent , smoking status or CRP . Colectomy free survival was 59 % at 2 years . No patient experienced a major adverse event . CONCLUSION : DB00051 shows some efficacy as a maintenance strategy in Ulcerative Colitis , but only a limited proportion of patients remain well on continued treatment at 2 years .", "DB00051 ( antitumour necrosis factor - α ) treatment of hidradenitis suppurativa ameliorates skin inflammation : an in situ and ex vivo study . BACKGROUND : Hidradenitis suppurativa ( HS ) is a difficult - to - manage disease . Randomized controlled trials with antitumour necrosis factor ( P01375 ) - α biologics have been conducted and in most studies disease activity was reduced . However , the mechanism of action in HS skin is so far unknown . OBJECTIVES : To assess whether anti - P01375 - α treatment affects in situ cytokine production and frequency of inflammatory cell populations in HS lesional skin . METHODS : Nine patients with HS , participating in a larger placebo - controlled , double - blind phase IIb clinical trial on the efficacy and safety of adalimumab in patients with moderate to severe HS ( M10 - 467 ) , were randomized and treated for 16weeks . In a mechanism - of - action substudy , biopsies were obtained at fixed time points pre - and post - treatment . One part of the biopsy was cultured for 24h for cytokine release in the culture medium , while another part was used for in situ analysis . RESULTS : Secretion of cytokines , including interleukin ( IL ) - 1β , Q07325 [ monokine induced by interferon - γ ( Q07325 ) ] , P22301 , IL - 11 , B - lymphocyte chemoattractant ( O43927 ) and Q16552 , was significantly elevated in HS . DB00051 treatment was associated with decreased production of cytokines in HS skin , especially IL - 1β , Q07325 ( Q07325 ) and O43927 . Treatment significantly reduced the number of CD11c +, P08571 + and P34810 + cells in HS lesional skin . The numbers of CD3 + and P01730 + T cells , and P11836 + and CD138 + B cells were also reduced by adalimumab treatment . CONCLUSIONS : DB00051 treatment inhibits important cytokines and inflammatory cell numbers in lesional HS skin , especially levels of IL - 1β and numbers of inflammatory CD11c + dendritic cells .", "___MASK70___ block of cloned human T - type voltage - gated calcium channels . ___MASK70___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .", "DB00051 : new indication . Severe Crohn ' s disease : a second P01375 alpha antagonist , subcutaneous administration .", "Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK85___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK27___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "Role of adalimumab in the management of children and adolescents with juvenile idiopathic arthritis and other rheumatic conditions . Treatment of children and adolescents with juvenile idiopathic arthritis and other pediatric rheumatic diseases has evolved . Where once there was only a limited arsenal of medications , with significant side effects and inadequate efficacy , today , with an increased understanding of the pathogenesis of these diseases , there is a wider variety of more targeted and effective treatments . P01375 - α is a cytokine involved in a number of inflammatory pathways in pediatric rheumatic diseases . The emergence of biologic modifiers that target P01375 - α has been pivotal in providing the ability to deliver early and aggressive treatment . DB00051 , a recombinant monoclonal antibody to P01375 - α , is an important therapeutic option , which affords children and adolescents with chronic illnesses an improved quality of life ." ]

[ "___MASK10___", "___MASK12___", "___MASK17___", "___MASK27___", "___MASK36___", "___MASK44___", "___MASK4___", "___MASK70___", "___MASK85___" ]

[ "Evidence for anterograde transport and transcytosis of botulinum neurotoxin A ( DB00083 ) . Botulinum neurotoxin type A ( DB00083 ) is a metalloprotease that blocks synaptic transmission via the cleavage of P60880 ( synaptosomal - associated protein of 25 kDa ) . DB00083 is successfully used in clinical neurology for the treatment of several neuromuscular pathologies and pain syndromes . Despite its widespread use , relatively little is known on DB00083 intracellular trafficking in neurons . Using the visual pathway as a model system , here we show that catalytically active DB00083 is capable of undergoing anterograde axonal transport and transcytosis . Following DB00083 injection into the rat eye , significant levels of DB00083 - cleaved P60880 appeared in the retinorecipient layers of the superior colliculus ( SC ) . Anterograde propagation of DB00083 effects required axonal transport , ruling out a systemic spread of the toxin . Cleaved P60880 was present in presynaptic structures of the tectum , but retinal terminals were devoid of the immunoreactivity , indicative of transcytosis . Experiments based on sequential administration of DB00083 and BoNT / E showed a persistent catalytic activity of DB00083 in tectal cells following its injection into the retina . Our findings demonstrate that catalytically active DB00083 is anterogradely transported from the eye to the SC and transcytosed to tectal synapses . These data are important for a more complete understanding of the mechanisms of action of DB00083 .", "Persistence of botulinum neurotoxin action in cultured spinal cord cells . Primary dissociated fetal mouse spinal cord cultures were used to study the mechanisms underlying the differences in persistence of botulinum neurotoxin A ( DB00083 ) and botulinum neurotoxin / E ( BoNT / E ) activities . Spinal cord cultures were exposed to DB00083 ( 0 . 4 pM ) for 2 - 3 days , which converted approximately half of the P60880 to an altered form lacking the final nine C - terminal residues . The distribution of toxin - damaged to control P60880 remained relatively unchanged for up to 80 days thereafter . Application of a high concentration of BoNT / E ( 250 pM ) either 25 or 60 days following initial intoxication with DB00083 converted both normal and DB00083 - truncated P60880 into a single population lacking the final 26 C - terminal residues . Excess BoNT / E was removed by washout , and recovery of intact P60880 was monitored by Western blot analysis . The BoNT / E - truncated species gradually diminished during the ensuing 18 days , accompanied by the reappearance of both normal and DB00083 - truncated P60880 . Return of DB00083 - truncated P60880 was observed in spite of the absence of DB00083 in the culture medium during all but the first 3 days of exposure . These results indicate that proteolytic activity associated with the DB00083 light chain persists inside cells for > 11 weeks , while recovery from BoNT / E is complete in < 3 weeks . This longer duration of enzymatic activity appears to account for the persistence of serotype A action .", "Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK8___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .", "Different time courses of recovery after poisoning with botulinum neurotoxin serotypes A and E in humans . Botulinum toxin serotypes A and E ( DB00083 and / E ) cleave the carboxy - terminus of synaptosomal associated protein - 25 ( P60880 ) removing nine and 26 residues , respectively . To investigate the effect of these lesions of the same target molecule , 11 volunteers were injected with 3 IU of DB00083 in the extensor digitorum brevis ( Q9BV40 ) muscle of one foot and with 3 IU of BoNT / E in the contralateral one . In addition , seven volunteers were similarly injected with mixtures of DB00083 + BoNT / E . Compound muscular action potential ( CMAP ) was measured at different time intervals and the percentage variation of CMAP ( % CMAP ) was calculated . Unexpectedly , a much faster recovery of % CMAP after BoNT / E injections was observed . Double poisoned EBD muscles recovered similarly to BoNT / E . So , a larger deletion of the P60880 molecule caused by BoNT / E leads to a faster functional recovery .", "Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK44___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .", "DB09341 intolerance and diabetes are observed in the long - term follow - up of nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the Q09428 gene . OBJECTIVE : To report the long - term follow - up of three nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the Q09428 gene . RESEARCH DESIGN AND METHODS : Oral glucose tolerance test ( OGTT ) and venous 24 - h glucose - insulin profile were performed yearly from adolescence . RESULTS : Patient 1 ( now aged 31 years ) developed insulin - dependent diabetes at the age of 25 years . In patient 2 ( now aged 17 years ) , impaired fasting glucose and a diabetic OGTT response with normal A1C values have been observed since the age of 10 years . In patient 3 ( now aged 24 years ) , intolerant OGTT response and hyperglycemic episodes with normal A1C have been observed since the age of 16 years . All patients presented relatively low insulin levels during hyperglycemia , normal BMI , and negative autoantibodies ( Q99259 antibody , insulinoma - associated protein 2 , and islet cell antibody ) . CONCLUSIONS : Development of glucose metabolism impairment ranging from glucose intolerance to insulin - dependent diabetes is observed in the evolution of these patients .", "Protein oriented ligation on nanoparticles exploiting O6 - alkylguanine - DNA transferase ( P60880 ) genetically encoded fusion . A bimodular genetic fusion comprising a delivery module ( scFv ) and a capture module ( P60880 ) is proposed as a novel strategy for the site - specific covalent conjugation of targeting peptides to nanoparticles . An scFv mutant selective for P04626 tumor antigen is chosen as the targeting ligand . P60880 - scFv is immobilized on magnetofluorescent nanoparticles and its targeting efficiency against P04626 - positive cells is assessed by flow cytometry and immunofluorescence .", "A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than P60880 substrate . Botulinum neurotoxin serotype A is the most lethal of all known toxins . Here , we report the crystal structure , along with SAR data , of the zinc metalloprotease domain of DB00083 bound to a potent peptidomimetic inhibitor ( K ( i )= 41 nM ) that resembles the local sequence of the P60880 substrate . Surprisingly , the inhibitor adopts a helical conformation around the cleavage site , in contrast to the extended conformation of the native substrate . The backbone of the inhibitor ' s P1 residue displaces the putative catalytic water molecule and concomitantly interacts with the \" proton shuttle \" E224 . This mechanism of inhibition is aided by residue contacts in the conserved S1 ' pocket of the substrate binding cleft and by the induction of new hydrophobic pockets , which are not present in the apo form , especially for the P2 ' residue of the inhibitor . Our inhibitor is specific for DB00083 as it does not inhibit other BoNT serotypes or thermolysin .", "Q8TAS1 induces proliferation and the cell cycle progression through the phosphorylation of P46527 in leukemia cells . CEM , MOLT4 and P60880 - B15 cells were transduced with lentivirus - mediated siRNA Q8TAS1 gene . The mRNA expressions of Q8TAS1 were successfully reduced in all cell lines . On the other hand , the mRNA expressions of p27 ( Kip1 ) in CEM , MOLT4 and P60880 - B15 cells were not affected by the transduction with siRNA Q8TAS1 gene . We showed that Q8TAS1 protein directly interacted with p27 ( Kip1 ) protein , and reduction of Q8TAS1 inhibited the S10 phosphorylation of p27 ( Kip1 ) in leukemia cells . On these cells transfected with siRNA Q8TAS1 , the inhibition of S10 phosphorylation of p27 ( Kip1 ) was strongly suppressed cell proliferation in a time - dependent manner . Moreover , the inhibition of S10 phosphorylation of p27 ( Kip1 ) increased a significant population in G0 / P55008 fraction . These data demonstrated that the Q8TAS1 activity was induced during G0 / P55008 , and it promotes cell cycle progression by phosphorylation of S10 on p27 ( Kip1 ) . We showed that Q8TAS1 mRNA expression was increased in primary leukemia specimens ( acute myelogenous leukemia ( AML ) ; 37 , myelodysplastic syndrome ( P43034 ) ; 72 , acute lymphoblastic leukemia ( ALL ) ; 23 ) , and the mean ratios of Q8TAS1 to G3PDH in AML , P43034 and ALL specimens were 3 . 62 +/- 0 . 68 , 3 . 27 +/- 0 . 73 and 3 . 17 +/- 0 . 58 , respectively . Moreover , we found that Q8TAS1 protein was overexpressed in all 132 adults cases of various leukemias , including 37 AML ( 8 M1 , 12 M2 , 2 M3 , 7 M4 , 8 M5 ) , 72 P43034 ( 42 RAEB - I , 30 REAB - II ) and 23 ALL ( 23 Q401N2 ) . This study demonstrates that the elevated levels of Q8TAS1 protein in leukemia cells promote the cell cycle progression in leukemia cells .", "Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking / fusion machinery . N - and P / Q - type calcium channels are localized in high density in presynaptic nerve terminals and are crucial elements in neuronal excitation - secretion coupling . In addition to mediating Ca2 + entry to initiate transmitter release , they are thought to interact directly with proteins of the synaptic vesicle docking / fusion machinery . As outlined in the preceding article , these calcium channels can be purified from brain as a complex with SNARE proteins which are involved in exocytosis . In addition , N - type and P / Q - type calcium channels are co - localized with syntaxin in high - density clusters in nerve terminals . Here we review the role of the synaptic protein interaction ( synprint ) sites in the intracellular loop II - III ( L ( II - III ) ) of both alpha1B and alpha1A subunits of N - type and P / Q - type calcium channels , which bind to syntaxin , P60880 , and synaptotagmin . DB01373 has a biphasic effect on the interactions of N - type calcium channels with SNARE complexes , stimulating optimal binding in the range of 10 - 20 microM . PKC or P62158 KII phosphorylation of the N - type synprint peptide inhibits interactions with native brain SNARE complexes containing syntaxin and P60880 . Introduction of the synprint peptides into presynaptic superior cervical ganglion neurons reversibly inhibits EPSPs from synchronous transmitter release by 42 % . At physiological Ca2 + concentrations , synprint peptides cause an approximate 25 % reduction in transmitter release of injected frog neuromuscular junction in cultures , consistent with detachment of 70 % of the docked vesicles from calcium channels based on a theoretical model . Together , these studies suggest that presynaptic calcium channels not only provide the calcium signal required by the exocytotic machinery , but also contain structural elements that are integral to vesicle docking , priming , and fusion processes .", "Adeno - associated virus transfer of a gene encoding P60880 resistant to botulinum toxin A attenuates neuromuscular paralysis associated with botulism . Advances in viral gene therapy have opened new possibilities for treating a range of motor neuron diseases , but these have not yet been translated into clinically applicable therapies because of difficulties in delivery to susceptible / damaged neurons , ambiguities in the identity of gene ( s ) implicated , and a paucity of means to quantify any physiological improvement . Most of these hurdles can be overcome by using the neuromuscular paralysis induced by botulinum neurotoxin type A ( DB00083 ) as a prototype disease . Furthermore , because human botulism , occasionally fatal , causes prolonged muscle disablement as a result of the intraneuronal persistence of the toxin ' s P60880 ( S25 ) - cleaving protease , development of a genetic approach could lead to a potential treatment for this debilitating disease . Adeno - associated viral delivery of a cleavage - resistant S25 gene ( S25 - R198T ) to chromaffin cells in vitro yielded exocytotically active S25 - R198T that diminished subsequent blockade by DB00083 of evoked catecholamine release . Evaluation in vivo , by administering this virus into rat spinal cord before injecting DB00083 , showed a decreased inhibition of acetylcholine release as reflected in elevated retention of neuromuscular transmission . A similar , although smaller , protection of synaptic transmission from the toxin was seen after peripherally injecting the therapeutic virus . Such therapy also curtailed nerve sprouting normally induced by DB00083 . This first demonstration of the utility of a DNA - based therapy for botulism paves the way for further advances in its treatment and for application to genetic disorders of motor neurons .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK39___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "Anti - nociceptive effect of a conjugate of DB05875 and light chain of botulinum neurotoxin type A . Neuropathic pain is a debilitating condition resulting from damage to sensory transmission pathways in the peripheral and central nervous system . A potential new way of treating chronic neuropathic pain is to target specific pain - processing neurons based on their expression of particular receptor molecules . We hypothesized that a toxin - neuropeptide conjugate would alter pain by first being taken up by specific receptors for the neuropeptide expressed on the neuronal cells . Then , once inside the cell the toxin would inhibit the neurons ' activity without killing the neurons , thereby providing pain relief without lesioning the nervous system . In an effort to inactivate the nociceptive neurons in the trigeminal nucleus caudalis in mice , we targeted the NK1 receptor ( P25103 ) using DB05875 ( SP ) . The catalytically active light chain of botulinum neurotoxin type A ( LC / A ) was conjugated with SP . Our results indicate that the conjugate DB00083 - LC : SP is internalized in cultured P25103 - expressing neurons and also cleaves the target of botulinum toxin , a component - docking motif necessary for release of neurotransmitters called P60880 . The conjugate was next tested in a murine model of DB01229 - induced neuropathic pain . An intracisternal injection of DB00083 - LC : SP decreased thermal hyperalgesia as measured by the operant orofacial nociception assay . These findings indicate that conjugates of the light chain of botulinum toxin are extremely promising agents for use in suppressing neuronal activity for extended time periods , and that DB00083 - LC : SP may be a useful agent for treating chronic pain .", "Accelerated intoxication of GABAergic synapses by botulinum neurotoxin A disinhibits stem cell - derived neuron networks prior to network silencing . Botulinum neurotoxins ( BoNTs ) are extremely potent toxins that specifically cleave SNARE proteins in peripheral synapses , preventing neurotransmitter release . Neuronal responses to BoNT intoxication are traditionally studied by quantifying SNARE protein cleavage in vitro or monitoring physiological paralysis in vivo . Consequently , the dynamic effects of intoxication on synaptic behaviors are not well - understood . We have reported that mouse embryonic stem cell - derived neurons ( ESNs ) are highly sensitive to BoNT based on molecular readouts of intoxication . Here we study the time - dependent changes in synapse - and network - level behaviors following addition of DB00083 to spontaneously active networks of glutamatergic and GABAergic ESNs . Whole - cell patch - clamp recordings indicated that DB00083 rapidly blocked synaptic neurotransmission , confirming that ESNs replicate the functional pathophysiology responsible for clinical botulism . Quantitation of spontaneous neurotransmission in pharmacologically isolated synapses revealed accelerated silencing of GABAergic synapses compared to glutamatergic synapses , which was consistent with the selective accumulation of cleaved P60880 at Q99259 (+) pre - synaptic terminals at early timepoints . Different latencies of intoxication resulted in complex network responses to DB00083 addition , involving rapid disinhibition of stochastic firing followed by network silencing . Synaptic activity was found to be highly sensitive to P60880 cleavage , reflecting the functional consequences of the localized cleavage of the small subpopulation of P60880 that is engaged in neurotransmitter release in the nerve terminal . Collectively these findings illustrate that use of synaptic function assays in networked neurons cultures offers a novel and highly sensitive approach for mechanistic studies of toxin : neuron interactions and synaptic responses to BoNT .", "Substrate recognition mechanism of VAMP / synaptobrevin - cleaving clostridial neurotoxins . Botulinum neurotoxins ( BoNTs ) and tetanus neurotoxin ( TeNT ) inhibit neurotransmitter release by proteolyzing a single peptide bond in one of the three soluble N - ethylmaleimide - sensitive factor attachment protein receptors P60880 , syntaxin , and vesicle - associated membrane protein ( VAMP ) / synaptobrevin . TeNT and BoNT / B , D , F , and G of the seven known BoNTs cleave the synaptic vesicle protein VAMP / synaptobrevin . Except for BoNT / B and TeNT , they cleave unique peptide bonds , and prior work suggested that different substrate segments are required for the interaction of each toxin . Although the mode of P60880 cleavage by DB00083 and E has recently been studied in detail , the mechanism of VAMP / synaptobrevin proteolysis is fragmentary . Here , we report the determination of all substrate residues that are involved in the interaction with BoNT / B , D , and F and TeNT by means of systematic mutagenesis of VAMP / synaptobrevin . For each of the toxins , three or more residues clustered at an N - terminal site remote from the respective scissile bond are identified that affect solely substrate binding . These exosites exhibit different sizes and distances to the scissile peptide bonds for each neurotoxin . Substrate segments C - terminal of the cleavage site ( P4 - P4 ' ) do not play a role in the catalytic process . Mutation of residues in the proximity of the scissile bond exclusively affects the turnover number ; however , the importance of individual positions at the cleavage sites varied for each toxin . The data show that , similar to the P60880 proteolyzing DB00083 and E , VAMP / synaptobrevin - specific clostridial neurotoxins also initiate substrate interaction , employing an exosite located N - terminal of the scissile peptide bond .", "Association of botulinum neurotoxin serotype A light chain with plasma membrane - bound P60880 . The Clostridium botulinum neurotoxins ( BoNTs ) cleave SNARE proteins , which inhibit binding and thus fusion of neurotransmitter vesicles to the plasma membrane of peripheral neurons . BoNTs comprise an N - terminal light chain ( LC ) and C - terminal heavy chain , which are linked by a disulfide bond . There are seven serotypes ( A - G ) of BoNTs based upon immunological neutralization . Although the binding and entry of DB00083 into neurons has been subjected to considerable investigation , the intracellular events that allow DB00083 to efficiently cleave P60880 within neurons is less well understood . Earlier studies showed that intracellular LC / A bound to the plasma membrane of neurons . In this study , intracellular LC / A is shown to directly bind P60880 on the plasma membrane . Solid phase binding showed that the N - terminal residues of LC / A bound residues 80 - 110 of P60880 , which was also observed in cultured neurons . Association of the N - terminal 8 amino acids of LC / A and residues 80 - 110 of P60880 also enhanced substrate cleavage . These findings explain how LC / A associates with P60880 on the plasma membrane and provide a basis for LC / A cleavage of P60880 within the SNARE complex .", "Alpha - latrotoxin rescues P60880 from DB00083 - mediated proteolysis in embryonic stem cell - derived neurons . The botulinum neurotoxins ( BoNTs ) exhibit zinc - dependent proteolytic activity against members of the core synaptic membrane fusion complex , preventing neurotransmitter release and resulting in neuromuscular paralysis . No pharmacologic therapies have been identified that clinically relieve botulinum poisoning . The black widow spider venom α - latrotoxin ( LTX ) has the potential to attenuate the severity or duration of BoNT - induced paralysis in neurons via the induction of synaptic degeneration and remodeling . The potential for LTX to antagonize botulinum poisoning was evaluated in embryonic stem cell - derived neurons ( ESNs ) , using a novel screening assay designed around the kinetics of DB00083 activation . Exposure of ESNs to 400 pM LTX for 6 . 5 or 13 min resulted in the nearly complete restoration of uncleaved P60880 within 48 h , whereas treatment with 60 mM K (+) had no effect . Time - lapse imaging demonstrated that LTX treatment caused a profound increase in Ca ( 2 +) influx and evidence of excitotoxicity , though ESNs remained viable 48 h after LTX treatment . This is the first instance of a cell - based treatment that has shown the ability to eliminate BoNT activity . These data suggest that LTX treatment may provide the basis for a new class of therapeutic approach to BoNT intoxication and may contribute to an improved understanding of long - term mechanisms of BoNT intoxication and recovery . They further demonstrate that ESNs are a novel , responsive and biologically relevant model for LTX research and BoNT therapeutic drug discovery .", "A protein chip membrane - capture assay for botulinum neurotoxin activity . Botulinum neurotoxins A and B ( DB00083 and B ) are neuromuscular blocking agents which inhibit neurotransmission by cleaving the intra - cellular presynaptic SNARE proteins P60880 and P63027 , localized respectively in plasma membrane and synaptic vesicles . These neurotoxins are both dangerous pathogens and powerful therapeutic agents with numerous clinical and cosmetic applications . Consequently there is a need for in vitro assays of their biological activity to screen for potential inhibitors and to replace the widely used in vivo mouse assay . Surface plasmon resonance ( SPR ) was used to measure membrane vesicle capture by antibodies against P60880 and P63027 . Substrate cleavage by BoNTs modified capture providing a method to assay toxin activity . Firstly using synaptic vesicles as a substrate , a comparison of the EC ( 50 ) s for BoNT / B obtained by SPR , ELISA or flow cytometry indicated similar sensitivity although SPR assays were more rapid . Sonication of brain or neuronal cultures generated plasma membrane fragments with accessible intra - cellular epitopes adapted to measurement of DB00083 activity . SPR responses were proportional to antigen concentration permitting detection of as little as 4 pM P60880 in crude lysates . DB00083 activity was assayed using monoclonal antibodies that specifically recognize a P60880 epitope generated by the proteolytic action of the toxin . Incubation of intact primary cultured neurons with DB00083 yielded an EC ( 50 ) of 0 . 5 pM . The SPR biosensor method was sensitive enough to monitor DB00083 and B activity in cells cultured in a 96 - well format providing an alternative to experimental animals for toxicological assays .", "Catalytic properties of botulinum neurotoxin subtypes A3 and A4 . Botulinum toxins ( BoNT ) are zinc proteases ( serotypes A - G ) which cause flaccid paralysis through the cleavage of SNARE proteins within motor neurons . DB00083 was originally organized into two subtypes , BoNT / A1 and BoNT / A2 , which are approximately 95 % homologous and possess similar catalytic activities . Subsequently , two additional subtypes were identified , BoNT / A3 ( Loch Maree ) and BoNT / A4 ( 657Ba ) , which are 81 and 88 % homologous with BoNT / A1 , respectively . Alignment studies predicted that BoNT / A3 and BoNT / A4 were sufficiently different from BoNT / A1 to affect P60880 binding and cleavage . Recombinant light chain ( LC ) of BoNT / A3 ( LC / A3 ) and BoNT / A4 ( LC / A4 ) were subjected to biochemical analysis . LC / A3 cleaved P60880 at 50 % of the rate of LC / A1 but cleaved SNAPtide at a faster rate than LC / A1 , while LC / A4 cleaved P60880 and SNAPtide at slower rates than LC / A1 . LC / A3 and LC / A4 had similar K ( m ) values for P60880 relative to LC / A1 , while the k ( cat ) for LC / A4 was 10 - fold slower than that for LC / A1 , suggesting a defect in substrate cleavage . Neither LC / A3 nor LC / A4 possessed autocatalytic activity , a property of LC / A1 and LC / A2 . Thus , the four subtypes of DB00083 bind P60880 with similar affinity but have different catalytic capacities for P60880 cleavage , SNAPtide cleavage , and autocatalysis . The catalytic properties identified among the subtypes of LC / A may influence strategies for the development of small molecule or peptide inhibitors as therapies against botulism .", "Ca ( 2 +) influx and DB02527 elevation overcame botulinum toxin A but not tetanus toxin inhibition of insulin exocytosis . Previous reports showed that cleavage of vesicle - associated membrane protein - 2 ( P63027 ) and synaptosomal - associated protein of 25 kDa ( P60880 ) by clostridial neurotoxins in permeabilized insulin - secreting beta - cells inhibited Ca ( 2 +)- evoked insulin secretion . In these reports , the soluble N - ethylmaleimide - sensitive factor attachment protein target receptor proteins might have formed complexes , which preclude full accessibility of the putative sites for neurotoxin cleavage . In this work , P63027 and P60880 were effectively cleaved before they formed toxin - insensitive complexes by transient transfection of insulinoma HIT or P01308 - 1 cells with tetanus toxin ( TeTx ) or botulinum neurotoxin A ( DB00083 ) , as shown by immunoblotting and immunofluorescence microscopy . This resulted in an inhibition of Ca ( 2 +) ( glucose or DB00761 ) - evoked insulin release proportionate to the transfection efficiency ( 40 - 50 % ) and an accumulation of insulin granules . With the use of patch - clamp capacitance measurements , Ca ( 2 +)- evoked exocytosis by membrane depolarization to - 10 mV was abolished by TeTx ( 6 % of control ) but only moderately inhibited by DB00083 ( 30 % of control ) . Depolarization to 0 mV to maximize Ca ( 2 +) influx partially overcame DB00083 ( 50 % of control ) but not TeTx inhibition . Of note , DB02527 activation potentiated Ca ( 2 +)- evoked secretion by 129 % in control cells but only 55 % in DB00083 - transfected cells and had negligible effects in TeTx - transfected cells . These results indicate that , whereas P63027 is absolutely necessary for insulin exocytosis , the effects of P60880 depletion on exocytosis , perhaps on insulin granule pool priming or mobilization steps , could be partially reversed by higher levels of Ca ( 2 +) or DB02527 potentiation .", "Comparison of the catalytic properties of the botulinum neurotoxin subtypes A1 and A5 . Clostridium botulinum neurotoxins ( BoNTs ) cause the life - threatening disease botulism through the inhibition of neurotransmitter release by cleaving essential SNARE proteins . There are seven serologically distinctive types of BoNTs and many subtypes within a serotype have been identified . BoNT / A5 is a recently discovered subtype of type A botulinum neurotoxin which possesses a very high degree of sequence similarity and identity to the well - studied A1 subtype . In the present study , we examined the endopeptidase activity of these two DB00083 subtypes and our results revealed significant differences in substrate binding and cleavage efficiency between subtype A5 and A1 . Distinctive hydrolysis efficiency was observed between the two toxins during cleavage of the native substrate P60880 versus a shortened peptide mimic . N - terminal truncation studies demonstrated that a key region of the P60880 , including the amino acid residues at 151 through 154 located in the remote binding region of the substrate , contributed to the differential catalytic properties between A1 and A5 . Elevated binding affinity of the peptide substrate resulted from including these important residues and enhanced BoNT / A5 ' s hydrolysis efficiency . In addition , mutations of these amino acid residues affect the proteolytic performance of the two toxins in different ways . This study provides a better understanding of the biological activity of these toxins , their performance characteristics in the Endopep - MS assay to detect BoNT in clinical samples and foods , and is useful for the development of peptide substrates .", "Botulinum neurotoxin A selectively cleaves the synaptic protein P60880 . Neurotransmitter release is potently blocked by a group of structurally related toxin proteins produced by Clostridium botulinum . Botulinum neurotoxin type B ( BoNT / B ) and tetanus toxin ( TeTx ) are zinc - dependent proteases that specifically cleave synaptobrevin ( VAMP ) , a membrane protein of synaptic vesicles . Here we report that inhibition of transmitter release from synaptosomes caused by botulinum neurotoxin A ( DB00083 ) is associated with the selective proteolysis of the synaptic protein P60880 . Furthermore , isolated or recombinant L chain of DB00083 cleaves P60880 in vitro . Cleavage occurred near the carboxyterminus and was sensitive to divalent cation chelators . In addition , a glutamate residue in the DB00083 L chain , presumably required to stabilize a water molecule in the zinc - containing catalytic centre , was required for proteolytic activity . These findings demonstrate that DB00083 acts as a zinc - dependent protease that selectively cleaves P60880 . Thus , a second component of the putative fusion complex mediating synaptic vesicle exocytosis is targeted by a clostridial neurotoxin .", "Inhibitory effect of botulinum toxin type A on the NANC system in rat respiratory models of neurogenic inflammation . This study investigated whether botulinum toxin type A ( DB00083 ) inhibits respiratory neurogenic inflammation in the non - adrenergic , non - cholinergic ( NANC ) transmitter system in rats . Neurogenic inflammation models were induced in Sprague Dawley ( SD ) rats through bilateral cerebral artery occlusion ( BCAO ) for different times ( 0 , 30 and 60 min ) or by stimulation with capsaicin at different doses ( 5 or 15 g / kg ) . Pre - Bötzinger Complex - Spikes and the expression of DB05875 , synaptosomal - associated protein - 25 ( P60880 ) , and reactive oxygen species ( ROS ) were detected with or without pretreatment of rats with DB00083 ( 15 or 30 U / kg ) . BCAO reduced pre - Bot C spike activity ( spike / s ) and increased the breath rate ( breaths / s ) in an unstable pattern in comparison to controls , while pretreatment with DB00083 slightly reduced this phenomenon . Pretreatment with DB00083 inhibited BCAO - or capsaicin - induced increases in expression of P60880 , DB05875 , and ROS in a dose - dependent manner in brainstem and lung tissue . DB00083 exerts a suppressive effect on neurogenic inflammation via non - adrenergic , non - cholinergic transmitters . These results add to the body of evidence elucidating the non - cholinergic effects of DB00083 in the context of neurogenic inflammation .", "Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK73___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK73___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .", "Peroxisome proliferator - activated receptors ( Q07869 ) agonists affect cell viability , apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors . The nuclear receptors PPARs ( peroxisome proliferator - activated receptors ) are transcription factors activated by specific ligands . PPARs play an important role in carcinogenesis , inflammation , atherosclerosis , lipid metabolism and diabetes . There is evidence that activation of PPARs by specific ligands is able to suppress the growth of different types of human cancer by mechanisms including the growth arrest , apoptosis and induction of differentiation , although the detailed signalling pathways have not been completely elucidated to date . The aim of our study was to determine whether synthetic ligands of PPARalpha and PPARgamma could affect the viability , proliferation , differentiation , apoptosis and expression of some cell cycle related proteins in glial tumor cell lines . The study was performed on human glioblastoma cell lines U - 87 MG , T98G , A172 and U - 118 MG . Cell lines were treated by ligands of PPARalpha ( bezafibrate , gemfibrozil ) and PPARgamma ( ciglitazone ) . MTT , flow cytometry , TUNEL assay and immunoblotting were used for detection of changes in cell viability , proliferation , differentiation and apoptosis . ___MASK50___ , ciglitazone and gemfibrozil inhibited viability of glioblastoma cell lines . The synthetic ligands significantly reduced or induced the expression of cyclins , P46527 , p21Waf1 / Cip1 , MDM - 2 , Bcl - 2 , Bax , PARP , Caspase 3 , androgen receptors , etc . and did not affect the expression of the differentiation marker P14136 . Flow cytometry confirmed arrest of the cell cycle although the detection of apoptosis was controversial . Apart from hypolipidemic and hypoglycaemic effects , Q07869 ligands may also have significant cytostatic effects of potential use in anticancer treatment .", "Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK81___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK81___ is also being investigated as part of triplet drug regimens . ___MASK81___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .", "Therapeutic effectiveness of botulinum neurotoxin A : potent blockade of autonomic transmission by targeted cleavage of only the pertinent P60880 . In search of a basis for the impressive potency of an endoprotease that cleaves P60880 , botulinum neurotoxin type A ( DB00083 ) , in treating numerous diseases due to hyper - active autonomic nerves , truncation of its target and inhibition of neurotransmission were studied in rat sympathetic neurons . DB05232 - sensitive spontaneous cholinergic neurotransmission was blocked > 80 % by 1 pM DB00083 despite cleaving < 20 % of the P60880 . A maximum cleavage of ∼ 60 % P60880 could be achieved with > 1 nM DB00083 , despite an absence of non - cleavable P60880 in the detergent - solubilised neurons . In contrast , BoNT / E ( 100 nM ) truncated nearly all the P60880 in the intact cells , but was unable to block neurotransmission at low concentrations like DB00083 . Chimeras created by inserting the acceptor - binding HC domain of DB00083 into BoNT / E still cleaved all the P60880 , indicating ubiquitous expression of DB00083 acceptors . Accordingly , SV2 and P60880 were found to be co - expressed and broadly co - localised in neurons , but absent from non - neuronal cells . On the other hand , partial cleavage by the DB00083 protease persisted upon replacing its HC with counterparts from BoNT / E or BoNT / B . Moreover , limited cleavage of P60880 was conferred onto the protease from BoNT / E when fused to the N - terminus of DB00083 . Thus , the DB00083 protease is uniquely well - adapted for selectively inactivating the P60880 directly involved in neurotransmission ; this together with the toxin ' s acceptor and its target being localised on the peri - somatic boutons likely contribute to its exceptional therapeutic utility in the clinic .", "Enhancement of the endopeptidase activity of botulinum neurotoxin by its associated proteins and dithiothreitol . Botulinum neurotoxins type A ( DB00083 ) , the most toxic substance known to man , is produced by Clostridium botulinum type A as a complex with a group of neurotoxin - associated proteins ( NAPs ) , possibly through a polycistronic expression of a clustered group of genes . The botulinum neurotoxin complex is the only known example of a protein complex where a group of proteins ( NAPs ) protect another protein ( BoNT ) against acidity and proteases of the GI tract . We now report that NAPs also potentiate the DB01593 endopeptidase activity of DB00083 in both in vitro and in vivo assays against its known intracellular target protein , 25 kDa synaptosomal associated protein ( P60880 ) . While DB00083 exhibited no protease activity prior to reduction with dithiothreitol ( DTT ) , the DB00083 complex exhibited a high protease activity even in its nonreduced form . Our results suggest that the bacterial production of NAPs along with BoNT is designed for the NAPs to play an accessory role in the neurotoxin function , in contrast to their previously known limited role in protecting the neurotoxin in the GI tract and in the external environment . Structural features of DB00083 change considerably upon disulfide reduction , as revealed by near - UV circular dichroism spectroscopy . DB00083 in the reduced form adopts a more flexible structure than in the unreduced form , as also indicated by large differences in DeltaH values ( 155 vs 248 kJ mol - 1 ) of temperature - induced unfolding of DB00083 .", "Expression and purification of catalytically active , non - toxic endopeptidase derivatives of Clostridium botulinum toxin type A . Clostridium botulinum neurotoxin type A is a potently toxic protein of 150 kDa with specific endopeptidase activity for the SNARE protein P60880 . Proteolytic cleavage of DB00083 with trypsin leads to removal of the C - terminal domain responsible for neuronal cell binding . Removal of this domain result in a catalytically active , non - cell - binding derivative termed LH ( N )/ A . We have developed a purification scheme to prepare LH ( N )/ A essentially free of contaminating DB00083 . LH ( N )/ A prepared by this scheme retains full enzymatic activity , is stable in solution , and is of low toxicity as demonstrated in a mouse toxicity assay . In addition , LH ( N )/ A has minimal effect on release of neurotransmitter from a primary cell culture model . Both the mouse bioassay and in vitro release assay suggest DB00083 is present at less than 1 in 10 ( 6 ) molecules of LH ( N )/ A . This represents a significant improvement on previously reported figures for LH ( N )/ A , and also the light chain domain , previously purified from DB00083 . To complement the preparation of LH ( N )/ A from holotoxin , DNA encoding LH ( N )/ A has been introduced into Escherichia coli to facilitate expression of recombinant product . Expression and purification parameters have been developed to enable isolation of soluble , stable endopeptidase with a toxicity profile enhanced on that of LH ( N )/ A purified from DB00083 . The recombinant - derived material has been used to prepare antisera that neutralise a DB00083 challenge . The production of essentially DB00083 - free LH ( N )/ A by two different methods and the possibilities for exploitation are discussed .", "Neutralization of botulinum neurotoxin by a human monoclonal antibody specific for the catalytic light chain . BACKGROUND : Botulinum neurotoxins ( BoNT ) are a family of category A select bioterror agents and the most potent biological toxins known . Cloned antibody therapeutics hold considerable promise as BoNT therapeutics , but the therapeutic utility of antibodies that bind the BoNT light chain domain ( LC ) , a metalloprotease that functions in the cytosol of cholinergic neurons , has not been thoroughly explored . METHODS AND FINDINGS : We used an optimized hybridoma method to clone a fully human antibody specific for the LC of serotype A BoNT ( DB00083 ) . The 4LCA antibody demonstrated potent in vivo neutralization when administered alone and collaborated with an antibody specific for the HC . In Neuro - 2a neuroblastoma cells , the 4LCA antibody prevented the cleavage of the DB00083 proteolytic target , P60880 . Unlike an antibody specific for the HC , the 4LCA antibody did not block entry of DB00083 into cultured cells . Instead , it was taken up into synaptic vesicles along with DB00083 . The 4LCA antibody also directly inhibited DB00083 catalytic activity in vitro . CONCLUSIONS : An antibody specific for the DB00083 LC can potently inhibit DB00083 in vivo and in vitro , using mechanisms not previously associated with BoNT - neutralizing antibodies . Antibodies specific for BoNT LC may be valuable components of an antibody antidote for BoNT exposure .", "Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK100___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .", "Longer - acting and highly potent chimaeric inhibitors of excessive exocytosis created with domains from botulinum neurotoxin A and B . Various human neurogenic hyper - excitability disorders are successfully treated with type A or B BoNT ( botulinum neurotoxin ) . The DB00083 complex is widely used because of its longer - lasting benefits ; also , autonomic side - effects are more often reported for BoNT / B . To establish if this distinct effect of BoNT / B could be exploited therapeutically , DB00083 was modified so that it would bind the more abundant BoNT / B acceptor in rodents while retaining its desirable persistent action . The advantageous protease and translocation domain of DB00083 were recombinantly combined with the acceptor - binding moiety of type B [ H ( C )/ B ( C - terminal half of BoNT / B heavy chain ) ] , creating the chimaera AB . This purified protein bound the BoNT / B acceptor , displayed enhanced capability relative to type A for intraneuronally delivering its protease , cleaved P60880 ( synaptosome - associated protein of 25 kDa ) and induced a more prolonged neuromuscular paralysis than DB00083 in mice . The BA chimaera , generated by substituting H ( C )/ A ( C - terminal half of DB00083 heavy chain ) into BoNT / B , exhibited an extremely high specific activity , delivered the BoNT / B protease via the DB00083 acceptor into neurons , or fibroblast - like synoviocytes that lack P60880 , cleaving the requisite isoforms of VAMP ( vesicle - associated membrane protein ) . Both chimaeras inhibited neurotransmission in murine bladder smooth muscle . BA has the unique ability to reduce exocytosis from non - neuronal cells expressing the DB00083 - acceptor and utilising VAMP , but not P60880 , in exocytosis .", "Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK26___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .", "Botulinum neurotoxin C1 cleaves both syntaxin and P60880 in intact and permeabilized chromaffin cells : correlation with its blockade of catecholamine release . The seven types ( A -- G ) of botulinum neurotoxin ( BoNT ) are DB01593 - dependent endoproteases that potently block neurosecretion . Syntaxin is presently thought to be the sole substrate for BoNT / C1 , and synaptosomal - associated protein of Mr = 25 000 ( P60880 ) is selectively proteolyzed by types A and E . In this study , the effects of C1 on Ca2 + - regulated exocytosis of dense core granules from adreno - chromaffin cells were examined together with its underlying molecular action . Intact chromaffin cells were exposed to the toxin , and catecholamine release therefrom was then measured in conjunction with the monitoring of syntaxin cleavage by Western blotting . A good correlation was obtained between degradation of syntaxin 1A / B and reduction in Ca2 +- or Ba2 +- dependent secretion . However , blotting with antibodies against a C - terminal peptide of P60880 revealed the additional disappearance of immunoreactivity , with the same toxin concentration dependency as syntaxin breakdown . Notably , the cleaved P60880 product was similar in size to that produced by DB00083 ; however , contamination of BoNT / C1 by serotypes A or E was eliminated . Therefore , it is concluded that syntaxin 1A / B and P60880 are cleaved in intact cells poisoned with only C1 . Notably , C1 treatment of chromaffin cells abolished Ca2 + - evoked secretion following digitonin permeabilization , compared with partial inhibition by DB00083 , suggesting the importance of syntaxin for catecholamine release . Unexpectedly , C1 failed to proteolyze a soluble recombinant P60880 , even though it served as an efficient substrate for DB00083 . These interesting observations suggest that C1 can only efficiently cleave P60880 in intact cells , possibly due to the existence therein of a unique conformation and / or the participation of accessory factors .", "On the action of botulinum neurotoxins A and E at cholinergic terminals . Botulinum neurotoxins type A and E ( DB00083 and / E ) are metalloproteases with a unique specificity for P60880 ( synaptosomal - associated protein of 25 kDa ) , an essential protein component of the neuroexocytotic machinery . It was proposed that this specificity is based on the recognition of a nine - residue sequence , termed SNARE motif , which is common to the other two SNARE proteins : VAMP ( vesicle - associated membrane protein ) and syntaxin , the only known substrates of the other six clostridial neurotoxins . Here we report on recent studies which provide evidence for the involvement of the SNARE motif present in P60880 in its interaction with DB00083 and / E by following the kinetics of proteolysis of P60880 mutants deleted of SNARE motifs . We show that a single copy of the motif is sufficient for DB00083 and / E to recognise P60880 . While the copy of the motif proximal to the cleavage site is clearly involved in recognition , in its absence , other more distant copies of the motif are able to support proteolysis . We also report on studies of poisoning human neuromuscular junctions with either DB00083 or BoNT / E and describe the unexpected finding that the time of recovery of function after poisoning is much shorter in the case of type E with respect to type A intoxication . These data are discussed in terms of the different sites of action of the two toxins within P60880 .", "Recombinant P60880 is an effective substrate for Clostridium botulinum type A toxin endopeptidase activity in vitro . Bacterial neurotoxins are now being used routinely for the treatment of neuromuscular conditions . Alternative assays to replace or to complement in vivo bioassay methods for assessment of the safety and potency of these botulinum neurotoxin - based therapeutic products are urgently needed . Advances made in understanding the mode of action of clostridial neurotoxins have provided the basis for the development of alternative mechanism - based assay methods . Thus , the identification of P60880 ( synaptosomal - associated protein of molecular mass 25 kDa ) as the intracellular protein target which is selectively cleaved during poisoning by botulinum neurotoxin type A ( DB00083 ) has enabled the development of a functional in vitro assay for this toxin . Using recombinant DNA methods , a segment of P60880 ( aa residues 134 - 206 ) spanning the toxin cleavage site was prepared as a fusion protein to the maltose - binding protein in Escherichia coli . The fusion protein was purified by affinity chromatography and the fragment isolated after cleavage with Factor Xa . Targeted antibodies specific for the N and C termini of P60880 , as well as the toxin cleavage site , were prepared and used in an immunoassay to demonstrate DB00083 endopeptidase activity towards recombinant P60880 substrates . The reaction required low concentrations of reducing agents which were inhibitory at higher concentrations as were metal chelators and some inhibitors of metallopeptidases . The endopeptidase assay has proved to be more sensitive than the mouse bioassay for detection of toxin in therapeutic preparations . A good correlation with results obtained in the in vivo bioassay ( r = 0 . 95 , n = 23 ) was demonstrated . The endopeptidase assay described here may provide a suitable replacement assay for the estimation of the potency of type A toxin in therapeutic preparations .", "Depolarization after resonance energy transfer ( DARET ) : a sensitive fluorescence - based assay for botulinum neurotoxin protease activity . The DARET ( depolarization after resonance energy transfer ) assay is a coupled Förster resonance energy transfer ( FRET ) - fluorescence polarization assay for botulinum neurotoxin type A or E ( DB00083 or BoNT / E ) proteolytic activity that relies on a fully recombinant substrate . The substrate consists of blue fluorescent protein ( Q9ULX5 ) and green fluorescent protein ( GFP ) flanking P60880 ( synaptosome - associated protein of 25 kDa ) residues 134 - 206 . In this assay , the substrate is excited with polarized light at 387 nm , which primarily excites the Q9ULX5 , whereas emission from the GFP is monitored at 509 nm . Energy transfer from the Q9ULX5 to the GFP in the intact substrate results in a substantial depolarization of the GFP emission . The energy transfer is eliminated when the fluorescent domains separate on cleavage by the endopeptidase , and emission from the directly excited GFP product fragment is then highly polarized , resulting in an overall increase in polarization . This increase in polarization can be monitored to assay the proteolytic activity of DB00083 and BoNT / E in real time . It allows determination of the turnover rate of the substrate and the kinetic constants ( V ( max ) and k ( cat ) ) based on the concentration of cleaved substrate determined directly from the measurements using the additivity properties of polarization . The assay is amenable to high - throughput applications .", "Truncated P60880 ( 1 - 197 ) , like botulinum neurotoxin A , can inhibit insulin secretion from HIT - T15 insulinoma cells . We and others have previously shown that insulin - secreting cells of the pancreas express high levels of P60880 ( synaptosomal - associated protein of 25 kDa ) , a 206 - amino acid t - SNARE ( target soluble N - ethylmaleimide - sensitive factor attachment protein receptors ) implicated in synaptic vesicle exocytosis . In the present study , we show that P60880 is required for insulin secretion by transient transfection of Botulinum Neurotoxin A ( DB00083 ) into insulin - secreting HIT - T15 cells . Transient expression of DB00083 cleaved the endogenous as well as overexpressed P60880 proteins and caused significant reductions in K + and glucose - evoked secretion of insulin . To determine whether the inhibition of release was due to the depletion of functional P60880 or the accumulation of proteolytic by - products , we transfected cells with P60880 proteins from which the C - terminal nine amino acids had been deleted to mimic the effects of the toxin . This modified P60880 ( amino acids 1 - 197 ) remained bound to the plasma membrane but was as effective as the toxin at inhibiting insulin secretion . Microfluorimetry revealed that the inhibition of secretion was due neither to changes in basal cytosolic Ca2 + levels nor in Ca2 + influx evoked by K (+)- mediated plasma membrane depolarization . Electron microscopy revealed that cells transfected with either DB00083 or truncated P60880 contained significantly higher numbers of insulin granules , many of which clustered close to the plasma membrane . Together , these results demonstrate that functional P60880 proteins are required for insulin secretion and suggest that the inhibitory action of DB00083 toxin on insulin secretion is in part caused by the production of the plasma membrane - bound cleavage product , which itself interferes with insulin granule docking and fusion .", "Inhibition of natural killer ( NK ) cell activity against varicella - zoster virus ( VZV ) - infected fibroblasts and lymphocyte activation in response to VZV antigen by nitric oxide - releasing agents . The addition of nitric oxide ( NO ) - releasing agents , S - nitroso - N - acetyl - DL - penicillamine ( P60880 ) , 1 - hydroxy - 2 - oxo - 2 , 3 - bis ( 2 - aminoethyl )- 1 - triazene ( NOC18 ) , 30 { (+/-)-( E )- ethyl - 2 '- [ ( E ) - hydroxyimino ] - 5 - nitro - 3 - hexenecarbam oyl } - pyridine ( NOR4 ) significantly inhibited NK cell activity against VZV - infected cells , while antibody - dependent cell - mediated cytotoxicity ( ADCC ) against VZV - infected cells was unaffected . Interferon - alpha ( IFN - alpha ) production by non - adherent peripheral blood mononuclear cells ( NPBMC ) cultured with VZV - infected cells was decreased by the addition of NO - releasing agents . Lymphocyte proliferation and the expression P60568 receptor ( CD25 ) in response to VZV antigen were also inhibited by the addition of NO - releasing agents . These results suggest that the production of NO by an inflammatory process may lead to inhibition of NK cell - and T cell - mediated immunity to VZV infection .", "Dual effects of nimesulide , a P35354 inhibitor , in human platelets . DB04743 ( CAS 51803 - 78 - 2 ) has been shown to exert marked anti - inflammatory effect in several in vivo models of inflammation . Since nimesulide is considered to be a selective inhibitor of P35354 , it has not been studied in detail in relation to its mechanistic effects on platelets , which express P23219 . This study was conducted to investigate the effects of nimesulide in platelet aggregation . We show that nimesulide ( 1 - 100 microM ) inhibited platelet aggregation induced by adrenaline ( 20 - 200 microM ) . It also inhibited thromboxane A2 ( TXA2 ) formation by platelets at low concentration ( IC50 ; 1 microM ) . However , much lower concentrations of nimesulide ( 0 . 01 - 0 . 1 microM ) potentiated the aggregatory response of subthreshold concentrations of adrenaline ( 0 . 2 - 2 microM ) . Such an effect was blocked by Ca2 +- channel blockers , verapamil and diltiazem ( IC50 : 7 and 46 microM , respectively ) , nitric oxide donor , P60880 ( IC50 ; 2 microM ) and cinchonine ( 10 nM ) but not by genistein ( up to 10 microM ) . These results are indicative of the concentration - dependent dual effects of nimesulide on human platelet aggregation . The synergistic effect of low doses of nimesulide and adrenaline seems to be mediated through inhibition of multiple signalling pathways .", "Novel chimeras of botulinum and tetanus neurotoxins yield insights into their distinct sites of neuroparalysis . Botulinum neurotoxin ( BoNT ) A or E and tetanus toxin ( TeTx ) bind to motor - nerve endings and undergo distinct trafficking ; their light - chain ( LC ) proteases cleave soluble N - ethylmaleimide - sensitive factor attachment protein receptors ( SNAREs ) peripherally or centrally and cause flaccid or spastic paralysis , respectively . To seek protein domains responsible for local blockade of transmitter release ( BoNTs ) rather than retroaxonal transport to spinal neurons ( TeTx ) , their acceptor - binding moieties ( H ( C ) ) -- or in one case , heavy chain ( HC ) -- were exchanged by gene recombination . Each chimera , expressed and purified from Escherichia coli , entered rat cerebellar neurons to cleave their substrates , blocked in vitro nerve - induced muscle contractions , and produced only flaccid paralysis in mice . Thus , the local cytosolic delivery of DB00083 or BoNT / E proteases and the contrasting retrograde transport of TeTx are not specified solely by their HC or H ( C ) ; DB00083 LC translocated locally irrespective of being targeted by either of the latter TeTx domains . In contrast , BoNT / E protease fused to a TeTx enzymatically inactive mutant ( TeTIM ) caused spastic paralysis and cleaved P60880 in spinal cord but not the injected muscle . Apparently , TeTIM precludes cytosolic release of BoNT / E protease at motor nerve endings . It is deduced that the LCs of the toxins , acting in conjunction with HC domains , dictate their local or distant destinations .", "Second generation steroidal 4 - aminoquinolines are potent , dual - target inhibitors of the botulinum neurotoxin serotype A metalloprotease and P . falciparum malaria . Significantly more potent second generation 4 - amino - 7 - chloroquinoline ( 4 , 7 - ACQ ) based inhibitors of the botulinum neurotoxin serotype A ( DB00083 ) light chain were synthesized . Introducing an amino group at the C ( 3 ) position of the cholate component markedly increased potency ( IC50 values for such derivatives ranged from 0 . 81 to 2 . 27 μM ) . Two additional subclasses were prepared : bis ( steroidal )- 4 , 7 - ACQ derivatives and bis ( 4 , 7 - ACQ ) cholate derivatives ; both classes provided inhibitors with nanomolar - range potencies ( e . g . , the Ki of compound 67 is 0 . 10 μM ) . During DB00083 challenge using primary neurons , select derivatives protected P60880 by up to 89 % . Docking simulations were performed to rationalize the compounds ' in vitro potencies . In addition to specific residue contacts , coordination of the enzyme ' s catalytic zinc and expulsion of the enzyme ' s catalytic water were a consistent theme . With respect to antimalarial activity , the compounds provided better IC90 activities against chloroquine resistant ( CQR ) malaria than CQ , and seven compounds were more active than mefloquine against CQR strain W2 .", "Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin - sensitive neurons . Unlike most classical analgesics , botulinum toxin type A ( DB00083 ) does not alter acute nociceptive thresholds , and shows selectivity primarily for allodynic and hyperalgesic responses in certain pain conditions . We hypothesized that this phenomenon might be explained by characterizing the sensory neurons targeted by DB00083 in the central nervous system after its axonal transport . DB00083 ' s central antinociceptive activity following its application into the rat whisker pad was examined in trigeminal nucleus caudalis ( P24821 ) and higher - level nociceptive brain areas using DB00083 - cleaved synaptosomal - associated protein 25 ( P60880 ) and c - Fos immunohistochemistry . Occurrence of cleaved P60880 in P24821 was examined after nonselective ganglion ablation with formalin or selective denervation of capsaicin - sensitive ( vanilloid receptor - 1 or Q8NER1 - expressing ) neurons , and in relation to different cellular and neuronal markers . Regional c - Fos activation and effect of Q8NER1 - expressing afferent denervation on toxin ' s antinociceptive action were studied in formalin - induced orofacial pain . DB00083 - cleaved P60880 was observed in P24821 , but not in higher - level nociceptive nuclei . Cleaved P60880 in P24821 disappeared after formalin - induced trigeminal ganglion ablation or capsaicin - induced sensory denervation . Occurrence of cleaved P60880 in P24821 and DB00083 antinociceptive activity in formalin - induced orofacial pain were prevented by denervation with capsaicin . Cleaved P60880 localization demonstrated toxin ' s presynaptic activity in Q8NER1 - expressing neurons . DB00083 reduced the c - Fos activation in P24821 , locus coeruleus , and periaqueductal gray . Present experiments suggest that DB00083 alters the nociceptive transmission at the central synapse of primary afferents . Targeting of Q8NER1 - expressing neurons might be associated with observed selectivity of DB00083 action only in certain types of pain .", "Proteolysis of P60880 by types E and A botulinal neurotoxins . Clostridial neurotoxins , tetanus toxin ( TeTx ) and the seven related but serologically distinct botulinal neurotoxins ( DB00083 to BoNT / G ) , are potent inhibitors of synaptic vesicle exocytosis in nerve endings . Recently it was reported that the light chains of clostridial neurotoxins act as zinc - dependent metalloproteases which specifically cleave synaptic target proteins such as synaptobrevin / VAMPs , HPC - 1 / syntaxin ( BoNT / C1 ) , and P60880 ( DB00083 ) . We show here that BoNT / E , like DB00083 , cleaves P60880 , as generated by in vitro translation or by expression in Escherichia coli . BoNT / E cleaves the Arg180 - Ile181 bond . This site is different from that of DB00083 , which cleaves P60880 between the amino acid residues Gln197 and Arg198 . These findings further support the view that clostridial neurotoxins have evolved from an ancestral protease recognizing the exocytotic fusion machinery of synaptic vesicles whereby individual toxins target different members of the membrane fusion complex .", "No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK34___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK34___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK34___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK34___ among adults with ADHD .", "The C - terminus of botulinum neurotoxin type A light chain contributes to solubility , catalysis , and stability . Botulinum neurotoxin type A ( DB00083 ) is the etiological agent responsible for botulism , a disease characterized by peripheral neuromuscular blockade . DB00083 is produced by Clostridium botulinum as a single chain protein that is activated by proteolytic cleavage to form a 50 kDa light chain ( LC , 448 amino acids ) and a disulfide bond - linked 100 kDa heavy chain ( HC , 847 amino acids ) . Whilst HC comprises the receptor binding and translocation domains , LC is a DB01593 - endopeptidase that cleaves at a single glutaminyl - arginine bond corresponding to residues 197 and 198 at the C - terminus of P60880 . Cleavage of P60880 uncouples the neural exocytosis docking / fusion machinery . LC / A ( LC 1 - 448 ) and several C - terminal deletion proteins of LC / A were engineered and expressed as DB00117 - tagged fusion proteins in Escherichia coli . LC 1 - 448 was purified , but precipitated upon storage . Approximately 40 % of LC 1 - 448 was a covalent dimer due to the formation of inter - chain disulfide bond formation at Cys430 . Conversion of Cys430 to DB00133 abolished dimer formation of LC 1 - 448 , but did not improve solubility . Three C - terminal deletion peptides were engineered ; LC 1 - 425 and LC 1 - 418 were expressed and could be purified as soluble and stable proteins , whilst LC 1 - 398 was soluble , but not stable to storage . Kinetic studies showed that LC 1 - 448 and LC 1 - 425 efficiently cleaved Q86UG4 - P60880 and the fluorescent substrate SNAPtide , while LC 1 - 418 catalyzed the cleavage of both the P60880 and the fluorescent substrate SNAPtide with a similar Km , but at a 10 - fold slower kcat . Thus , regions within the C - terminus of LC / A contribute to solubility , stability , and catalysis .", "Novel chimeras of botulinum neurotoxins A and E unveil contributions from the binding , translocation , and protease domains to their functional characteristics . Hyperexcitability disorders of cholinergically innervated muscles are treatable with botulinum neurotoxin ( BoNT ) A . The seven serotypes ( A - G ) potently block neurotransmission by binding to presynaptic receptors , undergoing endocytosis , transferring to the cytosol , and inactivating proteins essential for vesicle fusion . Although DB00083 and BoNT / E cleave P60880 , albeit at distinct sites , BoNT / E blocks neurotransmission faster and more potently . To identify the domains responsible for these characteristics , the C - terminal heavy chain portions of DB00083 and BoNT / E were exchanged to create chimeras AE and EA . After high yield expression in Escherichia coli , these single chain chimeras were purified by two - step chromatography and activated by conversion to disulfide - linked dichains . In vitro , each entered neurons , cleaved P60880 , and blocked neuromuscular transmission while causing flaccid paralysis in vivo . Acidification - dependent translocation of the light chain to the cytosol occurred more rapidly for BoNT / E and EA than for DB00083 and AE because the latter pair remained susceptible for longer to inhibitors of the vesicular proton pump , and DB00083 proved less sensitive . The receptor - binding and protease domains do not seem to be responsible for the speeds of intoxication ; rather the N - terminal halves of their heavy chains are implicated , with dissimilar rates of cytosolic transfer of the light chains being due to differences in pH sensitivity . AE produced the most persistent muscle weakening and therefore has therapeutic potential . Thus , proof of principle is provided for tailoring the pharmacological properties of these toxins by protein engineering .", "Regulation by nitric oxide of endotoxin - induced tissue factor and plasminogen activator inhibitor - 1 in endothelial cells . The increase in nitric oxide ( NO ) production in lipopolysaccharide ( LPS ) - induced sepsis is thought to contribute to the development of shock . However , NO could also play an antithrombotic role . Little is known about the modulating effect of NO on the endothelial overexpression and production of tissue factor ( TF ) and plasminogen activator inhibitor - 1 ( P05121 ) occurring in endotoxemia . We analyzed the effect of N ( G )- nitro - L - arginine - methyl - ester ( L - NAME ) , an inhibitor of NO synthases , and S - nitroso - N - acetyl - D , L - penicillamine ( P60880 ) , a NO donor , on the expression and synthesis of TF and P05121 by LPS - challenged human umbilical vein endothelial cells ( HUVEC ) : L - NAME enhanced the increase in TF mRNA and antigen levels ( P < 0 . 05 ) observed in LPS - treated HUVEC ; P60880 down - regulated the LPS - induced TF increment ( p < 0 . 05 ) . However , no effects of NO on regulation of the LPS - dependent increase in P05121 could be seen . Thus , NO could play an antithrombotic role in sepsis by down - regulating the endothelial overexpression and production of TF .", "Disruption of pancreatic beta - cell lipid rafts modifies Kv2 . 1 channel gating and insulin exocytosis . In pancreatic beta - cells , the predominant voltage - gated Ca ( 2 +) channel ( Ca ( V ) 1 . 2 ) and K (+) channel ( K ( V ) 2 . 1 ) are directly coupled to SNARE ( soluble N - ethylmaleimide - sensitive factor attachment protein ( P60880 ) receptor ) proteins . These SNARE proteins modulate channel expression and gating and closely associate these channels with the insulin secretory vesicles . We show that K ( V ) 2 . 1 and Ca ( V ) 1 . 2 , but not K ( V ) 1 . 4 , Q09428 , or Kir6 . 2 , target to specialized cholesterol - rich lipid raft domains on beta - cell plasma membranes . Similarly , the SNARE proteins syntaxin 1A , P60880 , and P63027 , but not Munc - 13 - 1 or n - Sec1 , are associated with lipid rafts . Disruption of the lipid rafts by depleting membrane cholesterol with methyl - beta - cyclodextrin shunts K ( V ) 2 . 1 , Ca ( V ) 1 . 2 , and SNARE proteins out of lipid rafts . Furthermore , methyl - beta - cyclodextrin inhibits K ( V ) 2 . 1 but not Ca ( V ) 1 . 2 channel activity and enhances single - cell exocytic events and insulin secretion . Membrane compartmentalization of ion channels and SNARE proteins in lipid rafts may be critical for the temporal and spatial coordination of insulin release , forming what has been described as the excitosome complex .", "The destructive effect of botulinum neurotoxins on the SNARE protein : P60880 and synaptic membrane fusion . Synaptic exocytosis requires the assembly of syntaxin 1A and P60880 on the plasma membrane and synaptobrevin 2 ( P63027 ) on the vesicular membrane to bridge the two opposite membranes . It is believed that the three SNARE proteins assemble in steps along the dynamic assembly pathway . The C - terminus of P60880 is known to be the target of botulinum neurotoxins ( DB00083 and BoNT / E ) that block neurotransmitters release in vivo . In this study , we employed electron paramagnetic resonance ( EPR ) spectroscopy to investigate the conformation of the P60880 C - terminus in binary and ternary SNARE complexes . The fluorescence lipid mixing assay shows that the C - terminal of P60880 is essential for membrane fusion , and that the truncated P60880 mutants cleaved by DB00083 and BoNT / E display different inhibition effects on membrane fusion : P60880 - 25E ( Δ26 ) abolishes the fusion activity of the SNARE complex , while P60880 - 25A ( Δ9 ) loses most of its function , although it can still form a SDS - resistant SNARE complex as the wild - type P60880 . CW - EPR spectra validate the unstable structures of the SNARE complex formed by P60880 mutants . We propose that the truncated P60880 mutants will disrupt the assembly of the SNARE core complex , and then inhibit the synaptic membrane fusion accordingly .", "Mechanism of substrate recognition by botulinum neurotoxin serotype A . Botulinum neurotoxins ( BoNTs ) are zinc proteases that cleave SNARE proteins to elicit flaccid paralysis by inhibiting neurotransmitter - carrying vesicle fusion to the plasma membrane of peripheral neurons . Unlike other zinc proteases , BoNTs recognize extended regions of P60880 for cleavage ; however , the molecular basis for this extended substrate recognition is unclear . Here , we define a multistep mechanism for recognition and cleavage of P60880 by DB00083 . P60880 initially binds along the belt region of DB00083 , which aligns the Q15084 residue to the S5 pocket at the periphery of the active site . Although the exact order of each step of recognition of P60880 by DB00083 at the active site is not clear , the initial binding could subsequently orient the P4 '- residue of P60880 to form a salt bridge with the S4 '- residue , which opens the active site allowing the P1 '- residue access to the S1 '- pocket . Subsequent hydrophobic interactions between the P09131 residue of P60880 and the S3 pocket optimize alignment of the scissile bond for cleavage . This explains how the BoNTs recognize and cleave specific coiled SNARE substrates and provides insight into the development of inhibitors to prevent botulism .", "Recombinant holotoxoid vaccine against botulism . The botulinum neurotoxins ( BoNT ) are the most toxic proteins for humans and designated \" Category A Select Agents . \" The current vaccine against botulism is in limited supply , and there is a need to develop new vaccine strategies . A recombinant DB00083 toxoid was produced in Clostridium botulinum that contained a double amino acid substitution , R363A Y365F ( termed DB00083 ( RYM ) ) . DB00083 ( RYM ) was noncatalytic for P60880 and nontoxic for mice . Immunization with DB00083 ( RYM ) protected mice from challenge at levels that were similar to chemically inactivated DB00083 toxoid . DB00083 ( RYM ) elicited an immune response against the light - chain and heavy - chain components of the toxin . Neutralizing anti - DB00083 ( RYM ) sera blocked BoNT toxicity in primary cortical neurons and blocked ganglioside binding by the heavy chain . DB00083 ( RYM ) represents a viable vaccine candidate for a holotoxoid against botulism .", "Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .", "Common and distinct fusion proteins in axonal growth and transmitter release . We have used the proteolytic properties of botulinum and tetanus neurotoxins ( BoNT , TeNT ) to cleave three proteins of the membrane fusion machinery , P60880 , VAMP / synaptobrevin , and syntaxin , in developing and differentiated rat central neurons in vitro . Then , we have studied the capacity of neurons to extend neurites , make synapses , and release neurotransmitters . All the toxins showed the expected specificity with the exception that BoNT / C cleaved P60880 in addition to syntaxin and induced rapid neuronal death . In developing neurons , cleavage of P60880 with DB00083 inhibited axonal growth and prevented synapse formation . In contrast , cleavage of VAMP with TeNT or BoNT / B had no effects on neurite extension and synaptogenesis . All the toxins tested inhibited transmitter release in differentiated neurons , and cleavage of VAMP resulted in the strongest inhibition . These data indicate that P60880 is involved in vesicle fusion for membrane expansion and transmitter release , whereas VAMP is selectively involved in transmitter release . In addition , our results support the hypothesis that synaptic activity is not essential for synapse formation in vitro .", "Synthesis of substrates and inhibitors of botulinum neurotoxin type A metalloprotease . Botulinum neurotoxin ( BoNT ) metalloproteases and related proteases are the most selective proteases known . X - ray crystal structures suggest that the active sites of the native enzymes exist in catalytically incompetent forms that must be activated by substrate binding . In order to characterize the postulated substrate - induced conformational changes for enzyme activation , we synthesized a series of transition - state analog inhibitors in which the dipeptide cleavage site is replaced by tetrahedral intermediate analogs within the minimal substrate peptide sequence . In this paper , we report our efforts to design inhibitors of DB00083 metalloprotease . We confirm that an effective substrate sequence for DB00083 metalloprotease is a 17 - mer peptide corresponding to residues 187 - 203 of P60880 . A more stable substrate , Nle202SNAP - 25 [ 187 - 203 ] was synthesized in order to develop an assay for proteolytic activity of DB00083 metalloprotease that can be used to monitor time - dependent inhibition . Alpha - thiol amide analogs of Gln - 197 were incorporated via solid - phase peptide synthesis into both 17 - mer minimal peptide substrate sequences . The synthesis , characterization and inhibition kinetics for the alpha - thiol amide analogs of holotoxin A substrate are described . These substrate - derived inhibitors were shown to be submicromolar inhibitors of DB00083 catalytic activity .", "Virulent Mycobacterium fortuitum restricts NO production by a gamma interferon - activated J774 cell line and phagosome - lysosome fusion . The virulence of different isolates of Mycobacterium has been associated with two morphologically distinguishable colonial variants : opaque ( SmOp ) and transparent ( SmTr ) . In this report we used an in vitro assay to compare macrophage ( Mphi ) responses to SmOp and SmTr Mycobacterium fortuitum variants , taking advantage of the fact that these variants were derived from the same isolate . Cells preactivated or not with gamma interferon ( P01579 ) were infected with SmOp or SmTr M . fortuitum . We showed that SmOp and SmTr induced different levels of nitric oxide ( NO ) production by P01579 - stimulated Mphi . Indeed , the amount of P01579 - induced NO production by J774 cells was 4 . 8 to 9 . 0 times higher by SmOp ( 23 . 1 to 37 . 7 micro M ) compared to SmTr infection ( 3 . 9 to 4 . 8 micro M ) ( P = 0 . 0332 ) , indicating that virulent SmTr bacilli restricted NO production . In addition , P01579 - induced NO production by Mphi was higher when correlated with reduction of only avirulent SmOp bacillus viability . P60880 ( S - nitroso - N - acetyl - DL - penicillamine ) - induced NO production did not modify SmTr viability , indicating its resistance to nitrogen radicals . Electron microscopy studies were performed to evaluate the capacity of phagosomes to fuse with lysosomes labeled with bovine serum albumin - colloidal gold particles . By 24 h postinfection , 69 % more phagosome - containing SmOp variant had fused with lysosomes compared to the SmTr - induced phagosomes . In conclusion , these data indicate that virulent SmTr bacilli may escape host defense by restricting P01579 - induced NO production , resisting nitrogen toxic radicals , and limiting phagosome fusion with lysosomes .", "Correlation of cleavage of P60880 with muscle function in a rat model of Botulinum neurotoxin type A induced paralysis . Injection of botulinum neurotoxin serotype A ( DB00083 ) into muscle results in cleavage of the synaptosomal associated protein of 25 kDa ( P60880 ) and relatively long - term paralysis . However , nerve - terminal sprouting , which appears to require intact P60880 , has been reported to occur much earlier . The difference between the long - term paralysis induced by injection of DB00083 and the short time needed for sprouting led us to investigate the relationship between DB00083 catalyzed cleavage of P60880 and muscle function . The effect of DB00083 on P60880 present in nerve endings innervating gastrocnemius muscles of rats was monitored over time . Cleaved P60880 was found in nerve terminals innervating the muscles within 24h of inoculation with DB00083 and was present more than 2 months later . Comparison of the ratios of cleaved to intact P60880 from the onset of DB00083 - induced paralysis until function was regained indicated that paralysis was probable when the ratio of cleaved to intact P60880 was greater than 0 . 35 .", "Direct biosensor detection of botulinum neurotoxin endopeptidase activity in sera from patients with type A botulism . Botulinum neurotoxin A ( DB00083 ) has intrinsic endoprotease activity specific for P60880 , a key protein for presynaptic neurotransmitter release . The inactivation of P60880 by DB00083 underlies botulism , a rare but potentially fatal disease . There is a crucial need for a rapid and sensitive in vitro serological test for DB00083 to replace the current in vivo mouse bioassay . Cleavage of P60880 by DB00083 generates neo - epitopes which can be detected by binding of a monoclonal antibody ( mAb10F12 ) and thus measured by surface plasmon resonance ( SPR ) . We have explored two SPR assay formats , with either mAb10F12 or His6 - P60880 coupled to the biosensor chip . When DB00083 was incubated with P60880 in solution and the reaction products were captured on a mAb - coated chip , a sensitivity of 5 fM ( 0 . 1LD50 / ml serum ) was obtained . However , this configuration required prior immunoprecipitation of DB00083 . A sensitivity of 0 . 5 fM in 10 % serum ( 0 . 1 LD50 / ml serum ) was attained when P60880 was coupled directly to the chip , followed by sequential injection of DB00083 samples and mAb10F12 into the flow system to achieve on - chip cleavage and detection , respectively . This latter format detected DB00083 endoprotease activity in 50 - 100 µl serum samples from all patients ( 11 / 11 ) with type A botulism within 5h . No false positives occurred in sera from healthy subjects or patients with other neurological diseases . The automated chip - based procedure has excellent specificity and sensitivity , with significant advantages over the mouse bioassay in terms of rapidity , required sample volume and animal ethics .", "Regulated secretion is impaired in AtT - 20 endocrine cells stably transfected with botulinum neurotoxin type A light chain . Botulinum neurotoxin type A ( DB00083 ) inhibits neurotransmitter release by specific cleavage of P60880 , a synaptosome - associated protein also expressed in the DB01285 secretory cell line AtT - 20 . Expression of light chain DB00083 ( L - DB00083 ) gene transfected into AtT - 20 cells resulted in a cleaved form of P60880 indistinguishable from that generated by bona fide DB00083 . L - DB00083 - transfected cells showed no difference in replication rate , viability , or phenotype , compared with control AtT - 20 cells . In contrast , L - DB00083 - transfected cells could not be induced to secrete DB01285 upon stimulation by 8 - bromo - DB02527 or DB00761 . In addition , alpha - latrotoxin induced DB01285 release from control cells , but not from L - DB00083 - transfected cells . These experiments suggest an important role for P60880 in regulated secretion from AtT - 20 cells and underline the usefulness of this cell system as a tool for the study of the molecular mechanism of peptide hormone secretion ." ]

[ "___MASK100___", "___MASK26___", "___MASK34___", "___MASK39___", "___MASK44___", "___MASK50___", "___MASK73___", "___MASK81___", "___MASK8___" ]

[ "P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration - response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed .", "DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "CXC - chemokine receptor 4 antagonist DB06809 promotes cardiac functional recovery after ischemia / reperfusion injury via endothelial nitric oxide synthase - dependent mechanism . BACKGROUND : CXC - chemokine receptor 4 ( P61073 ) regulates the retention of stem / progenitor cells in the bone marrow ( BM ) , and the P61073 antagonist DB06809 improves recovery from coronary ligation injury by mobilizing stem / progenitor cells from the BM to the peripheral blood . Thus , we investigated whether DB06809 also improves recovery from ischemia / reperfusion injury , which more closely mimics myocardial infarction in patients , because blood flow is only temporarily obstructed . METHODS AND RESULTS : Mice were treated with single subcutaneous injections of DB06809 ( 5 mg / kg ) or saline after ischemia / reperfusion injury . Three days later , histological measurements of the ratio of infarct area to area at risk were smaller in DB06809 - treated mice than in mice administered saline , and echocardiographic measurements of left ventricular function were greater in the DB06809 - treated mice at week 4 . P61073 (+) cells were mobilized for just 1 day in both groups , but the mobilization of sca1 (+)/ flk1 (+) cells endured for 7 days in DB06809 - treated mice compared with just 1 day in the saline - treated mice . DB06809 upregulated BM levels of endothelial nitric oxide synthase ( P29474 ) and 2 targets of P29474 signaling , matrix metalloproteinase - 9 and soluble P21583 . Furthermore , the loss of BM P29474 expression abolished the benefit of DB06809 on sca1 (+)/ flk1 (+) cell mobilization without altering the mobilization of P61073 (+) cells , and the cardioprotective effects of DB06809 were retained in P29474 - knockout mice that had been transplanted with BM from wild - type mice but not in wild - type mice with P29474 - knockout BM . CONCLUSIONS : DB06809 prolongs BM progenitor mobilization and improves recovery from ischemia / reperfusion injury , and these benefits appear to occur through a previously unidentified link between DB06809 and BM P29474 expression .", "DB00435 synthases : regulation and function . DB00435 ( NO ) , the smallest signalling molecule known , is produced by three isoforms of NO synthase ( NOS ; EC 1 . 14 . 13 . 39 ) . They all utilize l - arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide - adenine - dinucleotide phosphate ( NADPH ) , flavin adenine dinucleotide ( DB03147 ) , flavin mononucleotide ( Q68DA7 ) , and ( 6R -) DB00360 ( BH ( 4 ) ) . All NOS bind calmodulin and contain haem . P29475 ( P29475 , NOS I ) is constitutively expressed in central and peripheral neurons and some other cell types . Its functions include synaptic plasticity in the central nervous system ( CNS ) , central regulation of blood pressure , smooth muscle relaxation , and vasodilatation via peripheral nitrergic nerves . Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection . Phosphodiesterase 5 inhibitors ( sildenafil , vardenafil , and tadalafil ) require at least a residual P29475 activity for their action . P35228 ( NOS II ) can be expressed in many cell types in response to lipopolysaccharide , cytokines , or other agents . P35228 generates large amounts of NO that have cytostatic effects on parasitic target cells . P35228 contributes to the pathophysiology of inflammatory diseases and septic shock . P29474 ( P29474 , NOS III ) is mostly expressed in endothelial cells . It keeps blood vessels dilated , controls blood pressure , and has numerous other vasoprotective and anti - atherosclerotic effects . Many cardiovascular risk factors lead to oxidative stress , P29474 uncoupling , and endothelial dysfunction in the vasculature . Pharmacologically , vascular oxidative stress can be reduced and P29474 functionality restored with renin - and angiotensin - converting enzyme - inhibitors , with angiotensin receptor blockers , and with statins .", "DB00360 as another EDRF in man . Endotoxin and inflammatory cytokines downregulate expression of constitutive nitric oxide synthase ( P29474 ) in human vascular endothelial cells with concomitant increase of tetrahydrobiopterin synthesis in these cells and parallel upregulation of inducible NOS expression in smooth muscle cells , indicating compartmentalized nitric oxide ( NO ) production under septic conditions in man . In this report the compartmentalization has been further studied using dual chamber cell cultures with inflammatory activated human endothelial cells . We show that endothelial cells secrete BH4 vectorially into the basal direction thereby providing underlining smooth muscle cells with the cofactor necessary for NO production . Furthermore , by laser Doppler velocimetry we show that intraarterial infusion of BH4 induces strong vasodilatation in man . Consumption of L - arginine and production of cyclic GMP increased and therefore imply NO as second messenger . Thus the discovery of an endothelium - derived factor regulating NOS activity would reconcile the concept of an inflammatory EDRF that is not NO itself but results in NO - dependent vasodilatation in man .", "Therapeutic effect of enhancing endothelial nitric oxide synthase ( P29474 ) expression and preventing P29474 uncoupling . DB00435 ( NO ) produced by the endothelium is an important protective molecule in the vasculature . It is generated by the enzyme endothelial NO synthase ( P29474 ) . Similar to all NOS isoforms , functional P29474 transfers electrons from nicotinamide adenine dinucleotide phosphate ( NADPH ) , via the flavins flavin adenine dinucleotide and flavin mononucleotide in the carboxy - terminal reductase domain , to the heme in the amino - terminal oxygenase domain . Here , the substrate L - arginine is oxidized to L - citrulline and NO . Cardiovascular risk factors such as diabetes mellitus , hypertension , hypercholesterolaemia or cigarette smoking reduce bioactive NO . These risk factors lead to an enhanced production of reactive oxygen species ( ROS ) in the vessel wall . NADPH oxidases represent major sources of this ROS and have been found upregulated in the presence of cardiovascular risk factors . NADPH - oxidase - derived superoxide avidly reacts with P29474 - derived NO to form peroxynitrite ( ONOO (-) ) . The essential NOS cofactor ( 6R -) DB00360 ( BH ( 4 ) ) is highly sensitive to oxidation by this ONOO (-) . In BH ( 4 ) deficiency , oxygen reduction uncouples from NO synthesis , thereby converting NOS to a superoxide - producing enzyme . Among conventional drugs , compounds interfering with the renin - angiotensin - aldosterone system and statins can reduce vascular oxidative stress and increase bioactive NO . In recent years , we have identified a number of small molecules that have the potential to prevent P29474 uncoupling and , at the same time , enhance P29474 expression . These include the protein kinase C inhibitor midostaurin , the pentacyclic triterpenoids ursolic acid and betulinic acid , the P29474 enhancing compounds AVE9488 and AVE3085 , and the polyphenolic phytoalexin trans - resveratrol . Such compounds enhance NO production from P29474 also under pathophysiological conditions and may thus have therapeutic potential .", "[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK89___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .", "Glucocorticoids inhibit tetrahydrobiopterin - dependent endothelial function . DB00360 ( BH4 ) acts as an important co - factor for endothelial nitric oxide synthase ( P29474 ) . Glucocorticoids have been shown to inhibit expression of the rate - limiting enzyme for tetrahydrobiopterin synthesis , GTP cyclohydrolase , in other cell types . We hypothesized that endothelium - dependent vasodilator responses would be blunted in rats made hypertensive with dexamethasone . Further , we hypothesized that treatment of rat vascular segments with dexamethasone would result in attenuation of endothelial function accompanied by decreased GTP cyclohydrolase expression . We report that endothelium - dependent relaxation responses to the calcium ionophore A23187 are reduced in aortic rings from dexamethasone - hypertensive rats compared with sham values . Dexamethasone incubation abolishes contraction to Nomega - nitro - L - arginine ( DB04223 , 10 (- 5 ) M ) in endothelium - intact aortic rings , and inhibits expression of GTP cyclohydrolase . We conclude that inhibition of BH4 synthesis by glucocorticoid regulation of GTP cyclohydrolase expression may contribute to reduced endothelium - dependent vasodilation characteristic of glucocorticoid - induced hypertension .", "P01308 like growth factor - 1 selectively regulates the expression of matrix metalloproteinase - 2 in malignant H - ras transformed cells . The present study demonstrates alterations in the regulation of matrix metalloproteinase - 2 ( P08253 ) expression in response to insulin like growth factor - 1 ( DB01277 ) in a H - ras transformed cell line , P01024 , which is capable of metastasis formation . These changes in P08253 expression in response to DB01277 treatment did not occur in either non - transformed parental 10 T 1 / 2 cells or in H - ras transformed cells ( Q13224 cells ) which are capable of benign tumour formation . DB01277 treatment of P01024 cells resulted in increased expression of P08253 gelatinolytic activity and increased expression of P08253 mRNA levels . The DB01277 mediated alterations in P08253 mRNA levels were dependent upon de novo protein synthesis and independent of transcriptional events , but dependent upon post - transcriptional regulatory events . Most notably , DB01277 can regulate P08253 mRNA expression in P01024 cells through a mechanism involving P08253 message stabilization . This study demonstrates aspects of the temporal regulatory mechanisms of P08253 expression in response to insulin - like growth factor - 1 in a H - ras transformed fibrosarcoma cell line capable of metastasis formation and thereby , provides further insight into the altered growth regulatory program associated with H - ras mediated cellular transformation and malignant progression .", "DB09140 metabolism by endothelial nitric - oxide synthase . Nitric - oxide synthase ( NOS ) catalyzes both coupled and uncoupled reactions that generate nitric oxide and reactive oxygen species . DB09140 is often the overlooked substrate , and the oxygen metabolism catalyzed by NOS has been poorly defined . In this paper we focus on the oxygen stoichiometry and effects of substrate / cofactor binding on the endothelial NOS isoform ( P29474 ) . In the presence of both L - arginine and tetrahydrobiopterin , P29474 is highly coupled ( > 90 % ) , and the measured stoichiometry of O ( 2 )/ NADPH is very close to the theoretical value . We report for the first time that the presence of L - arginine stimulates oxygen uptake by P29474 . The fact that nonhydrolyzable L - arginine analogs are not stimulatory indicates that the occurrence of the coupled reaction , rather than the accelerated uncoupled reaction , is responsible for the L - arginine - dependent stimulation . The presence of DB00360 quenched the uncoupled reactions and resulted in much less reactive oxygen species formation , whereas the presence of redox - incompetent 7 , 8 - dihydrobiopterin demonstrates little quenching effect . These results reveal different mechanisms for oxygen metabolism for P29474 as opposed to P29475 and , perhaps , partially explain their functional differences .", "P30793 gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells : effects on nitric oxide synthase activity , protein levels and dimerisation . OBJECTIVES : DB00360 ( BH4 ) is an essential cofactor for endothelial nitric oxide synthase ( P29474 ) activity . BH4 levels are regulated by de novo biosynthesis ; the rate - limiting enzyme is P30793 ( GTPCH ) . BH4 activates and promotes homodimerisation of purified P29474 protein , but the intracellular mechanisms underlying BH4 - mediated P29474 regulation in endothelial cells remain less clear . We aimed to investigate the role of BH4 levels in intracellular P29474 regulation , by targeting the BH4 synthetic pathway as a novel strategy to modulate intracellular BH4 levels . METHODS : We constructed a recombinant adenovirus , AdGCH , encoding human GTPCH . We infected human endothelial cells with AdGCH , investigated the changes in intracellular biopterin levels , and determined the effects on P29474 enzymatic activity , protein levels and dimerisation . RESULTS : GTPCH gene transfer in EAhy926 endothelial cells increased BH4 > 10 - fold compared with controls ( cells alone or control adenovirus infection ) , and greatly enhanced NO production in a dose - dependent , P29474 - specific manner . We found that P29474 was principally monomeric in control cells , whereas GTPCH gene transfer resulted in a striking increase in P29474 homodimerisation . Furthermore , the total amounts of both native P29474 protein and a recombinant P29474 - GFP fusion protein were significantly increased following GTPCH gene transfer . CONCLUSIONS : These findings suggest that GTPCH gene transfer is a valid approach to increase BH4 levels in human endothelial cells , and provide new evidence for the relative importance of different mechanisms underlying BH4 - mediated P29474 regulation in intact human endothelial cells . Additionally , these observations suggest that GTPCH may be a rational target to augment endothelial BH4 and normalise P29474 activity in endothelial dysfunction states .", "The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase : an EPR spin trapping study . Augmentation of superoxide levels has been linked to impaired relaxation in hypertension , diabetes and hypercholesterolaemia . Purified endothelial nitric oxide synthase ( P29474 ) generates superoxide under limited availability of DB00360 ( BH ( 4 ) ) . Thus alterations in endothelial BH ( 4 ) levels have been postulated to stimulate superoxide production from P29474 . This possibility was examined by determining the concentration - dependent effects of BH ( 4 ) , and its analogues , on superoxide formation by P29474 . Superoxide was quantified by EPR spin trapping , which is the only available technique to quantify superoxide from P29474 . Using 5 - ethoxycarbonyl - 5 - methyl - pyrroline N - oxide , we show that only fully reduced BH ( 4 ) diminished superoxide release from P29474 , with efficiency BH ( 4 ) > 6 - methyl - BH ( 4 ) > 5 - methyl - BH ( 4 ) . In contrast , partially oxidized BH ( 4 ) analogues , 7 , 8 - dihydrobiopterin ( 7 , 8 - BH ( 2 ) ) and sepiapterin had no effect . Neither l - arginine nor N ( G )- nitro - l - arginine methyl ester ( l - NAME ) abolished superoxide formation . Together , BH ( 4 ) and l - arginine stimulated . NO production at maximal rates of 148 nmol / min per mg of protein . These results indicate that BH ( 4 ) acts as a \" redox switch \" , decreasing superoxide release and enhancing . NO formation . This role was verified by adding 7 , 8 - BH ( 2 ) or sepiapterin to fully active P29474 . Both 7 , 8 - BH ( 2 ) and sepiapterin enhanced superoxide release while inhibiting DB00435 formation . Collectively , these results indicate that the ratio between oxidized and reduced BH ( 4 ) metabolites tightly regulates superoxide formation from P29474 . The pathological significance of this scenario is discussed .", "Acute heat stress induces edema and nitric oxide synthase upregulation and down - regulates mRNA levels of the Q05586 , Q12879 and Q13224 subunits in the rat hippocampus . The influence of heat stress on constitutive isoform of neuronal nitric oxide synthase ( P29474 ) and DB01221 receptor gene expression in hippocampus was examined in a rat model . Subjection of animals to 4 h heat stress at 38 degrees C resulted in a marked upregulation of P29474 in the hippocampus accompanied with a marked general expansion and edematous cell changes . On the other hand DB01221 receptor messenger RNA encoding Q05586 , Q12879 and Q13224 subunits showed a marked downregulation in the hippocampus of heat stressed rats compared to the controls . Our results show that upregulation of P29474 is instrumental in heat stress associated edema and cell injury . Furthermore , an increased production of NO as evident with upregulation of P29474 appears to be a key factor in the downregulation of DB01221 receptor gene expression in heat stress .", "Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK71___ , and 86 % ± 8 % in Q8NE62 - ___MASK71___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK71___ , and 86 % ± 8 % in Q8NE62 - ___MASK71___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 .", "___MASK84___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .", "P15692 activates Q13224 phosphorylation through Dab1 pathway . Vascular endothelial growth factor ( P15692 ) and reelin are two major signaling pathways involved in many neuronal functions including neurogenesis and neuronal migration . Both P15692 and reelin have been shown to regulate DB01221 type glutamate receptor ( NMDAR ) activity via independent mechanisms . However , it is not known whether the above signaling pathways influence each other on NMDAR regulation . We demonstrate that Disabled 1 ( Dab1 ) , a downstream signaling molecule of reelin pathway mediates P15692 - induced regulation of NMDAR subunit Q13224 . Furthermore , P15692 treatment led to the association of P15692 receptor - 2 ( Flk1 ) and reelin receptor ( apolipoprotein E receptor 2 , ApoER2 ) , and Dab1 as well as Q13224 activation were Flk1 - dependent . Moreover , P15692 treatment could significantly rescue the deficits in phospho - Dab1 levels in reeler ( Reln -/- ) neurons . Our results suggest a major role of P15692 in the regulation of reelin signaling , and Dab1 as a key molecule in the cross talk between reelin and P15692 signaling pathways .", "P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK89___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK89___ is in clinical development as an orally active agent .", "The role of tetrahydrobiopterin and dihydrobiopterin in ischemia / reperfusion injury when given at reperfusion . Reduced nitric oxide ( NO ) bioavailability and increased oxidative stress are major factors mediating ischemia / reperfusion ( I / R ) injury . DB00360 ( BH ( 4 ) ) is an essential cofactor of endothelial NO synthase ( P29474 ) to produce NO , whereas dihydrobiopterin ( BH ( 2 ) ) can shift the P29474 product profile from NO to superoxide , which is further converted to hydrogen peroxide ( H ( 2 ) O ( 2 ) ) and cause I / R injury . The effects of BH ( 4 ) and BH ( 2 ) on oxidative stress and postreperfused cardiac functions were examined in ex vivo myocardial and in vivo femoral I ( 20 min ) / R ( 45 min ) models . In femoral I / R , BH ( 4 ) increased NO and decreased H ( 2 ) O ( 2 ) releases relative to saline control , and these effects correlated with improved postreperfused cardiac function . By contrast , BH ( 2 ) decreased NO release relative to the saline control , but increased H ( 2 ) O ( 2 ) release similar to the saline control , and these effects correlated with compromised postreperfused cardiac function . In conclusion , these results suggest that promoting P29474 coupling to produce NO and decrease H ( 2 ) O ( 2 ) may be a key mechanism to restore postreperfused organ function during early reperfusion .", "Pulmonary hypertension in the newborn P30793 - deficient mouse . DB00360 ( BH4 ) is a regulator of endothelial nitric oxide synthase ( P29474 ) activity . Deficient levels result in P29474 uncoupling , with a shift from nitric oxide to superoxide generation . The hph - 1 mutant mouse has deficient P30793 ( GTPCH1 ) activity , resulting in low BH4 tissue content . The adult hph - 1 mouse has pulmonary hypertension , but whether such condition is present from birth is not known . Thus , we evaluated newborn animals ' pulmonary arterial medial thickness , biopterin content ( BH4 + BH2 ) , H ( 2 ) O ( 2 ) and P29474 , right ventricle - to - left ventricle + septum ( RV / LV + septum ) ratio , near - resistance pulmonary artery agonist - induced force , and endothelium - dependent and - independent relaxation . The lung biopterin content was inversely related to age for both types , but significantly lower in hph - 1 mice , compared to wild - type animals . As judged by the RV / LV + septum ratio , newborn hph - 1 mice have pulmonary hypertension and , after a 2 - week 13 % oxygen exposure , the ratios were similar in both types . The pulmonary arterial agonist - induced force was reduced ( P < 0 . 01 ) in hph - 1 animals and no type - dependent difference in endothelium - dependent or - independent vasorelaxation was observed . Compared to wild - type mice , the lung H ( 2 ) O ( 2 ) content was increased , whereas the P29474 expression was decreased ( P < 0 . 01 ) in hph - 1 animals . The pulmonary arterial medial thickness , a surrogate marker of vascular remodeling , was increased ( P < 0 . 01 ) in hph - 1 compared to wild - type mice . In conclusion , our data suggest that pulmonary hypertension is present from birth in the GTPCH1 - deficient mice , not as a result of impaired vasodilation , but secondary to vascular remodeling .", "DB00360 : pleiotropic roles in cardiovascular pathophysiology . DB00360 ( BH4 ) functions as a cofactor in several important enzyme systems . Substantial evidence implicates BH4 as a key regulator of endothelial nitric oxide synthase ( P29474 ) in the setting of endothelial dysfunction and atherosclerosis . Investigators have now taken early steps in addressing the potential of BH4 as a therapeutic strategy . However , it has become more apparent that the role of BH4 in other enzymatic pathways , including other NOS isoforms and the aromatic amino acid hydroxylases , may have a bearing on important aspects of cardiovascular homeostasis . Together with P29474 , these enzymes may play key roles in diverse cardiovascular disease states such as ischaemia - reperfusion injury , cardiac hypertrophy , cardiac autonomic function and pulmonary hypertension . This review provides an overview of the role of BH4 in cardiovascular pathophysiology .", "Inhibitor of G protein - coupled receptor kinase 2 normalizes vascular endothelial function in type 2 diabetic mice by improving β - arrestin 2 translocation and ameliorating Akt / P29474 signal dysfunction . In type 2 diabetes , although Akt / endothelial NO synthase ( P29474 ) activation is known to be negatively regulated by G protein - coupled receptor kinase 2 ( P25098 ) , it is unclear whether the P25098 inhibitor would have therapeutic effects . Here we examined the hypotensive effect of the P25098 inhibitor and its efficacy agonist both vascular ( aortic ) endothelial dysfunction ( focusing especially on the Akt / P29474 pathway ) and glucose intolerance in two type 2 diabetic models ( ob / ob mice and nicotinamide + streptozotocin - induced diabetic mice ) . Mice were treated with a single injection of the P25098 inhibitor or vehicle , and the therapeutic effects were compared by examining vascular function and by Western blotting . The P25098 inhibitor lowered blood pressure in both diabetic models but not in their age - matched controls . The P25098 inhibitor significantly improved clonidine - induced relaxation only in diabetic ( ob / ob and DM ) mice , with accompanying attenuations of P25098 activity and translocation to the plasma membrane . These protective effects of the P25098 inhibitor may be attributable to the augmented Akt / P29474 pathway activation ( as evidenced by increases in Akt phosphorylation at DB00133 ( 473 ) and at DB00156 ( 308 ) , and P29474 phosphorylation at DB00133 ( 1177 ) ) and to the prevention of the P25098 translocation and promotion of β - arrestin 2 translocation to the membrane under clonidine stimulation . Moreover , the P25098 inhibitor significantly improved the glucose intolerance seen in the ob / ob mice . Our work provides the first evidence that in diabetes , the P25098 inhibitor ameliorates vascular endothelial dysfunction via the Akt / P29474 pathway by inhibiting P25098 activity and enhancing β - arrestin 2 translocation under clonidine stimulation , thereby contributing to a blood pressure - lowering effect . We propose that the P25098 inhibitor may be a promising therapeutic agent for cardiovascular complications in type 2 diabetes .", "Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP - cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE - knockout mice . OBJECTIVE : Increased production of reactive oxygen species and loss of endothelial nitric oxide ( NO ) bioactivity are key features of vascular disease states such as atherosclerosis . DB00360 ( BH4 ) is a required cofactor for NO synthesis by endothelial nitric oxide synthase ( P29474 ) ; pharmacologic studies suggest that reduced BH4 availability may be an important mediator of endothelial dysfunction in atherosclerosis . We aimed to investigate the importance of endothelial BH4 availability in atherosclerosis using a transgenic mouse model with endothelial - targeted overexpression of the rate - limiting enzyme in BH4 synthesis , GTP - cyclohydrolase I ( GTPCH ) . METHODS AND RESULTS : Transgenic mice were crossed into an ApoE knockout ( ApoE - KO ) background and fed a high - fat diet for 16 weeks . Compared with ApoE - KO controls , transgenic mice ( ApoE - KO / P30793 - P01266 ) had higher aortic BH4 levels , reduced endothelial superoxide production and P29474 uncoupling , increased cGMP levels , and preserved NO - mediated endothelium dependent vasorelaxations . Furthermore , aortic root atherosclerotic plaque was significantly reduced in ApoE - KO / P30793 - P01266 mice compared with ApoE - KO controls . CONCLUSIONS : These findings indicate that BH4 availability is a critical determinant of P29474 regulation in atherosclerosis and is a rational therapeutic target to restore NO - mediated endothelial function and reduce disease progression .", "Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .", "Molecular mechanisms of impaired endothelial function associated with insulin resistance . Dysfunction of the endothelium in large - and medium - sized arteries plays a central role in atherogenesis . The insulin resistance syndrome encompasses more than a subnormal response to insulin - mediated glucose disposal . Patients with this syndrome also frequently display elevated blood pressure , hyperlipidemia , and dysfibinolysis , even without any clinically manifested alteration in plasma glucose concentrations . Of note endothelial dysfunction and atherosclerosis also have been demonstrated in patients with hypertension , which is one of the features of the syndrome of insulin resistance . P01308 - induced vasodilation , which is mediated by the release of nitric oxide ( NO ) release , is impaired in obese individuals who display insulin resistance . Although it is tempting to speculate that loss of endothelium - dependent vasodilation and increased vasoconstriction might be etiological factors of elevated blood pressure , the factors contributing to NO - mediated endothelial dysfunction in the insulin - resistant state are not fully defined . Experimental evidences suggest that ( 6R ) - DB00360 ( BH ( 4 ) ) , the natural and essential cofactor of NO synthases ( NOS ) , plays a crucial role not only in increasing the rate of NO generation by NOS but also in controlling the formation of superoxide anion ( O ( 2 )(-) ) in the endothelial cells . Under insulin - resistant conditions where BH ( 4 ) levels are suboptimal , in addition to a reduced synthesis of NO , an accelerated inactivation of NO by O ( 2 )(-) within the vascular wall was observed . Furthermore , oral supplementation of BH ( 4 ) restored endothelial function and relieved oxidative tissue damage , through activation of P29474 in the aorta of insulin - resistant rats . These results indicate that abnormal pteridine metabolism contributes to causing endothelial dysfunction and the enhancement of vascular oxidative stress in the insulin - resistant state .", "Impairment of endothelial - myocardial interaction increases the susceptibility of cardiomyocytes to ischemia / reperfusion injury . Endothelial - myocardial interactions may be critically important for ischemia / reperfusion injury . DB00360 ( BH4 ) is a required cofactor for nitric oxide ( NO ) production by endothelial NO synthase ( P29474 ) . Hyperglycemia ( HG ) leads to significant increases in oxidative stress , oxidizing BH4 to enzymatically incompetent dihydrobiopterin . How alterations in endothelial BH4 content impact myocardial ischemia / reperfusion injury remains elusive . The aim of this study was to examine the effect of endothelial - myocardial interaction on ischemia / reperfusion injury , with an emphasis on the role of endothelial BH4 content . Langendorff - perfused mouse hearts were treated by triton X - 100 to produce endothelial dysfunction and subsequently subjected to 30 min of ischemia followed by 2 h of reperfusion . The recovery of left ventricular systolic and diastolic function during reperfusion was impaired in triton X - 100 treated hearts compared with vehicle - treated hearts . Cardiomyocytes ( CMs ) were co - cultured with endothelial cells ( ECs ) and subsequently subjected to 2 h of hypoxia followed by 2 h of reoxygenation . Addition of ECs to CMs at a ratio of 1 ∶ 3 significantly increased NO production and decreased lactate dehydrogenase activity compared with CMs alone . This EC - derived protection was abolished by HG . The addition of 100 µM sepiapterin ( a BH4 precursor ) or overexpression of P30793 ( the rate - limiting enzyme for BH4 biosynthesis ) in ECs by gene trasfer enhanced endothelial BH4 levels , the ratio of P29474 dimer / monomer , P29474 phosphorylation , and NO production and decreased lactate dehydrogenase activity in the presence of HG . These results demonstrate that increased BH4 content in ECs by either pharmacological or genetic approaches reduces myocardial damage during hypoxia / reoxygenation in the presence of HG . Maintaining sufficient endothelial BH4 is crucial for cardioprotection against hypoxia / reoxygenation injury .", "Role of monoamine oxidases in the exaggerated 5 - hydroxytryptamine - induced tension development of human isolated preeclamptic umbilical artery . We investigated the role ( s ) of monoamine oxidases ( MAOs ) on the altered 5 - hydroxytryptamine ( 5 - HT , serotonin ) - induced tension development of the isolated umbilical artery of preeclamptic pregnancy of Chinese women . An enhanced 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy was observed when compared with that of normal pregnancy . The enhanced component of 5 - HT - induced tension development was eradicated by clorgyline ( a P21397 inhibitor ) . Blockade of P29474 ( endothelial isoform nitric oxide synthase ) ( N ( omega )- nitro - L - arginine methyl ester ) , 5 - HT transporter ( citalopram ) , 5 - HT receptor subtypes ( 5HT2B , SB 204741 ; P28335 , RS 102221 ; P34969 , SB 269970 ) , and endothelium denudation of the umbilical artery of normal pregnancy mimicked the enhanced 5 - HT - induced tension development as observed in the preeclamptic tissues . In contrast , no apparent changes in 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy were observed with the same pharmacological manipulations . A decreased protein expression levels of P21397 and P29474 ( no P35228 and P27338 expression was detected ) and no change in caveolin - 1 and 5 - HT transporter expression were demonstrated in the umbilical artery ( endothelium intact ) lysate of preeclamptic pregnancy , compared to that of the umbilical artery of normal pregnancy . Thus , in the umbilical artery of preeclamptic pregnancy , a decrease of P21397 and P29474 protein expression levels are probably associated with , or responsible for , the exaggerated 5 - HT - induced tension development .", "Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK60___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .", "A pivotal role for tryptophan 447 in enzymatic coupling of human endothelial nitric oxide synthase ( P29474 ) : effects on tetrahydrobiopterin - dependent catalysis and P29474 dimerization . DB00360 ( BH4 ) is a required cofactor for the synthesis of NO by NOS . Bioavailability of BH4 is a critical factor in regulating the balance between NO and superoxide production by endothelial NOS ( P29474 coupling ) . Crystal structures of the mouse inducible NOS oxygenase domain reveal a homologous BH4 - binding site located in the dimer interface and a conserved tryptophan residue that engages in hydrogen bonding or aromatic stacking interactions with the BH4 ring . The role of this residue in P29474 coupling remains unexplored . We overexpressed human P29474 W447A and W447F mutants in novel cell lines with tetracycline - regulated expression of human P30793 , the rate - limiting enzyme in BH4 synthesis , to determine the importance of BH4 and DB00150 - 447 in P29474 uncoupling . NO production was abolished in P29474 - W447A cells and diminished in cells expressing W447F , despite high BH4 levels . P29474 - derived superoxide production was significantly elevated in W447A and W447F versus wild - type P29474 , and this was sufficient to oxidize BH4 to 7 , 8 - dihydrobiopterin . In uncoupled , BH4 - deficient cells , the deleterious effects of W447A mutation were greatly exacerbated , resulting in further attenuation of NO and greatly increased superoxide production . P29474 dimerization was attenuated in W447A P29474 cells and further reduced in BH4 - deficient cells , as demonstrated using a novel split Renilla luciferase biosensor . Reduction of cellular BH4 levels resulted in a switch from an P29474 dimer to an P29474 monomer . These data reveal a key role for DB00150 - 447 in determining NO versus superoxide production by P29474 , by effects on BH4 - dependent catalysis , and by modulating P29474 dimer formation .", "P01375 inhibits flow and insulin signaling leading to NO production in aortic endothelial cells . Endothelial cells release nitric oxide ( NO ) acutely in response to increased \" flow \" or fluid shear stress ( FSS ) , and the increase in NO production is correlated with enhanced phosphorylation and activation of endothelial nitric oxide synthase ( P29474 ) . Both vascular endothelial growth factor and FSS activate endothelial protein kinase B ( P31749 ) by way of incompletely understood pathway ( s ) , and , in turn , P31749 phosphorylates P29474 at DB00133 - 1179 , causing its activation . In this study , we found that either FSS or insulin stimulated insulin receptor substrate - 1 ( P35568 ) tyrosine and serine phosphorylation and increased P35568 - associated phosphatidylinositol 3 - kinase activity , phosphorylation of P31749 DB00133 - 473 , phosphorylation of P29474 DB00133 - 1179 , and NO production . Brief pretreatment of bovine aortic endothelial cells with tumor necrosis factor - alpha ( P01375 ) inhibited the above described FSS - or insulin - stimulated protein phosphorylation events and almost totally inhibited FSS - or insulin - stimulated NO production . These data indicate that FSS and insulin regulate P29474 phosphorylation and NO production by overlapping mechanisms . This study suggests one potential mechanism for the development of endothelial dysfunction in disease states with alterations in insulin regulation and increased P01375 levels .", "Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague - Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0 . 02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real - time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .", "Cell - autonomous role of endothelial P30793 and tetrahydrobiopterin in blood pressure regulation . DB00360 ( BH4 ) is an essential cofactor for endothelial nitric oxide synthase ( P29474 ) function and NO generation . Augmentation of BH4 levels can prevent P29474 uncoupling and can improve endothelial dysfunction in vascular disease states . However , the physiological requirement for de novo endothelial cell BH4 biosynthesis in P29474 function remains unclear . We generated a novel mouse model with endothelial cell - specific deletion of P30793 , encoding P30793 , an essential enzyme for BH4 biosynthesis , to test the cell - autonomous requirement for endothelial BH4 biosynthesis in vivo . Mice with a floxed P30793 allele ( P30793 ( fl / fl ) ) were crossed with Tie2cre mice to delete P30793 in endothelial cells . P30793 ( fl / fl ) Tie2cre mice demonstrated virtually absent endothelial NO bioactivity and significantly greater O2 ( •- ) production . P30793 ( fl / fl ) Tie2cre aortas and mesenteric arteries had enhanced vasoconstriction to phenylephrine and impaired endothelium - dependent vasodilatations to acetylcholine and SLIGRL . Endothelium - dependent vasodilatations in P30793 ( fl / fl ) Tie2cre aortas were , in part , mediated by P29474 - derived hydrogen peroxide ( H2O2 ) , which mediated vasodilatation through soluble guanylate cyclase . Ex vivo supplementation of aortic rings with the BH4 analogue sepiapterin restored normal endothelial function and abolished P29474 - derived H2O2 production in P30793 ( fl / fl ) Tie2cre aortas . P30793 ( fl / fl ) Tie2cre mice had higher systemic blood pressure than wild - type littermates , which was normalized by NOS inhibitor , NG - nitro - L - arginine methyl ester . Taken together , these studies reveal an endothelial cell - autonomous requirement for P30793 and BH4 in regulation of vascular tone and blood pressure and identify endothelial cell BH4 as a pivotal regulator of NO versus H2O2 as alternative P29474 - derived endothelial - derived relaxing factors .", "DB03886 metabolism and P29474 expression during hypoxic pulmonary hypertension in mice . DB00360 ( BH4 ) , which fosters the formation of and stabilizes endothelial NO synthase ( P29474 ) as an active dimer , tightly regulates P29474 coupling / uncoupling . Moreover , studies conducted in genetically - modified models demonstrate that BH4 pulmonary deficiency is a key determinant in the pathogenesis of pulmonary hypertension . The present study thus investigates biopterin metabolism and P29474 expression , as well as the effect of sepiapterin ( a precursor of BH4 ) and P29474 gene deletion , in a mice model of hypoxic pulmonary hypertension . In lungs , chronic hypoxia increased BH4 levels and P29474 expression , without modifying dihydrobiopterin ( BH2 , the oxidation product of BH4 ) levels , GTP cyclohydrolase - 1 or dihydrofolate reductase expression ( two key enzymes regulating BH4 availability ) . In intrapulmonary arteries , chronic hypoxia also increased expression of P29474 , but did not induce destabilisation of P29474 dimers into monomers . In hypoxic mice , sepiapterin prevented increase in right ventricular systolic pressure and right ventricular hypertrophy , whereas it modified neither remodelling nor alteration in vasomotor responses ( hyper - responsiveness to phenylephrine , decrease in endothelium - dependent relaxation to acetylcholine ) in intrapulmonary arteries . Finally , deletion of P29474 gene partially prevented hypoxia - induced increase in right ventricular systolic pressure , right ventricular hypertrophy and remodelling of intrapulmonary arteries . Collectively , these data demonstrate the absence of BH4 / BH2 changes and P29474 dimer destabilisation , which may induce P29474 uncoupling during hypoxia - induced pulmonary hypertension . Thus , even though P29474 gene deletion and sepiapterin treatment exert protective effects on hypoxia - induced pulmonary vascular remodelling , increase on right ventricular pressure and / or right ventricular hypertrophy , these effects appear unrelated to biopterin - dependent P29474 uncoupling within pulmonary vasculature of hypoxic wild - type mice .", "Bi - modal dose - dependent cardiac response to tetrahydrobiopterin in pressure - overload induced hypertrophy and heart failure . The exogenous administration of tetrahydrobiopterin ( BH4 ) , an essential cofactor of nitric oxide synthase ( NOS ) , has been shown to reduce left ventricular hypertrophy , fibrosis , and cardiac dysfunction in mice with pre - established heart disease induced by pressure - overload . In this setting , BH4 re - coupled endothelial NOS ( P29474 ) , with subsequent reduction of NOS - dependent oxidative stress and reversal of maladaptive remodeling . However , recent studies suggest the effective BH4 dosing may be narrower than previously thought , potentially due to its oxidation upon oral consumption . Accordingly , we assessed the dose response of daily oral synthetic sapropterin dihydrochloride ( 6 - R - l - erythro - DB00360 , DB00360 ) on pre - established pressure - overload cardiac disease . Mice ( n = 64 ) were administered 0 - 400mg / kg / d BH4 by ingesting small pre - made pellets ( consumed over 15 - 30 min ) . In a dose range of 36 - 200mg / kg / d , DB00360 suppressed cardiac chamber remodeling , hypertrophy , fibrosis , and oxidative stress with pressure - overload . However , at both lower and higher doses , BH4 had less or no ameliorative effects . The effective doses correlated with a higher myocardial BH4 / BH2 ratio . However , BH2 rose linearly with dose , and at the 400mg / kg / d , this lowered the BH4 / BH2 ratio back toward control . These results expose a potential limitation for the clinical use of BH4 , as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals . This article is part of a special issue entitled '' Key Signaling Molecules in Hypertrophy and Heart Failure . ''", "P00374 protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency . DB00360 ( BH4 ) is a required cofactor for the synthesis of NO by endothelial nitric oxide synthase ( P29474 ) , and endothelial BH4 bioavailability is a critical factor in regulating the balance between NO and superoxide production ( P29474 coupling ) . Biosynthesis of BH4 is determined by the activity of GTP - cyclohydrolase I ( GTPCH ) . However , BH4 levels may also be influenced by oxidation , forming 7 , 8 - dihydrobiopterin ( BH2 ) , which promotes P29474 uncoupling . Conversely , dihydrofolate reductase ( P00374 ) can regenerate BH4 from BH2 , but whether P00374 is functionally important in maintaining P29474 coupling remains unclear . To investigate the mechanism by which P00374 might regulate P29474 coupling in vivo , we treated wild - type , BH4 - deficient ( hph - 1 ) , and GTPCH - overexpressing ( P30793 - Tg ) mice with methotrexate ( MTX ) , to inhibit BH4 recycling by P00374 . MTX treatment resulted in a striking elevation in BH2 and a decreased BH4 : BH2 ratio in the aortas of wild - type mice . These effects were magnified in hph - 1 but diminished in P30793 - Tg mice . Attenuated P29474 activity was observed in MTX - treated hph - 1 but not wild - type or P30793 - Tg mouse lung , suggesting that inhibition of P00374 in BH4 - deficient states leads to P29474 uncoupling . Taken together , these data reveal a key role for P00374 in regulating the BH4 vs BH2 ratio and P29474 coupling under conditions of low total biopterin availability in vivo .", "DB00360 prevents endothelial dysfunction and restores adiponectin levels in rats . Oxidative stress induces endothelial dysfunction and hypoadiponectinemia . We previously reported that supplementation with tetrahydrobiopterin ( BH4 ) , one of the most potent naturally occurring reducing agents and an essential cofactor of enzymatic NO synthase ( NOS ) , ameliorates endothelial dysfunction and reverses hypoadiponectinemia as a result of oxidative stress in rats . To further confirm this hypothesis , we investigated the effects of treatment with BH4 on endothelium - dependent relaxation and adiponectin levels during oxidative stress in fructose - fed rats , which provide an animal model for the metabolic syndrome . Ingestion of a fructose diet for 8 weeks significantly impaired endothelium - dependent arterial relaxation in aortic strips and decreased plasma adiponectin levels , as well as adiponectin mRNA levels within adipose tissue . However , oral supplementation with BH4 ( 10 mg / kg day ) over the final 4 weeks leads to a significant partial reversal of impaired endothelium - dependent arterial relaxation , as well as normalization of plasma adiponectin and fat adiponectin mRNA levels . Moreover , BH4 treatment of the fructose - fed rats significantly reduced the lipid peroxidation content of aorta , heart , liver , and kidney tissues , which were increased in fructose - fed rats . This effect of BH4 treatment may be due to its function as a cofactor for P29474 , as well as its anti - oxidative effects . Thus , BH4 might show promise for the treatment of oxidative stress - induced disorders , including the metabolic syndrome .", "Mechanism of purinergic activation of endothelial nitric oxide synthase in endothelial cells . BACKGROUND : Decreased endothelial nitric oxide ( NO ) synthase ( P29474 ) activity and NO production are critical contributors to the endothelial dysfunction and vascular complications observed in many diseases , including diabetes mellitus . Extracellular nucleotides activate P29474 and increase NO generation ; however , the mechanism of this observation is not fully clarified . METHODS AND RESULTS : To elucidate the signaling pathway ( s ) leading to nucleotide - mediated P29474 phosphorylation at DB00133 - 1177 , human umbilical vein endothelial cells were treated with several nucleotides , including DB00171 , UTP , and ADP , in the presence or absence of selective inhibitors . These experiments identified P47900 , P41231 , and possibly P51582 as the purinergic receptors involved in P29474 phosphorylation and demonstrated that this process was adenosine independent . Nucleotide - induced P29474 phosphorylation and activity were inhibited by BAPTA - AM ( an intracellular free calcium chelator ) , rottlerin ( a protein kinase Cdelta inhibitor ) , and protein kinase Cdelta siRNA . In contrast , blockade of AMP - activated protein kinase , calcium / calmodulin - dependent kinase II , calcium / calmodulin - dependent kinase kinase , serine / threonine protein kinase B , protein kinase A , extracellular signal - regulated kinase 1 / 2 , and p38 mitogen - activated protein kinase did not affect nucleotide - mediated P29474 phosphorylation . CONCLUSIONS : The present study indicates that extracellular nucleotide - mediated P29474 phosphorylation is calcium and protein kinase Cdelta dependent . This newly identified signaling pathway opens new therapeutic avenues for the treatment of endothelial dysfunction .", "Inactivation of nitric oxide synthase isoforms by diaminoguanidine and NG - amino - L - arginine . Diaminoguanidine ( DAG ) and NG - amino - L - arginine each produced a time - and concentration - dependent inactivation of the citrulline - forming activity of all three NOS isoforms . DAG inactivates both the NADPH - oxidase and the citrulline - forming activities of GH3 pituitary P29475 while NG - amino - L - arginine inactivates only its citrulline - forming activity . The inactivation by DAG of GH3 P29475 NADPH - oxidase and citrulline forming activities is stimulated by ( 6R ) - DB00360 ( BH4 ) cofactor , follows pseudo - first - order kinetics and is not substrate saturable . DAG - induced inactivation of the citrulline - forming activity for the P35228 and P29474 isoforms displayed maximal inactivation rates of 0 . 37 and 0 . 14 min - 1 and Ki values of 385 and 670 microM , respectively . At 1 mM DAG and saturating BH4 , half - times of inactivation of 0 . 7 , 8 , and 2 min were observed for the P29475 , P29474 , and P35228 isoforms , respectively . NG - Amino - L - arginine - induced inactivation of the citrulline - forming activity of the P29475 , P35228 , and P29474 isoforms displayed maximal inactivation rates of 0 . 35 , 0 . 26 , and 0 . 53 min - 1 and Ki values of 0 . 3 , 3 , and 2 . 5 microM , respectively . The inactivation of the NOS activities by both DAG and NG - amino - L - arginine in preincubations required the presence of oxygen and Ca2 + , consistent with an inactivation mechanism that requires active metabolism by NOS . Methylguanidine and 1 , 1 - dimethylguanidine exhibited a reversible inhibition pattern in contrast to all three NOS isoforms . Neither agent exhibited significant isoform selectivity .", "___MASK36___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK36___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .", "Molecular mechanisms of endothelial NO synthase uncoupling . DB00435 ( NO ) is a gaseous signaling molecule and effector in various biological processes . In mammalian cells , NO is produced by a family of NO synthases ( NOS ) . Three NOS isoforms have been identified as : neuronal NOS ( P29475 ) , inducible NOS ( P35228 ) , and endothelial NOS ( P29474 ) . In addition to NO , NOS also produces superoxide anion . This phenomenon is named NOS uncoupling as superoxide generation mainly occurs when NOS is not coupled with its cofactor or substrate . P29475 was first found to produce superoxide under L - arginine depletion condition . Further studies demonstrated that superoxide production is a general feature of all three NOS isoforms . In particular , superoxide generated from uncoupled P29474 has been found to play critical roles in the process of various cardiovascular diseases . Although NOS was first found to produce superoxide only when uncoupled with its cofactor or substrate , recent studies reveal that oxygen reduction to superoxide is an intrinsic process amid NO synthesis . DB00360 plays a controlling role in preventing superoxide release from the P29474 oxygenase domain . Besides tetrahydrobiopterin , the regulation of P29474 uncoupling by the interactions with other proteins , protein phosphorylation , S - glutathionylation , and endogenous L - arginine derivatives , will be discussed in this review .", "Effects of tetrahydrobiopterin oral treatment in hypoxia - induced pulmonary hypertension in rat . Endothelial nitric oxide synthase ( P29474 ) plays a major role in maintaining pulmonary vascular homeostasis . DB00360 ( BH4 ) , an essential cofactor that stabilizes the dimerization of P29474 and balances nitric oxide ( NO ) and superoxide production , may have therapeutic potential in pulmonary hypertension . In the isolated perfused lung , we demonstrated a direct effect of exogenous administration of BH4 on pulmonary NO production , leading to acute vasorelaxation during the plateau phase of hypoxia - induced pulmonary vasoconstriction . In the chronic hypoxia - induced pulmonary hypertension rat model , chronic BH4 oral administration attenuated the pressor response to hypoxia ( mean pulmonary artery pressure ± standard error of the mean , 31 . 8 ± 0 . 5 mmHg at 100 mg / kg / day ; placebo group , 36 . 3 ± 0 . 6 mmHg ; P < 0 . 05 ) . During telemetric monitoring , right ventricular systolic pressure was reduced by approximately 50 % after 1 week of BH4 treatment at 100 mg / kg / day . BH4 at 100 mg / kg / day reduced right ventricular hypertrophy ( from 0 . 55 ± 0 . 01 to 0 . 50 ± 0 . 01 ; P < 0 . 05 ) and pulmonary vascular muscularization ( from 79 . 2 % ± 2 % to 65 . 2 % ± 3 % ; P < 0 . 01 ) . BH4 treatment enhanced lung P29474 activity and reduced superoxide production , with a net increase in cyclic guanosine monophosphate levels . BH4 is effective in attenuating pulmonary hypertension in the hypoxic rat model when given as a rescue therapy .", "___MASK39___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .", "Quantitative regulation of intracellular endothelial nitric - oxide synthase ( P29474 ) coupling by both tetrahydrobiopterin - P29474 stoichiometry and biopterin redox status : insights from cells with tet - regulated P30793 expression . DB00360 ( BH4 ) is a critical determinant of endothelial nitric - oxide synthase ( P29474 ) activity . In the absence of BH4 , P29474 becomes \" uncoupled \" and generates superoxide rather than NO . However , the stoichiometry of intracellular BH4 / P29474 interactions is not well defined , and it is unclear whether intracellular BH4 deficiency alone is sufficient to induce P29474 uncoupling . To address these questions , we developed novel cell lines with tet - regulated expression of human P30793 ( GTPCH ) , the rate - limiting enzyme in BH4 synthesis , to selectively induce intracellular BH4 deficiency by incubation with doxycycline . These cells were stably co - transfected to express a human P29474 - green fluorescent protein fusion protein , selecting clones expressing either low ( P30793 / P29474 - LOW ) or high ( P30793 / P29474 - HIGH ) levels . DB00254 abolished GTPCH mRNA expression and GTPCH protein , leading to markedly diminished total biopterin levels and a decreased ratio of BH4 to oxidized biopterins in cells expressing P29474 . Intracellular BH4 deficiency induced superoxide generation from P29474 , as assessed by N - nitro - L - arginine methyl ester inhibitable 2 - hydroxyethidium generation , and attenuated NO production . Quantitative analysis of cellular BH4 versus superoxide production between P30793 / P29474 - LOW and P30793 / P29474 - HIGH cells revealed a striking linear relationship between P29474 protein and cellular BH4 stoichiometry , with P29474 uncoupling at P29474 : BH4 molar ratio > 1 . Furthermore , increasing the intracellular BH2 concentration in the presence of a constant P29474 : BH4 ratio was sufficient to induce P29474 - dependent superoxide production . This specific , reductionist approach in a cell - based system reveals that P29474 : BH4 reaction stoichiometry together with the intracellular BH4 : BH2 ratio , rather than absolute concentrations of BH4 , are the key determinants of P29474 uncoupling , even in the absence of exogenous oxidative stress .", "The inhibition of the constitutive bovine endothelial nitric oxide synthase by imidazole and indazole agents . DB00155 formation by the Ca2 + P62158 - dependent nitric oxide synthase of bovine endothelium is inhibited reversibly by 7 - nitroindazole , 1 - phenylimidazole , and imidazole . As measured at 0 . 67 microM ( 6R ) - DB00360 ( BH4 ) , IC50 values of 0 . 8 , 200 , and 50 microM were determined for 7 - nitroindazole , 1 - phenylimidazole , and imidazole , respectively . Increasing concentrations of added BH4 cofactor increased the IC50 values for 7 - nitroindazole and 1 - phenylimidazole but did not alter the IC50 value for imidazole . 7 - nitroindazole inhibited citrulline formation by the endothelial P29474 noncompetitively versus arginine substrate but competitively versus BH4 with a Ki value of 0 . 8 microM . 1 - Phenylimidazole inhibited citrulline formation by the endothelial P29474 competitively versus both arginine substrate and BH4 with a Ki value of 50 microM . Imidazole inhibited citrulline formation competitively versus arginine substrate but noncompetitively versus BH4 with a Ki value of 50 microM . Neither 7 - nitroindazole , 1 - phenylimidazole , nor imidazole inhibited the cytochrome c reductase activity of endothelial P29474 at concentrations up to 5000 - fold higher than their Ki values for inhibition of citrulline formation . By comparison with the previously determined kinetic properties of the other nitric oxide synthase isoforms , these observations establish that 1 - phenylimidazole displays marked specificity for inhibiting the inducible nitric oxide synthase isoform and , since 7 - nitroindazole has been reported not to elevate blood pressure ( McCall et al . , 1991 , Br . J . Pharmacol . 102 , 234 - 238 ) , fails to confirm the expected insensitivity of the constitutive endothelial nitric oxide synthase to inhibition by 7 - nitroindazole .", "DB00360 : a critical cofactor for P29474 and a strategy in the treatment of endothelial dysfunction ?", "DB00360 has a glucose - lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase - dependent manner in diabetic mice . Endothelial nitric oxide synthase ( P29474 ) dysfunction induces insulin resistance and glucose intolerance . DB00360 ( BH4 ) is an essential cofactor of P29474 that regulates P29474 activity . In the diabetic state , BH4 is oxidized to 7 , 8 - dihydrobiopterin , which leads to P29474 dysfunction owing to P29474 uncoupling . The current study investigates the effects of BH4 on glucose metabolism and insulin sensitivity in diabetic mice . Single administration of BH4 lowered fasting blood glucose levels in wild - type mice with streptozotocin ( Q11206 ) - induced diabetes and alleviated P29474 dysfunction by increasing P29474 dimerization in the liver of these mice . Liver has a critical role in glucose - lowering effects of BH4 through suppression of hepatic gluconeogenesis . BH4 activated AMP kinase ( AMPK ) , and the suppressing effect of BH4 on gluconeogenesis was AMPK - dependent . In addition , the glucose - lowering effect and activation of AMPK by BH4 did not appear in mice with Q11206 - induced diabetes lacking P29474 . Consecutive administration of BH4 in ob / ob mice ameliorated glucose intolerance and insulin resistance . Taken together , BH4 suppresses hepatic gluconeogenesis in an P29474 - dependent manner , and BH4 has a glucose - lowering effect as well as an insulin - sensitizing effect in diabetic mice . BH4 has potential in the treatment of type 2 diabetes .", "DB00360 and P29474 dimer / monomer ratio -- a clue to P29474 uncoupling in diabetes ?", "Functional comparison of the endothelial nitric oxide synthase Glu298Asp polymorphic variants in human endothelial cells . The G894T endothelial nitric oxide synthase ( P29474 ) polymorphism results in a DB00142 to DB00128 substitution at position 298 . This position is located externally on the protein and as the regulation of P29474 is dependent on its subcellular localization and interaction with modulatory proteins , we aimed to address whether the substitution of DB00128 at 298 had any effect on these mechanisms . Initially , we developed a novel method to accurately determine molar quantities of each variant by expressing them as green fluorescent protein ( GFP ) fusion proteins and using recombinant adenoviruses to facilitate transient infection of human microvascular endothelial cells . DB00815 - polyacrylamide gel electrophoresis and Western blotting of eNOSAsp revealed a 135 - kDa proteolytic fragment which was not present with eNOSGlu . This proteolysis was prevented by using LDS buffer confirming that this differential cleavage is an artefact of sample preparation and unlikely to occur intracellularly . DB00435 was measured following stimulation with calcium ionophore or oestrogen in the presence of varying sepiapterin concentrations . GFP fluorescence was used to quantify the amount of fusion protein and calculate intracellular specific activity . There was no significant difference in intracellular specific activity between DB00142 and DB00128 P29474 in response to calcium ionophore or oestrogen . DB00360 supplementation increased P29474 activity of both variants in an identical manner . The presence of the GFP also facilitated the visualization of the variants by confocal microscopy and demonstrated that both localized to the plasma membrane and the Golgi . These findings demonstrate that the DB00128 substitution at 298 does not have a major effect in modulating P29474 activity in vivo .", "The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK77___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK77___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK77___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK77___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .", "Janus - faced role of endothelial NO synthase in vascular disease : uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal . Endothelial NO synthase ( P29474 ) is the predominant enzyme responsible for vascular NO synthesis . A functional P29474 transfers electrons from NADPH to its heme center , where L - arginine is oxidized to L - citrulline and NO . Common conditions predisposing to atherosclerosis , such as hypertension , hypercholesterolemia , diabetes mellitus and smoking , are associated with enhanced production of reactive oxygen species ( ROS ) and reduced amounts of bioactive NO in the vessel wall . NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology . NADPH oxidase - derived superoxide avidly interacts with P29474 - derived NO to form peroxynitrite ( ONOO (-) ) , which oxidizes the essential NOS cofactor ( 6R -) DB00360 ( BH ( 4 ) ) . As a consequence , oxygen reduction uncouples from NO synthesis , thereby rendering NOS to a superoxide - producing pro - atherosclerotic enzyme . Supplementation with BH ( 4 ) corrects P29474 dysfunction in several animal models and in patients . Administration of high local doses of the antioxidant L - ascorbic acid ( vitamin C ) improves endothelial function , whereas large - scale clinical trials do not support a strong role for oral vitamin C and / or E in reducing cardiovascular disease . Statins , angiotensin - converting enzyme inhibitors and AT1 receptor blockers have the potential of reducing vascular oxidative stress . Finally , novel approaches are being tested to block pathways leading to oxidative stress ( e . g . protein kinase C ) or to upregulate antioxidant enzymes .", "Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity . Although the proinflammatory and profibrotic actions of aldosterone ( Aldo ) on the vasculature have been reported , the effects and molecular mechanisms of Aldo on endothelial function are yet to be determined . We investigated how Aldo regulates endothelial NO synthase ( P29474 ) function in human umbilical vein endothelial cells ( HUVECs ) . HUVECs were incubated for 16 hours with Aldo 10 (- 7 ) mol / L . The concentration of reactive oxygen species was estimated by measuring 2 ', 7 '- dichlorodihydrofluorescein diacetate chemiluminescence . Signal transduction was estimated by Western immunoblots . Real - time RT - PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase - 1 and components of reduced nicotinamide - adenine dinucleotide phosphate oxidase . To eliminate the possible effect of the glucocorticoid receptor ( GR ) and to emphasize the role of mineralocorticoid receptor , we used GR small interfering RNA and knocked down GR expression in several experiments . NO output was estimated by intracellular cGMP concentration . Reactive oxygen species production increased significantly in Aldo - treated HUVECs but was abolished by pretreatment with eplerenone . Transcripts of p47 ( phox ) were increased by Aldo treatment . Vascular endothelial growth factor - induced P29474 DB00133 1177 but not Akt DB00133 473 phosphorylation levels were reduced significantly by pretreatment with Aldo . Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of P29474 DB00133 1177 in Aldo - treated cells , suggesting that protein phosphatase 2A was upregulated by Aldo via mineralocorticoid receptor . The decrease in NO output caused by Aldo pretreatment was reversed significantly by DB00360 , GTP cyclohydrolase - 1 overexpression , or p47 ( phox ) knockdown . These results suggest that Aldo inhibits P29474 function through bimodal mechanisms of DB00360 deficiency and protein phosphatase 2A activation .", "DB04540 attenuates linoleic acid - induced endothelial cell activation . Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis . Even though very low or high levels of cholesterol can compromise cellular functions , cholesterol is a critical membrane component and may protect the vascular endothelium from oxidative stress and polyunsaturated fatty acid - mediated inflammatory responses . We have previously shown that the parent omega - 6 fatty acid linoleic acid can markedly activate vascular endothelial cells . We now propose that membrane cholesterol can modify and inhibit linoleic acid - mediated endothelial cell dysfunction . To test this hypothesis , pulmonary artery endothelial cells were incubated with cholesterol ( 0 to 100 micromol / L ) for 24 hours and then treated with 90 micromol / L of linoleic acid ( 18 : 2n - 6 ) for 6 to 24 hours . In control cells , treatment with linoleic acid reduced intracellular glutathione levels and induced the DNA binding activity of nuclear factor - kappaB ( NF - kappaB ) leading to the upregulation of interleukin - 6 ( P05231 ) . In addition , the expression of endothelial nitric oxide synthase ( P29474 ) was altered , with linoleic acid increasing P29474 activity . In contrast , enrichment with cholesterol enhanced glutathione levels and reduced the linoleic acid - induced activation of NF - kappaBand the production of P05231 . Prior exposure to 50 micromol / L cholesterol also prevented the fatty acid - induced increase in P29474 activation . DB04540 loading activated peroxisome proliferator - activated receptor - gamma ( P37231 ) , a nuclear receptor that can decrease inflammatory responses . Furthermore , the P37231 agonist thiazolidinedione markedly downregulated the NF - kappaB activation mediated by linoleic acid . Our data suggest that signaling pathways linked to endothelial cell activation by prooxidant and proinflammatory insults may be influenced by cellular cholesterol levels .", "[ Roles of P26718 in cytokine - induced killer ( CIK ) against hematological malignant cells lines ] . This study was purposed to investigate the CIK cell cytotoxicity to hematological malignant cell lines by interaction P26718 receptors and corresponding ligands . The CIK cells was expanded from healthy individual with interferon ( IFN ) γ , CD3 monoclonal antibodies ( mAb ) and interleukin - 2 ( P60568 ) . The subset of lymphocyte and the expression of NK cell receptors on CIK cells was detected by flow cytometry ; P26718 ligand expression on hematological malignant cell lines was also analyzed by flow cytometry , the calcein acetoxymethyl ester ( P62158 ) was used for labeling target cells , then the cytotoxicity of CIK cells to hematological malignant cell lines was detected by flow cytometry . The results showed that most of CIK cells expressed CD3 ( 97 . 85 ± 1 . 95 % ) , CD3 (+) CD8 (+) cells and CD3 (+) CD56 (+) cells increased significantly as compared with un - cultured cells ( P < 0 . 001 ; P = 0 . 033 ) . About 86 % CIK cells expressed P26718 receptor but no other NK receptors such as CD158a , CD158b and NCR . Different levels of P26718 ligands were detected in hematological malignant cell lines U266 , K562 and Daudi . CIK cells showed high cytotoxicity to these three different cell lines , and this cytotoxicity was partially blocked by treating CIK cells with anti - P26718 antibody ( U266 52 . 67 ± 4 . 63 % vs 32 . 67 ± 4 . 81 % , P = 0 . 008 ; K562 71 . 67 ± 4 . 91 % vs 50 . 33 ± 4 . 91 % , P = 0 . 007 ; Daudi 68 . 67 ± 5 . 04 vs 52 . 67 ± 2 . 60 % , P = 0 . 024 ) . It is concluded that most of CIK cells express P26718 receptor , interaction of P26718 - P26718 ligands may be one of the mechanisms , by which CIK cells kill hematological malignant cells .", "Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .", "Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK26___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .", "Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK85___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK85___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK85___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .", "DB00360 regulation of P29474 redox function . DB00360 ( BH4 ) is an essential cofactor of nitric oxide synthase ( NOS ) . In the cardiovascular system , endothelial NOS ( P29474 ) has a major role in maintaining vascular tone and endothelial function , as well as in mediating many other vascular protective properties . Evidence from humans and animals have demonstrated that decreased BH4 bioavailability , with subsequent uncoupling of P29474 , has significant effects on the pathogenesis of endothelial dysfunction , which is a hallmark of vascular injury in cardiovascular disorders , including hypertension , hyperlipidemia , and diabetes . In this review , we discuss the synthesis of BH4 , its molecular mechanisms regulating P29474 coupling , the pathophysiologic roles of decreased BH4 bioavailability in cardiovascular diseases , and the potential therapeutic application of BH4 in clinics .", "DB00360 is present in high quantity in human milk and has a vasorelaxing effect on newborn rat mesenteric arteries . Breast milk reduces the incidence of necrotizing enterocolitis ( NEC ) . BH4 is a cofactor for endothelial NOS ( P29474 ) . Reduced BH4 levels , or its oxidation to dihydrobiopterin ( BH2 ) , uncouple P29474 resulting in formation of reactive oxygen species ( ROS ) that have been implicated in the pathogenesis of NEC . We evaluated colostrum and mature breast milk , as well as infant formula , BH4 and BH2 content . In addition , we tested the BH4 effect on the newborn rat mesenteric arterial vascular tone . BH4 and BH2 content increased 3 - fold in mature breast milk , when compared with colostrum ( p < 0 . 01 ) , without a change in their ratio . Infant formula had a negligible BH4 content and lower biopterins ratio , when compared with breast milk . P29474 is the predominant synthase isoform in newborn rat mesenteric arteries . In the presence of BH4 , mesenteric arteries contracted less to thromboxane A₂ analog U46619 ( p < 0 . 01 ) and this effect was abolished following P29474 inhibition . BH4 ( 10 ⁻ ⁶ M ) vasorelaxed the newborn rat mesenteric arteries . We conclude that when compared with infant formula , breast milk has a high BH4 content that increases as breastfeeding continues . Given its mesenteric arterial vasorelaxing effect , BH4 may play an important role in the reduced NEC incidence among breast fed infants .", "[ Molecular mechanism of cardiovascular damage induced by aldosterone ] . Although the pro - inflammatory and pro - fibrotic actions of aldosterone on the vasculature have been reported , the effects and molecular mechanisms of aldosterone on endothelial function are yet to be determined . We investigated how aldosterone regulates endothelial nitric oxide synthase ( P29474 ) function in human umbilical vein endothelial cells ( HUVECs ) . HUVECs were incubated for 16 hrs with 10 (- 7 ) mol / l of aldosterone . The concentration of reactive oxygen species ( ROS ) was estimated by measuring DCF chemiluminescence . Signal transduction was estimated by Western immunoblots . Realtime RT - PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase - 1 ( P30793 ) and components of NAD ( P ) H oxidase . In order to eliminate the possible effect of the glucocorticoid receptor ( GR ) , and to emphasize the role of mineralocorticoid receptor ( MR ) , we used GR siRNA and knocked down GR expression in several experiments . NO output was estimated by intracellular cGMP concentration . ROS production increased significantly in aldosterone - treated HUVEC , but was abolished by pre - treatment with eplerenone . Transcripts of p47 ( phox ) were increased by aldosterone treatment . Vascular endothelial growth factor ( P15692 ) - induced P29474 DB00133 1177 but not Akt DB00133 473 phosphorylation levels were reduced significantly by pretreatment with aldosterone . Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of P29474 DB00133 1177 in aldosterone - treated cells , suggesting that protein phosphatase ( PP ) 2A was upregulated by aldosterone via MR . The decrease in NO output caused by aldosterone pretreatment was reversed significantly by either DB00360 ( BH ( 4 ) ) , P30793 overexpression , or p47 ( phox ) knockdown . These results suggest that aldosterone inhibits P29474 function through bimodal mechanisms of BH ( 4 ) deficiency and PP2A activation .", "Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .", "Does vitamin C enhance nitric oxide bioavailability in a tetrahydrobiopterin - dependent manner ? In vitro , in vivo and clinical studies . DB00126 ( Asc ) has been shown to increase nitric oxide ( NO ) bioavailability and thereby improve endothelial function in patients showing signs of endothelial dysfunction . DB00360 ( BH₄ ) is a co - factor of endothelial nitric oxide synthase ( P29474 ) which may easily become oxidized to the inactive form dihydrobiopterin ( BH₂ ) . Asc may increase NO bioavailability by a number of mechanisms involving BH₄ and P29474 . Asc increases BH₄ bioavailability by either reducing oxidized BH₄ or preventing BH₄ from becoming oxidized in the first place . Asc could also increase NO bioavailability in a BH₄ - independent manner by increasing P29474 activity by changing its phosphorylation and S - nitrosylation status or by upregulating P29474 expression . In this review , we discuss the putative mechanisms by which Asc may increase NO bioavailability through its interactions with BH₄ and P29474 .", "The role of tetrahydrobiopterin in superoxide generation from P29474 : enzymology and physiological implications . DB00360 ( BH4 ) is a ubiquitous pteridine metabolite that serves as a NOS cofactor . Recently , we showed that BH4 efficiently inhibits superoxide generation from the heme group at the oxygenase domain of P29474 . This role indicates that BH4 acts as a redox switch in the catalytic mechanism of the enzyme , which may have important consequences in the physiology of the endothelium . Here the mechanism by which BH4 inhibits superoxide release from P29474 and the \" uncoupling \" effects of oxidized BH4 metabolites are presented . The implications of the disparate actions of fully reduced and oxidized BH4 metabolites in the control of P29474 biochemistry are discussed in the light of clinical data indicating that BH4 levels are important in the regulation of superoxide levels and of endothelial reactivity .", "Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44 . 1 ± 72 . 1 days ) were genetically analyzed for P51787 , Q12809 , P15382 - 5 , P63252 , Q14524 , P36382 , and P62158 by using denaturing high - performance liquid chromatography and direct sequencing . Whole - cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 and Q12809 cDNA . In 5 of 7 patients , we identified 4 mutations ( p . N1774D , p . T290fsX53 , p . F1486del and p . N406K ) in Q14524 , and 1 mutation ( p . G628D ) in Q12809 . N1774D , F1486del , and N406K in Q14524 displayed tetrodotoxin - sensitive persistent late Na (+) currents . By contrast , Q14524 - T290fsX53 was nonfunctional . Q12809 - G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 mutations , as well as loss of function associated with the Q12809 mutation .", "DB00360 supplementation reduces atherosclerosis and vascular inflammation in apolipoprotein E - knockout mice . BH4 ( tetrahydrobiopterin ) supplementation improves endothelial function in models of vascular disease by maintaining P29474 ( endothelial nitric oxide synthase ) coupling and NO ( nitric oxide ) bioavailability . However , the cellular mechanisms through which enhanced endothelial function leads to reduced atherosclerosis remain unclear . We have used a pharmaceutical BH4 formulation to investigate the effects of BH4 supplementation on atherosclerosis progression in ApoE - KO ( apolipoprotein E - knockout ) mice . Single oral dose pharmacokinetic studies revealed rapid BH4 uptake into plasma and organs . Plasma BH4 levels returned to baseline by 8 h after oral dosing , but remained markedly increased in aorta at 24 h . Daily oral BH4 supplementation in ApoE - KO mice from 8 weeks of age , for a period of 8 or 12 weeks , had no effect on plasma lipids or haemodynamic parameters , but significantly reduced aortic root atherosclerosis compared with placebo - treated animals . BH4 supplementation significantly reduced P19320 ( vascular cell adhesion molecule 1 ) mRNA levels in aortic endothelial cells , markedly reduced the infiltration of T - cells , macrophages and monocytes into plaques , and reduced T - cell infiltration in the adjacent adventitia , but importantly had no effect on circulating leucocytes . P30793 ( P30793 ) - transgenic mice , with a specific increase in endothelial BH4 levels , exhibited a similar reduction in vascular immune cell infiltration compared with BH4 - deficient controls , suggesting that BH4 reduces vascular inflammation via endothelial cell signalling . In conclusion , BH4 supplementation reduces vascular immune cell infiltration in atherosclerosis and may therefore be a rational therapeutic approach to reduce the progression of atherosclerosis ." ]

[ "___MASK26___", "___MASK36___", "___MASK39___", "___MASK60___", "___MASK71___", "___MASK77___", "___MASK84___", "___MASK85___", "___MASK89___" ]

[ "Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK37___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .", "Adenoviral expression of a urokinase receptor - targeted protease inhibitor inhibits neointima formation in murine and human blood vessels . BACKGROUND : Smooth muscle cell migration , in addition to proliferation , contributes to a large extent to the neointima formed in humans after balloon angioplasty or bypass surgery . P00747 activator / plasmin - mediated proteolysis is an important mediator of this smooth muscle cell migration . Here , we report the construction of a novel hybrid protein designed to inhibit the activity of cell surface - bound plasmin , which can not be inhibited by its natural inhibitors , such as alpha ( 2 )- antiplasmin . This hybrid protein , consisting of the receptor - binding amino - terminal fragment of uPA ( P39905 ) , linked to the potent protease inhibitor bovine pancreas trypsin inhibitor ( DB06692 ) , can inhibit plasmin activity at the cell surface . METHODS AND RESULTS : The effect of adenovirus - mediated P39905 . DB06692 expression on neointima formation was tested in human saphenous vein organ cultures . Infection of human saphenous vein segments with Ad . CMV . P39905 . DB06692 ( 5x10 ( 9 ) pfu / mL ) resulted in 87 . 5 +/- 3 . 8 % ( mean +/- SEM , n = 10 ) inhibition of neointima formation after 5 weeks , whereas Ad . CMV . P39905 or Ad . CMV . DB06692 virus had only minimal or no effect on neointima formation . The efficacy of P39905 . DB06692 in vivo was demonstrated in a murine model for neointima formation . Neointima formation in the femoral artery of mice , induced by placement of a polyethylene cuff , was strongly inhibited ( 93 . 9 +/- 2 % ) after infection with Ad . CMV . mATF . DB06692 , a variant of P39905 . DB06692 able to bind specifically to murine uPA receptor ; Ad . CMV . mATF and Ad . CMV . DB06692 had no significant effect . CONCLUSIONS : These data provide evidence that adenoviral transfer of a hybrid protein that binds selectively to the uPA receptor and inhibits plasmin activity directly on the cell surface is a powerful approach to inhibiting neointima formation and restenosis .", "Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .", "O15105 - deficient mice show growth retardation with reduced viability . O15105 is an inhibitory molecule induced by members of the transforming growth factor - β ( TGF - β ) family , including TGF - β , activin , nodal and bone morphogenetic proteins ( BMPs ) . To elucidate the in vivo functions of O15105 , we generated conditional O15105 - knockout mice in which the Mad homology 2 ( MH2 ) domain and the poly ( A ) signal sequence were flanked with loxP sites ( floxed ) . The O15105 - floxed mice exhibited no obvious phenotype . O15105 total - null mice on a C57BL / 6 background died within a few days of birth , whereas mice with an ICR background developed to adulthood but were significantly smaller than wild - type mice . Unexpectedly , phospho - Q15796 and phospho - P84022 were decreased in O15105 - deficient mouse embryonic fibroblast ( MEF ) cells , whereas phospho - Q15797 / 5 / 8 was similarly expressed in wild - type and O15105 - deficient MEF cells . Moreover , expression levels of TGF - β type I receptor ( P36897 ) were higher in O15105 - deficient MEF cells than in wild - type MEF cells . P00747 activator inhibitor - 1 ( P05121 ) and inhibitor of differentiation - 1 ( Id - 1 ) mRNA were similarly expressed in wild - type and O15105 - deficient MEF cells . Some differences were observed in mitogen - activated protein kinase ( MAPK ) - signalling between wild - type and O15105 - deficient MEF cells . We demonstrated that O15105 plays an important role in normal mouse growth and provide a useful tool for analysing O15105 functions in vivo .", "Regulation of P14061 and P18405 in lymphocytes . We previously reported lymphocyte expression of genes encoding enzymes required for steroid metabolism ; however , only 17beta - HSD and 5alpha - reductase showed significant enzyme activity . We now investigate regulation of lymphocyte expression for genes encoding 17beta - HSD and 5alpha - reductase . Cultured human T and B lymphoid cell lines and peripheral blood mononuclear cells were treated with known regulators of steroidogenic gene expression including forskolin , PMA , ionomycin , various steroids , interleukin ( IL ) - 4 , and P05231 . Treatment with 10 or 50 microM forskolin resulted in a 20 - 60 % reduction of expression for P14061 ( encoding 17beta - HSD I ) in T and B lymphoid cell lines and peripheral blood mononuclear cells , although such a change was not observed in the expression of P18405 ( encoding 5alpha - reductase I ) . No significant changes were found when cells were treated for 24 h with various concentrations of PMA or ionomycin . Incubation with 10 (- 9 ) to 10 (- 7 ) M androstenedione or estradiol increased expression of P14061 , while testosterone decreased the expression of this gene . P18405 expression was increased in the presence of 5alpha - ___MASK67___ although no consistent changes were observed when the cells were treated with testosterone . Other steroids , including dexamethasone , progesterone , and 6 - hydroxypregnanolone , produced no effects on expression of either P14061 or P18405 . Treatment with 0 . 1 - 10 ng / ml of P05112 or P05231 also did not effect significant changes in gene expression . These data implicate the involvement of the DB02527 - protein kinase signal transduction pathway in regulating lymphocyte expression of P14061 . Furthermore , it appears that lymphocyte P14061 and P18405 are regulated to some extent by specific steroids .", "Differential expression of urokinase - type plasminogen activator and plasminogen activator inhibitor - 1 in early and late gestational mouse skin and skin wounds . Early gestation fetal mouse skin heals without scars . P00747 activator inhibitor - 1 ( P05121 ) has been associated with postnatal organ fibrosis . We hypothesized that the relative balance between urokinase - type plasminogen activator ( uPA ) and P05121 expression in favor of uPA prevents scarring in early fetal skin wounds , whereas a change in favor of P05121 in late gestation results in wound scarring . To evaluate uPA and P05121 expression , 1 - mm skin wounds were made in Q14207 . 5 and E18 mice and harvested 24 , 48 , or 96 hours postwounding . DB06692 ( 2 mg / ml ) - coated beads were injected into selected Q14207 . 5 wounds . Normal skin and skin wounds were evaluated for uPA , P05121 , and collagen expression . We showed that in normal skin uPA level is higher in Q14207 . 5 than in E18 mice , while P05121 is lower in Q14207 . 5 than in E18 mice . After wounding , Q14207 . 5 wounds show a moderate increase in uPA and a minimal increase in P05121 . E18 wounds show a transient increase in uPA but a significant , sustained increase in P05121 . Addition of aprotinin to Q14207 . 5 wounds causes an increase in collagen deposition . We conclude that the differential expression of uPA and P05121 in the skin of early vs . late gestation mice may contribute to the degree of scar formation seen after cutaneous injury .", "Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation . Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome . We tested whether these components of metabolic syndrome , like dyslipidemia and glycemia , are responsive to carbohydrate restriction . Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate ( VLCKD ) ( 1504 kcal : % CHO : fat : protein = 12 : 59 : 28 ) or low in fat ( LFD ) ( 1478 kcal : % CHO : fat : protein = 56 : 24 : 20 ) for 12 weeks . In comparison to the LFD , the VLCKD resulted in an increased proportion of serum total n - 6 PUFA , mainly attributed to a marked increase in arachidonate ( 20 : 4n - 6 ) , while its biosynthetic metabolic intermediates were decreased . The n - 6 / n - 3 and arachidonic / eicosapentaenoic acid ratio also increased sharply . Total saturated fatty acids and 16 : 1n - 7 were consistently decreased following the VLCKD . Both diets significantly decreased the concentration of several serum inflammatory markers , but there was an overall greater anti - inflammatory effect associated with the VLCKD , as evidenced by greater decreases in P01375 , P05231 , P10145 , P13500 , P16581 , I - P62158 , and P05121 . Increased 20 : 4n - 6 and the ratios of 20 : 4n - 6 / 20 : 5n - 3 and n - 6 / n - 3 are commonly viewed as pro - inflammatory , but unexpectedly were consistently inversely associated with responses in inflammatory proteins . In summary , a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet .", "P39905 enhances survival of GM - P04141 dependent rat GMIR1 - microglial cells . Microglial activation and proliferation occur in nearly all forms of brain injury . The aim of this study was to investigate the influence of glial cell - line derived neurotrophic factor ( P39905 ) on proliferation and / or survival in a GMIR1 rat microglial cell line , which proliferates in response to granulocyte - macrophage - colony stimulating factor ( GM - P04141 ) . Endogenous P39905 and its receptor , GFRalpha - 1 , were detected in GMIR1 cells by ELISA and immunohistochemistry / Western blot , respectively . Recombinant P39905 strongly enhanced GMIR1 cell numbers and BrdU - incorporation , an effect inhibited by P39905 blocking antibodies . Inhibition of DB02527 / cGMP dependent protein kinase enhanced the P39905 - induced GMIR1 cell number . The results suggest that P39905 has synergistic survival promoting effects on microglia potentially via autocrine mechanisms .", "___MASK67___ interacts with P00533 / MAPK signalling and modulates P00533 levels in androgen receptor - positive LNCaP prostate cancer cells . P10275 ( AR ) signalling plays a pivotal role in prostate cancer pathogenesis and progression . However , androgen - mediated AR signalling is yet to be fully understood . P00533 and Q96HU1 kinase signalling pathways play predominant roles in AR function . Therefore , we investigated the interaction of P00533 signalling and AR activity in AR - positive LNCaP cells . We found that 5alpha - dihydrotestosterone ( ___MASK67___ ) and P01133 had a synergistic effect on AR activity as detected by a luciferase reporter system , although P01133 alone did not activate AR . Both P27361 / 2 and p38 were involved in ___MASK67___ and ___MASK67___ / P01133 - induced AR activation as detected by specific MEK and p38 inhibitors . Furthermore , 24 - h treatment of the cells with ___MASK67___ resulted in ubiquitination and down - regulation of the P00533 . This effect could be inhibited by the anti - androgen flutamide , suggesting an androgen - dependent mechanism . On the other hand , ___MASK67___ - treatment strongly increased AR levels in LNCaP cells . These data suggest a complex regulatory loop between activated AR and P00533 . In conclusion , activation of AR by both ___MASK67___ and P01133 / ___MASK67___ involves the Q96HU1 kinase pathway . Long - term activation of AR results in increase of AR levels , which through so far unknown regulatory mechanisms results in ubiquitination and degradation of the P00533 .", "Alterations in brain neurotrophic and glial factors following early age chronic methylphenidate and cocaine administration . Attention deficit hyperactivity disorder ( ADHD ) overdiagnosis and a pharmacological attempt to increase cognitive performance , are the major causes for the frequent ( ab ) use of psychostimulants in non - ADHD individuals . Methylphenidate is a non - addictive psychostimulant , although its mode of action resembles that of cocaine , a well - known addictive and abused drug . Neuronal - and glial - derived growth factors play a major role in the development , maintenance and survival of neurons in the central nervous system . We hypothesized that methylphenidate and cocaine treatment affect the expression of such growth factors . Beginning on postnatal day ( P01160 ) 14 , male Sprague Dawley rats were treated chronically with either cocaine or methylphenidate . The rats were examined behaviorally and biochemically at several time points ( P01160 35 , 56 , 70 and 90 ) . On P01160 56 , rats treated with cocaine or methylphenidate from P01160 14 through P01160 35 exhibited increased hippocampal glial - cell derived neurotrophic factor ( P39905 ) mRNA levels , after 21 withdrawal days , compared to the saline - treated rats . We found a significant association between cocaine and methylphenidate treatments and age progression in the prefrontal protein expression of brain derived neurotrophic factor ( P23560 ) . Neither treatments affected the behavioral parameters , although acute cocaine administration was associated with increased locomotor activity . It is possible that the increased hippocampal P39905 mRNA levels , may be relevant to the reduced rate of drug seeking behavior in ADHD adolescence that were maintained from childhood on methylphenidate . P23560 protein level increase with age , as well as following stimulant treatments at early age may be relevant to the neurobiology and pharmacotherapy of ADHD .", "Conditional loss of heparin - binding P01133 - like growth factor results in enhanced liver fibrosis after bile duct ligation in mice . Our aims were to evaluate the involvement of heparin - binding P01133 - like growth factor ( HB - P01133 ) in liver fibrogenesis of humans and mice and to elucidate the effect of HB - P01133 deficiency on cholestatic liver fibrosis using conditional HB - P01133 knockout ( KO ) mice . We first demonstrated that gene expression of HB - P01133 had a positive significant correlation with that of collagen in human fibrotic livers , and was increased in bile duct ligation ( BDL ) - induced fibrotic livers in mouse . We then generated conditional HB - P01133 knockout ( KO ) mice using the interferon inducible Mx - 1 promoter driven Cre recombinase transgene and wild type ( WT ) and KO mice were subjected to BDL . After BDL , KO mice exhibited enhanced liver fibrosis with increased expression of collagen , compared with WT mice . Finally , we used mouse hepatic stellate cells ( HSCs ) to examine the role of HB - P01133 in the activation of these cells and showed that HB - P01133 antagonized TGF - β - induced gene expression of collagen in mouse primary HSCs . Interestingly , HB - P01133 did not prevent the TGF - β - induced nuclear accumulation of P84022 , but did lead to stabilization of the Smad transcriptional co - repressor TG - interacting factor . In conclusion , our data suggest a possible protective role of HB - P01133 in cholestatic liver fibrosis .", "Cloning of a calmodulin kinase I homologue from Schizosaccharomyces pombe . By using ( 35 ) S - labeled calmodulin ( P62158 ) , we have isolated a full - length cDNA clone expressing the Schizosaccharomyces pombe homologue of calmodulin kinase I ( CaMK - I ) , a gene we have named cmk1 . It has been previously been shown in mammals that CaMK - I is a member of a P62158 - dependent protein kinase cascade that ultimately regulates transcription factors such as P39905 and DB02527 - response element - binding protein . The cmk1 cDNA encodes a 335 - amino acid protein with significant homology to mammalian CaMK - I , including a conserved sequence for phosphorylation by P62158 kinase kinase . We have expressed the cmk1 cDNA in bacteria and yeast , and we have shown that it is a P62158 - dependent protein kinase . A truncation mutant of cmk1 ( d320 ) failed to bind P62158 , indicating that the P62158 - binding domain is at the extreme C terminus of the protein . The mRNA for cmk1 is expressed in a cell cycle - dependent manner , peaking at or near the G ( 1 )/ S boundary . Overexpression of wild - type cmk1 in S . pombe caused no apparent effects on growth and division . However , mutation of a predicted regulatory site ( DB00156 - 192 ) to aspartic acid resulted in hyperactivation of CMK1 activity in the presence of P62158 and causes cell cycle arrest in vivo . Arrest is also accompanied by morphological defects . These results suggest the presence of a P62158 - dependent protein kinase cascade in yeast and indicate that cmk1 may be important in cell cycle progression , a process known to be dependent on P62158 in eukaryotic cells .", "Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK19___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .", "Serotonin induces the expression of tissue factor and plasminogen activator inhibitor - 1 in cultured rat aortic endothelial cells . Serotonin ( 5 - hydroxytryptamine , or 5 - HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5 - HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5 - HT ( 0 . 1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 ) , plasminogen activator inhibitor - 1 ( P05121 ) , and tissue - type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 were also measured . TF and P05121 mRNA were increased significantly in a concentration - and time - dependent manner . However , P10646 and TPA mRNA expression did not change . The inductions of TF and P05121 mRNAs were inhibited by a 5 - HT1 / 5 - HT2 receptor antagonist ( methiothepin ) and a selective 5 - Q13049 receptor antagonist ( D6RGH6 - 9042 ) . These results indicate that 5 - HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5 - Q13049 receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5 - HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation .", "Chemical coding of the human gastrointestinal nervous system : cholinergic , VIPergic , and catecholaminergic phenotypes . The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal ( GI ) tract . For this purpose , antibodies against the vesicular monoamine transporters ( P54219 / 2 ) , the vesicular acetylcholine transporter ( Q16572 ) , tyrosine hydroxylase ( TH ) , dopamine beta - hydroxylase ( P09172 ) , serotonin ( 5 - HT ) , vasoactive intestinal peptide ( P01282 ) , and protein gene product 9 . 5 ( P09936 ) were used . For in situ hybridization ( 35 ) S - labeled P54219 , Q05940 , and Q16572 riboprobes were used . In all regions of the human GI tract , 50 - 70 % of the neurons were cholinergic , as judged by staining for Q16572 . The human gut unlike the rodent gut exhibits a cholinergic innervation , which is characterized by an extensive overlap with VIPergic innervation . Neurons containing Q05940 constituted 14 - 20 % of all intrinsic neurons in the upper GI tract , and there was an equal number of TH - positive neurons . In contrast , P09172 was absent from intrinsic neurons . Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes . In conclusion , the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species , but also significant differences . P01282 is a cholinergic cotransmitter in the intrinsic innervation of the human gut . The substantial overlap between Q05940 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life . The absence of P09172 from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype .", "Changes in coagulation and fibrinolysis of post - P49591 osteonecrosis in a Chinese population . The purpose of this study was to detect changes in coagulation and fibrinolysis of post - severe acute respiratory syndrome ( P49591 ) Chinese patients with osteonecrosis , investigate the aetiology of post - P49591 osteonecrosis ( ON ) , and select the sensitive molecular markers for identifying the susceptible population . For this study , blood samples were collected from 88 patients with post - P49591 ON and 52 healthy people . Activated partial thromboplastin time ( APTT ) , protein C ( PC ) , antithrombin III ( DB11598 ) , plasminogen activator inhibitor ( P05121 ) , activated protein C resistance ( P25054 - R ) , plasminogen ( P00747 ) , von Willebrand ' s factor ( P04275 ) , D - dimer ( D - D ) , fibrinogen ( Fib ) , and homocysteine ( HCY ) were examined by enzyme - linked immunosorbent assay ( ELISA ) . We noted that blood agents of patients with ON changed obviously . APTT , PC , DB11598 , P05121 , P25054 - R , and P00747 were significantly different between the two groups . Hypercoagulation and hypofibrinolysis were found in patients with post - P49591 ON . Therefore , these examinations can be used to screen a population susceptible to ON . Measurements of APTT , PC , DB11598 , P05121 , P25054 - R , and P00747 are sensitive blood tests for screening purposes .", "Smad - dependent cooperative regulation of interleukin 2 receptor alpha chain gene expression by T cell receptor and transforming growth factor - beta . The interleukin 2 receptor alpha chain ( IL - 2Ralpha ) is a component of high affinity P60568 receptors and thus critically regulates T cell growth and other lymphoid functions . Five positive regulatory regions together control lineage - restricted and activation - dependent IL - 2Ralpha induction in response to antigen and P60568 . We now show that TGF - beta cooperates with T cell receptor ( TCR ) signaling to increase IL - 2Ralpha gene expression . Moreover , we identify a sixth positive regulatory region that regulates IL - 2Ralpha expression in cells treated with anti - CD3 + anti - P10747 as well as TGF - beta and show that this region contains binding sites for P84022 , AP - 1 , and DB02527 - responsive element - binding protein / P39905 proteins . The importance of Smad complexes is indicated by impaired IL - 2Ralpha induction by TGF - beta in P01730 + T cells from both P84022 -/- and Q13485 -/- mice . Thus , we have identified a novel positive regulatory region in the IL - 2Ralpha gene that mediates TGF - beta - dependent induction of the gene . These findings have implications related to IL - 2Ralpha expression on activated T cells and regulatory T cells .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK25___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "P00747 activator dependent pathways in the dissemination of human tumor cells in the chick embryo . We have previously shown that inhibition of uPA activity of a human tumor - HEp3 - results in a drastic reduction of its metastasis in the chick embryo . Using 125IUdR - labeled tumor cells , we have now studied the role of uPA in individual steps of tumor metastasis . We found that , 48 hr after inoculation of tumor cells on the P62158 , the organs of the embryos , inoculated with cells in which uPA was inhibited , contained 4 - fold less cells than the controls . Neither the initial advance of the tumor mass into the P62158 nor the process of extravasation was affected by the inhibition of tumor uPA . However , the infiltration of the P62158 mesenchyme by individual tumor cells was blocked when tumor uPA activity or production was inhibited . In addition , indirect evidence implicated uPA as an essential factor in the tumor cell intravasation .", "Effect of oncostatin M on uridine diphosphate - 5 '- glucuronosyltransferase 1A1 through cross talk with constitutive androstane receptor . Hyperbilirubinemia remains a common condition in neonates . The constitutive androstane receptor ( CAR ) is an orphan nuclear receptor that has been shown to participate in the activation of the uridine diphosphate - 5 '- glucuronosyltransferase 1A1 ( P22309 ) gene , which plays an important role in bilirubin clearance . Oncostatin M ( P13725 ) , a member of the P05231 family , is involved in the maturation of fetal hepatocytes . We have demonstrated that low P13725 levels are a potential indicator of neonatal jaundice and the need for phototherapy . In this study we examined the effects of P13725 on CAR - mediated signaling to investigate its potential role in neonatal jaundice via the CAR - P22309 pathway . We observed that P13725 positively augmented the CAR and P22309 expressions and CAR - mediated signaling in vivo and in vitro , through cross talk between the nuclear CAR receptor and the plasma membrane P13725 receptor , via the MAPK cascade . These data suggest that P13725 might play a role in bilirubin metabolism via the CAR - P22309 pathway .", "Anti - thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a P81605 model . Ischemia reperfusion injury ( IRI ) is pivotal for renal fibrosis development via peritubular capillaries injury . Coagulation represents a key mechanism involved in this process . Melagatran ( M ) , a thrombin inhibitor , was evaluated in an autotransplanted kidney model , using Large White pigs . To mimic deceased after cardiac death donor conditions , kidneys underwent warm ischemia ( WI ) for 60 min before cold preservation for 24 h in University of Wisconsin solution . Treatment with M before WI and / or in the preservation solution drastically improved survival at 3 months , reduced renal dysfunction related to a critical reduction in interstitial fibrosis , measured by Sirius Red staining . Tissue analysis revealed reduced expression of transforming growth factor - beta ( TGF - beta ) and activation level of its effectors phospho - P84022 , Q13485 and connective tissue growth factor ( P29279 ) after M treatment . Fibrinolysis activation was also observed , evidenced by downregulation of P05121 protein and gene expression . In addition , M reduced P26447 expression and vimentin staining , which are markers for epithelial mesenchymal transition , a major pathway to chronic kidney fibrosis . Finally , expression of oxidative stress markers Nox2 and P35228 was reduced . We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis , with a significantly positive effect on survival .", "P00747 activator is involved in the hCG - induced neutrophil extravasation and vasopermeability increase in the rat testis . The role of proteolytic enzymes in the hCG - induced increase in testicular vasopermeability and neutrophil extravasation was studied using protease inhibitors . An intra - testicular injection of hCG together with incubation medium conditioned by polymorphonuclear leucocytes ( PMNs ) caused a significant increase in vasopermeability and a coincident extravasation of PMN ' s from the postcapillary venules in the rat testis . When p - aminobenzamidine , a serine protease inhibitor which inhibits urokinase - type plasminogen activator , was administered together with hCG in the incubation medium , both the permeability increase and PMN extravasation were prevented . DB06692 , another serine protease inhibitor , and Eglin C , a specific neutrophil elastase and cathepsin G inhibitor were , however , without effect . None of these inhibitors caused any non - specific vascular effects in the testis at the concentrations used . These results support the concept that the hCG - induced increase in vasopermeability in the rat testis is related to extravasation of PMNs and suggest that urokinase - type plasminogen activator is involved in migration of these cells through the postcapillary venular walls .", "[ Conditions of the primary culture for rat hepatocytes and plasminogen activator release ] . The conditions of primary culture for rat hepatocytes was investigated on the releasing effect of P00747 Activator ( PA ) . The culture method using Collagen Coated Dish ( CCD - method ) which is currently available and the ordinary culture method using Plastic Culture Dish ( P61457 - method ) were employed for that purpose in a comparative way . The effect of the addition of some supplements , that is FN , DB06692 , P01133 were also investigated . The following results were obtained . The dissociated rat hepatocytes formed a monolayer with pavementlike morphology at 24 - 48 hours after seeding . No difference was observed in the morphology of hepatocytes during the culture period between the two methods , although CCD - method allowed 120 hours culture , whereas P61457 - method allowed 72 hours . The PA activity was demonstrated on the hepatocytes by either culture method according to the fibrinolysis autography . The cultured hepatocytes released PA into the medium continuously as long as the viability and morphology of the cells were maintained in good state . The PA activity reached the maximum after 96 hours culture in CCD - method , whereas it reached the maximum after 48 hours in P61457 - method . The addition of DB06692 to the culture medium was not necessary for PA release in CCD - method in contrast to P61457 - method . When P01133 was discontinued in the culture medium , the release of PA was reduced in association with the occurring of morphological disintegration of hepatocytes .", "[ Plasma exchange with very low molecular weight heparin CY 222 . Biological profile and therapeutic value ] . In a clinical , between - patient study we investigated the effects of a VLMW ___MASK76___ fragment ( CY 222 ) versus standard heparin ( SH ) in plasma exchanges ( n = 10 ) on coagulation factors ( CF ) . DB09222 ( FGN ) , II , V , VIIF + X , IX , XI , XII , VIIIc , VIIIRag , VIIIvwf and P01008 , ProtC , ProtS , P00747 ( Q9UQ90 ) , Activated P13726 time ( APTT ) , P00734 time ( PT ) , Thrombin time ( TT ) , anti factor Xa ( Axa ) , DDimer , Platelet count . ___MASK76___ was administered as a bolus and by infusion during the session , CY 222 as a bolus dose only ; 1 to 1 . 5 plasma volume was exchanged with substitution by 5 % albumin . Results ( mean , s . d . ) at the end of the session ( End ) and 4 hours later ( DB00451 ) were analyzed and showed no differences between groups ( with CY 222 and with SH ) for technical and clinical findings . Biologically , CF were similar in both groups except for Factor XII levels at the end of the session , and Factors II , V , XII at DB00451 . Prolonged APTT in all samples appear related to low FGN . Significant differences in Axa activities were found for each treatment when compared with its own standard , suggesting different ranges of activities of both drugs . Changes in D - dimer levels differed during the session and four hours after the session with the drug tested , and could be related to their mode of administration . Clinical efficiency and tolerance were excellent both with CY 222 and SH .", "Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .", "Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK40___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .", "[ A novel function of anti - fibrinolytic factor , P05121 , in the central nervous system : a possible role as the neurotrophic factor ] . P00747 activator inhibitor - 1 ( P05121 ) is a serpin that suppresses fibrinolysis by inhibiting the activity of plasminogen activator ( PA ) . Together with PA , P05121 is expressed in the central nervous system and may play a role in the regulation of PA activity . Our present study has demonstrated that , in cultures of PC - 12 neurons , depletion of P05121 from the culture medium induces disappearance of the cell ' s neurites and the cell death . DB06692 and antipain , the inhibitors of PA , were not counterparts of P05121 in the protection of neurite disappearance . We also found that P05121 had the abilities to promote release of the survival factors of neurons , P05231 and P15692 and activation of a survival serine / threonine kinase Akt . These results suggest that P05121 has physiological functions other than its role as PA inhibitor for the survival of neurons .", "Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .", "P00747 activator inhibitor - 1 is a downstream mediator of the P09936 - related oncogenic pathway in esophageal squamous cell carcinoma . BACKGROUND & MATERIALS AND METHODS : Recently , it has been proved that P09936 is an oncogene candidate for squamous cell carcinomas . To examine the P09936 - related oncogenic pathway , we tested for global patterns of gene expression in cancer cells following P09936 gene introduction using an oligonucleotide microarray approach . RESULTS : P00747 activator inhibitor - 1 ( P05121 ) was identified as an overexpressed gene in a P09936 - expressed esophageal squamous cancer cell line . To confirm the data obtained , we performed Northern analysis using a P09936 or a P05121 cDNA probe and found that P05121 mRNA was induced by P09936 expression in NUEC1 cells . We further examined endogenous P09936 and P05121 expression in 6 esophageal cancer cell lines . One cell line ( NUEC2 ) with P09936 expression exhibited P05121 expression , suggesting the possibility that P09936 might induce P05121 directly or indirectly . CONCLUSION : These results suggested that P05121 might be a novel downstream mediator of P09936 in esophageal squamous cell carcinomas .", "Novel function of androgen receptor - associated protein 55 / O43294 as a negative regulator of P84022 signaling . P10275 - associated protein 55 ( O43294 / O43294 ) belongs to the LIM protein superfamily and is featured by three or four N - terminal LD motifs and four C - terminal zinc finger - like LIM domains . Both LD motifs and LIM domains can serve as protein - protein interaction interfaces . Recently , we found that enforced expression of O43294 inhibits transforming growth factor - beta - mediated up - regulation of Smad binding element - luciferase reporter activity in NRP - 154 and NRP - 152 rat prostate and LNCaP human prostate cell lines . Moreover , O43294 also inhibits the induction of Smad - binding element 4 - luciferase and 3TP - luciferase ( a plasminogen activator inhibitor - 1 ( P05121 ) promoter construct ) reporters by constitutively active ( CA ) - P84022 in these cell lines . Co - immunoprecipitation studies suggest an interaction between O43294 and either CA - P84022 or wild - type P84022 in HEK293 cells that occurs through the MH2 domain of P84022 and the C terminus of O43294 with wild - type P84022 having stronger affinity than CA - P84022 to O43294 . O60760 pull - down assays demonstrate that this interaction can occur in a cell - free system . These results are consistent with the luciferase data showing that the C terminus of O43294 is critical for suppression of P84022 activity . Furthermore , using a mammalian two - hybrid system , we confirmed that O43294 interacts with the MH2 domain of P84022 and suppresses CA - P84022 - induced transcriptional responses . In conclusion , these results support that O43294 selectively intercepts transforming growth factor - beta signaling through an interaction of the LIM domain of O43294 with the MH2 domain of P84022 .", "P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK67___ ) in castrated male and female mice subjected to ___MASK67___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK67___ in mice CPs .", "Investigation of a potential protective mechanism against heparin - induced thrombocytopenia in patients on chronic intermittent hemodialysis . BACKGROUND : ___MASK76___ - induced thrombocytopenia ( HIT ) develops as a result of platelet ( Q02083 ) activation by anti - platelet factor 4 ( P02776 ) / heparin complex antibodies . Despite repeated exposure to heparin , patients undergoing chronic intermittent hemodialysis ( HD ) rarely develop HIT . We investigated the possibility that HD decreases / removes P02776 from Q02083 surfaces and / or plasma , thereby disfavoring immune complex formation as a mechanism of protection against HIT . MATERIALS AND METHODS : We enrolled 20 patients undergoing chronic HD at the Penn Presbyterian Medical Center . Blood samples were drawn before , during and after treatment in the presence and absence of heparin . P02776 , anti - P02776 / heparin antibody , heparin , and P16109 levels were measured . RESULTS : No patients demonstrated clinical symptoms of HIT . Q02083 surface P02776 levels decreased and plasma P02776 levels increased concurrently with the increase in plasma heparin concentration . In the absence of heparin , Q02083 surface and plasma P02776 levels were unchanged . Anti - P02776 / heparin antibodies , which were non - functional by the serotonin release assay , were detectable in 8 patients . Q02083 surface P16109 levels did not change during treatment . CONCLUSIONS : Removal of Q02083 surface and / or plasma P02776 as a mechanism of protection against HIT in patients undergoing HD is not supported by the results of our study , although the transient decrease in Q02083 surface P02776 in the presence of large amounts of heparin remains a candidate mechanism . The small sample size , single type of dialyzer membrane , and early sampling time points may have led to the inability to detect changes in P02776 levels . Future studies should explore other potential protective mechanisms .", "Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK4___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .", "[ Antiphospholipid antibodies and thrombosis : the putative mechanisms of hypercoagulable state in patients with anticardiolipin antibody ] . Antiphospholipid antibodies are well recognized as associated with serious clinical complications such as arterial and venous thrombosis and recurrent spontaneous abortion . These complications are collectively called antiphospholipid syndrome ( APS ) . The mechanisms responsible for the thrombosis are unclear . We reported three mechanisms . beta 2 - glycoprotein I ( beta 2GPI ) inhibited activated protein C ( P25054 ) activity and , furthermore , P25054 activity decreased by the addition of monoclonal aCL and beta 2GPI . Monoclonal anticardiolipin antibodies ( aCL ) seemed to enhance the inhibition of P25054 procoagulant activity caused by beta 2GPI . Monoclonal aCL in the presence of beta 2GPI also increased the activity of plasminogen activator inhibitor ( P05121 )- 1 in the mixture of tissue - plasminogen activator ( t - PA ) and P05121 by inhibiting the function of beta 2GPI , which increased the remaining t - PA activity in the mixture . The formation of thrombin - antithrombin complexes ( TAT ) in APS was impaired . The level of TAT in APS did not increase , however the level of prothrombin fragment 1 + 2 ( F1 + 2 ) increased . Therefore , free thrombin present in patients ' blood may contribute to thrombosis in APS . These reports indicate that thrombosis in APS may be caused by several thrombogenic factors that stimulate aCL .", "Evaluation of platelet activation , coagulation , and fibrinolytic activation in patients with symptomatic lacunar stroke . BACKGROUND : It is unclear whether hemostasis plays a role in the pathogenesis of ischemic stroke subtypes . OBJECTIVE : We aimed to investigate the possible relationship between different hemostatic markers and lacunar stroke . RESULTS : The study consisted of 30 patients with symptomatic lacunar stroke and 30 healthy age - matched healthy individuals . We analyzed the values of \" Mean Platelet Volume , \" D - dimer , \" soluble p - selectin , \" \" P00747 Activator Inhibitor Type - 1 \" ( P05121 ) , \" Thrombin - Activatable DB06692 \" ( Q96IY4 ) , and \" Platelet Factor 4 \" ( P02776 ) in patients with lacunar infarct and compared these values to those of control individuals . There were significant differences for D - dimer , mean platelet volume , thrombin - activatable fibrinolysis inhibitor , and platelet factor 4 values in symptomatic lacunar stroke group compared with the control group ( P < 0 . 01 ) . CONCLUSIONS : Different hemostatic factors may play a role in the pathogenesis of lacunar stroke . Evaluating the role of hemostatic factors on different types of strokes may help us identify new therapeutic strategies and different prognostic stratifications for ischemic stroke .", "Encapsulation of viral vectors for gene therapy applications . In gene therapy , a number of viruses are currently being used as vectors to provide transient expression of therapeutic proteins . A drawback of using free virus is that it gives a potent immune response , which reduces gene transfer and limits re - administration . An alternative delivery system is to encapsulate the virus in poly ( lactide - co - glycolide ) ( P00747 ) microspheres prior to administration . A recombinant adenovirus ( Ad ) expressing green fluorescent protein ( GFP ) was used to test the transduction efficiency of Ad encapsulated in microspheres on target cells . The number of infected cells that expressed GFP was measured by flow cytometry . It was demonstrated that encapsulated viral vectors could successfully transduce target cells with encapsulation efficiencies up to 23 % and that the level of transduction could be controlled by varying both the quantity of microspheres and the amount of Ad in the microspheres . High transduction efficiencies and its recognized biocompatibility make P00747 - encapsulated Ad an attractive alternative to the use of free virus in gene therapy applications . The infectivity of Ad was found to be significantly influenced by the processing conditions and changes in environmental factors . Free Ad and encapsulated Ad were able to infect both E1 complimenting cells ( P29320 293 ) and non - complimenting cells ( A549 ) , with the viral expression in P29320 293 cells being 2 . 1 times greater than for A549 cells .", "P00747 activator inhibitor - 1 ( P05121 ) expression in relation to hypoxia and oncoproteins in clinical cervical tumors . PURPOSE : Explore the role of plasminogen activator inhibitor - 1 ( P05121 ) in cervical cancer and its relationship to hypoxia and the expression of p53 , P12956 / 80 , and cyclin D1 . MATERIAL AND METHODS : The expression of P05121 , cyclin D1 , and p53 , together with tumor oxygenation , were determined in 43 consecutive patients suffering from localized cervical carcinoma . Oncoprotein expression was determined by immunohistochemistry . Tumor oxygenation was measured using a polarographic probe system , \" pO2 histography . \" RESULTS : P05121 expression was considered negative in 32 . 6 % and overexpressed in 18 . 6 % of cases . P12004 D1 showed a median expression of 5 . 0 ( range 0 - 70 ) . We observed a positive association between P05121 expression and altered p53 ( p = 0 . 049 ) and cyclin D1 ( p = 0 . 020 ) . An inverse association was detected between P05121 and P12956 / 80 expression ( p = 0 . 042 ) . P12004 D1 staining increased according to tumor volume ( r = 0 . 314 , p = 0 . 009 ) . We did not observe a significant association between P05121 and hypoxia or other clinicopathological parameters . CONCLUSION : The present results show that P05121 overexpression is associated with nonhomologous end - joining DNA repair down - regulation ( low P12956 / 80 expression ) and with increased p53 and cyclin D1 expression , and they suggest that P05121 plays a role in the tumor behavior in cervical carcinoma .", "Natriuretic peptide / natriuretic peptide receptor - A ( P16066 ) system has inhibitory effects in renal fibrosis in mice . OBJECT : This study was designed to examine whether natriuretic peptide / natriuretic peptide receptor - A ( P16066 ) system attenuates renal fibrosis in a unilateral ureteral obstruction ( UUO ) model and also examined the mechanism involved . METHODS : Three groups were studied : untreated UUO in wild - type mice ; untreated UUO in P16066 KO mice ; and P01160 treated ( 0 . 05 microg / kg / min ) UUO in wild - type mice . We measured histological and immunohistochemical findings ( alpha - SMA and F4 / 80 ) , tissue cGMP levels , various mRNA expression levels by real - time PCR analysis , and transcription factor levels ( AP - 1 and NF - kappaB ) in renal tissue . RESULTS : Compared with wild - type UUO mice , NPRA - KO UUO mice had abnormal morphological findings ( fibrous area : + 26 % , alpha - SMA expression : + 30 % ) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF - beta , collagen I , collagen III , P05121 , renin and angiotensinogen , whereas there were no differences in F4 / 80 positive cells or the mRNA expression levels of P05362 , osteopontin , or P13500 between the two groups . In contrast , P01160 pre - treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF - beta , collagen I , collagen III , P05121 , P05362 , osteopontin , P13500 , renin , and angiotensinogen . NPRA - KO UUO mice had higher AP - 1 levels than wild - type UUO mice and P01160 pre - treatment reduced AP - 1 and NF - kappaB activity . CONCLUSION : The endogenous natriuretic peptide / P16066 system may inhibit renal fibrosis partly via inhibition of the angiotensin / AP - 1 / TGF - beta / collagen pathway and exogenous P01160 pre - treatment may inhibit it partly via both the angiotensin / AP - 1 / TGF - beta / collagen and NF - kappaB / inflammatory pathways .", "Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK40___ ( ___MASK40___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK40___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK40___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "Potentiation of anti - angiogenic activity of heparin by blocking the P01008 - interacting pentasaccharide unit and increasing net anionic charge . ___MASK76___ , a potent anticoagulant used for the prevention of venous thromboembolism , has been recognized as a tumor angiogenesis inhibitor . Its limitation in clinical application for cancer therapy , however , arises from its strong anticoagulant activity , which causes associated adverse effects . In this study , we show the structural correlation of LHT7 , a previously developed heparin - based angiogenesis inhibitor , with its influence on P15692 blockade and its decreased anticoagulant activity . LHT7 was characterized as having average seven molecules of sodium taurocholates conjugated to one molecule of low - molecular - weight heparin ( LMWH ) . This study showed that the conjugation of sodium taurocholates selectively blocked interaction with antithrombin III ( P01008 ) while enhancing the binding with P15692 . This resulted in LHT7 to have negligible anticoagulant activity but potent anti - angiogenic activity . Following up on this finding , we showed that the bidirectional effect of sodium taurocholate conjugation was due to its unique structure , that is , the sterane core hindering the P01008 - binding pentasaccharide unit of LMWH with its bulky and rigid structural characteristics while the terminal sulfate group interacts with P15692 to produce stronger binding . In addition , we showed that LHT7 was localized in the tumor , especially on the endothelial cells . One explanation for this might be that LHT7 was delivered to the tumor via platelets .", "Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK67___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK67___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .", "Cyclopamine increases the radiosensitivity of human pancreatic cancer cells by regulating the DNA repair signal pathway through an epidermal growth factor receptor ‑ dependent pathway . Pancreatic cancer is an aggressive malignancy with a characteristic metastatic course of disease and resistance to conventional radiotherapy . As a result , the continual development of novel therapeutic agents is required to improve the current situation . In the present study , the effect of the hedgehog pathway inhibitor , cyclopamine , on cellular radiosensitivity was determined in K ‑ RASwt Colo ‑ 357 and K ‑ RASmt SW ‑ 1990 human pancreatic cancer cell lines using the clonogenic survival assay . Apoptosis and cell cycle distribution were detected using flow cytometry assay . Following irradiation ( 30 mins ) , residual double ‑ strand breaks were quantified by identification of γ ‑ P16104 foci of micronuclei and radiation ‑ induced γ ‑ P16104 , p ‑ Q13315 , DNA ‑ PKcs and P12956 expression was analyzed using western blot analysis . The epidermal growth factor ( P01133 ) and P01133 receptor ( P00533 ) inhibitor , gefitinib , were utilized to determine the related mechanisms . The results revealed that cyclopamine treatment significantly reduced cell clonogenic survival but failed to induce apoptosis and radiation ‑ induced G2 arrest . Flow cytometry revealed that cyclopamine treatment enhanced γ ‑ P16104 foci in Colo ‑ 357 and SW ‑ 1990 cells exposed to irradiation . In addition , radiation ‑ induced p ‑ Q13315 , DNA ‑ PKcs and P12956 were all inhibited . P01133 also rescued pancreatic cancer cells from cyclopamine ‑ induced P16104 phosphorylation following irradiation . Thus , cyclopamine enhanced the radiosensitivity of human pancreatic cancer cells , in part , through an EGFR ‑ dependent pathway , indicating a rational approach in combination with radiotherapy .", "Effect of glial cell line - derived neurotrophic factor on behavior and key members of the brain serotonin system in mouse strains genetically predisposed to behavioral disorders . The effect of glial cell line - derived neurotrophic factor ( P39905 ) on behavior and on the serotonin ( 5 - HT ) system of a mouse strain predisposed to depressive - like behavior , ASC / Icg ( Antidepressant Sensitive Cataleptics ) , in comparison with the parental \" nondepressive \" CBA / Lac mice was studied . Within 7 days after acute administration , P39905 ( 800 ng , i . c . v . ) decreased cataleptic immobility but increased depressive - like behavioral traits in both investigated mouse strains and produced anxiolytic effects in ASC mice . The expression of the gene encoding the key enzyme for 5 - HT biosynthesis in the brain , tryptophan hydroxylase - 2 ( Tph - 2 ) , and P08908 receptor gene in the midbrain as well as 5 - Q13049 receptor gene in the frontal cortex were increased in P39905 - treated ASC mice . At the same time , P39905 decreased P08908 and 5 - Q13049 receptor gene expression in the hippocampus of ASC mice . P39905 failed to change Tph2 , P08908 , or 5 - Q13049 receptor mRNA levels in CBA mice as well as 5 - HT transporter gene expression and P08908 and 5 - Q13049 receptor functional activity in both investigated mouse strains . The results show 1 ) a P39905 - induced increase in the expression of key genes of the brain 5 - HT system , Tph2 , P08908 , and 5 - Q13049 receptors , and 2 ) significant genotype - dependent differences in the 5 - HT system response to P39905 treatment . The data suggest that genetically defined cross - talk between neurotrophic factors and the brain 5 - HT system underlies the variability in behavioral response to P39905 .", "___MASK78___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK78___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK78___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK78___ inhibits activated T cells . We show that in vitro , ___MASK78___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK78___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK78___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK78___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK78___ to treat chronic inflammatory disease .", "DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .", "Lessons learned from the irinotecan metabolic pathway . ___MASK9___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK9___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK9___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .", "Phosphorylation of calmodulin by the epidermal - growth - factor - receptor tyrosine kinase . An epidermal - growth - factor ( P01133 )- receptor preparation isolated by calmodulin - affinity chromatography from rat liver plasma membranes is able to phosphorylate calmodulin . P62158 phosphorylation was enhanced 3 - 8 - fold by P01133 , was dependent on the presence of a polycation or basic protein and was inhibited by micromolar concentrations of Ca2 + . Phosphate incorporation into calmodulin occurs predominantly on tyrosine residues . Partial proteolysis of phosphocalmodulin by thrombin identifies Tyr99 , located in the third calcium - binding domain of calmodulin , as the phosphorylated residue . Stoichiometric measurements show a 32P / calmodulin molar ratio of approximately 1 when optimal phosphorylation conditions are used .", "P00747 activator in granulocyte - macrophage - P04141 transgenic mice . The pattern of expression of urokinase type plasminogen activator ( PA ) in granulocyte - macrophage - P04141 transgenic mice and their normal littermates was studied using RNAse protection assays and a plasminogen - dependent fibrinolytic assay for PA . DB00013 type PA mRNA was expressed at a high level in transgenic peritoneal cells and at a lower level in transgenic eye tissue and spleen , but not in equivalent tissue from the normal mice . Enzymically active PA was detectable in protein extracts from peritoneal cells taken from transgenic mice of less than 8 wk of age ( young mice ) but not from normals . Paradoxically , extracts from transgenic mice of more than 12 wk of age ( old mice ) showed little detectable PA activity despite continuing transcription in some mice of this age . The production of PA by peritoneal cells may be responsible for the spontaneous i . p . bleeding which is a feature of the transgenic mice and production in other tissues may help explain the local pathologic changes .", "The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK78___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .", "[ ___MASK4___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .", "Activation of MAPKs influences the expression of drug - metabolizing enzymes in primary human hepatocytes . We examined the effects of model activators of mitogen - activated protein kinases ( MAPKs ) on basal and rifampicin - , phenobarbital - and dioxin - inducible expression of phase I and phase II biotransformation enzymes in primary human hepatocytes . Cells were treated for 24 h with sorbitol ( SOR ) , anisomycin ( ANI ) and epidermal growth factor ( P01133 ) in the presence or absence of inducers . The levels of P04798 , P05177 , P20813 , P08684 , P22309 , O75795 , P50225 , Q06520 , O43704 , P08263 , P09210 mRNAs were determined . SOR and P01133 inhibited the expression of the tested genes , while ANI had no effect . We conclude that MAPKs play important role in the transcriptional regulation of drug - metabolizing enzymes ." ]

[ "___MASK19___", "___MASK25___", "___MASK37___", "___MASK40___", "___MASK4___", "___MASK67___", "___MASK76___", "___MASK78___", "___MASK9___" ]

[ "P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .", "Role played by disabled - 2 in albumin induced Q96HU1 Kinase signalling . Albumin has been shown to activate the mitogen activated protein kinase ( MAPK ) pathway in proximal tubular cells ( PTECs ) of the kidney . P98164 , the putative receptor for albumin has potential signalling properties . However , the mechanisms by which megalin signals are unclear . The adaptor phosphoprotein Disabled - 2 ( Dab2 ) is known to interact with the cytoplasmic tail of megalin and may be involved in albumin - mediated MAPK signalling . In this study , we investigated the role of Dab2 in albumin - mediated MAPK signalling and further studied the role of Dab2 in albumin - induced TGFbeta - 1 secretion , a MAPK dependent event . We used RNA interference to knockdown Dab2 protein abundance in HKC - 8 cells a model of human PTECs . Albumin activated P27361 , 2 and Elk - 1 in a MEK - 1 dependent manner and resulted in secretion of TGFbeta - 1 . In the absence of albumin , knockdown of Dab2 resulted in a trend towards increase in pERK1 , 2 consistent with its putative role as an inhibitor of cell proliferation . However albumin - induced P27361 , 2 activation was completely abolished by Dab2 knockdown . Dab2 knockdown did not however result in inhibition of albumin - induced TGFbeta - 1 secretion . These results suggest that Dab2 is a ligand dependent bi - directional regulator of P27361 , 2 activity by demonstrating that in addition to its more traditional role as an inhibitor of P27361 , 2 it may also activate P27361 , 2 .", "Expression of vitamin D receptor ( P11473 ) , cyclooxygenase - 2 ( P35354 ) and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) in benign and malignant ovarian tissue and DB00146 ( 25 ( OH2 ) D3 ) and prostaglandin E2 ( DB00917 ) serum level in ovarian cancer patients . Ovarian carcinomas are associated with increased inflammation which is based upon an up - regulation of inducible cyclooxygenase - 2 ( P35354 ) . Moreover , based on our previous published data , the extra - renal vitamin D metabolism seems to be dysregulated in comparison to healthy tissue . In order to gain further insight into the prostaglandin ( PG ) - and vitamin D - metabolism in ovarian carcinomas , the study aimed to evaluate the expression of the PG metabolising enzymes P35354 and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) compared to the vitamin D receptor ( P11473 ) in benign and malignant ovarian tissues . Additionally , we determined the DB00146 ( 25 ( OH2 ) D3 ) serum levels . Expression of P11473 , P35354 and P15428 was determined by Western blot analysis . Serum levels of 25 ( OH2 ) D3 and DB00917 were measured by chemiluminescence - based and colorimetric immunoassay . We detected significantly higher expressions of the PG metabolising enzymes P15428 and P35354 in malignant tissue and DB00917 serum levels were 2 - fold higher in tumour patients . Furthermore , we found an inverse correlation to the P11473 - expression which was 62 . 1 % lower in malignant tissues compared to that in benign tissues . Surprisingly , we could not detect any differences between the 25 ( OH2 ) D3 serum levels in either group ( n = 20 ) . These data suggest a correlation between PG - and vitamin D - metabolism in ovarian carcinomas .", "Antagonistic action of novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone analogs on differentiation of human leukemia cells ( HL - 60 ) induced by 1alpha , 25 - dihydroxyvitamin D3 . We examined the effects of two novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone ( 1alpha , 25 - lactone ) analogues on human promyelocytic leukemia cell ( HL - 60 ) differentiation using the evaluation system of the vitamin D nuclear receptor ( P11473 ) / vitamin D - responsive element ( DRE ) - mediated genomic action stimulated by 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) and its analogues . We found that the 1alpha , 25 - lactone analogues ( 23S ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9647 ) , and ( 23R ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9648 ) bound much more strongly to the P11473 than the natural ( 23S , 25R ) - DB00136 - 26 , 23 - lactone , but did not induce cell differentiation even at high concentrations ( 10 (- 6 ) M ) . Intriguingly , the differentiation of HL - 60 cells induced by DB00136 was inhibited by either TEI - 9647 or TEI - 9648 but not by the natural lactone . In contrast , retinoic acid or 12 - O - tetradecanoylphorbol - 13 - acetate - induced HL - 60 cell differentiation was not blocked by TEI - 9647 or TEI - 9648 . In separate studies , TEI - 9647 ( 10 (- 7 ) M ) was found to be an effective antagonist of both DB00136 ( 10 (- 8 ) M ) mediated induction of P38936 ( P38936 , CIP1 ) in HL - 60 cells and activation of the luciferase reporter assay in COS - 7 cells transfected with cDNA containing the DRE of the rat DB00146 - 24 - hydroxylase gene and cDNA of the human P11473 . Collectively the results strongly suggest that our novel 1alpha , 25 - lactone analogues , TEI - 9647 and TEI - 9648 , are specific antagonists of 1alpha , 25 ( OH ) 2D3 action , specifically P11473 / DRE - mediated genomic action . As such , they represent the first examples of antagonists , which act on the nuclear P11473 .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK89___ ) in castrated male and female mice subjected to ___MASK89___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK89___ in mice CPs .", "DB00146 attenuates experimental periodontitis through downregulation of O00206 and P23458 / P40763 signaling in diabetic mice . Vitamin D has been known to be closely associated with diabetes and periodontitis while the underlying mechanism has yet to be clarified . The present study aimed to discover the effect of 25 - hydroxyvitamin D3 ( 25 - OHD3 ) on glycemic control and periodontal health in mice with periodontitis superimposed on experimental diabetes ( known as diabetic periodontitis ) . We showed that 25 - OHD3 intraperitoneal injection attenuated diabetic periodontitis by reducing serum fasting blood glucose , glycosylated hemoglobin and P01375 - α levels , which led to decreased alveolar bone loss . Immunohistochemical staining and western blot analysis of gingival epithelia revealed that vitamin D receptor ( P11473 ) expression was enhanced upon 25 - OHD3 treatment , while toll - like receptor 4 ( O00206 ) expression was reduced . The expressions of Janus family kinase ( JAK ) 1 and signal transducer and activator of transcription ( P35610 ) 3 as well as their phosphorylation were inhibited in gingival epithelia of diabetic periodontitis mice , whereas the expression and phosphorylation of P42224 remained unchanged . These results suggest that 25 - OHD3 could improve diabetic periodontitis through downregulation of O00206 and P23458 / P40763 signaling in the gingival epithelium . Our study extends the previous findings on the regulation of diabetes with periodontitis , and may also provide a potential therapy for the patients with this disease .", "Microglial activation , increased P01375 and P31645 expression in the prefrontal cortex define stress - altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress - induced anhedonia affects the 5HT system and the expression of inflammation - related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 ) and the 5 - HT transporter ( P31645 ) in the pre - frontal area . Enhanced expression of 5HT ( 2A ) and P23219 in the pre - frontal area was observed in all stressed animals . In turn , indoleamine - 2 , 3 - dioxygenase ( P14902 ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti - inflammatory , and possibly , P01375 - targeted therapy for major depression .", "P50406 mediates defective brain development in monoamine oxidase A - deficient mouse embryos . Monoamine oxidases A and B ( P21397 and P27338 ) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines . In the adult central nervous system , MAOs have important functions for neurotransmitter homeostasis . Expression of MAO isoforms has been detected in the developing embryo . However , suppression of P27338 does not induce developmental alterations . In contrast , targeted inhibition and knockdown of P21397 expression ( E7 . 5 - E10 . 5 ) caused structural abnormalities in the brain . Here we explored the molecular mechanisms underlying defective brain development induced by P21397 knockdown during in vitro embryogenesis . The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures . Moreover , dysfunctional P21397 expression led to elevated levels of embryonic serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) , and we found that knockdown of serotonin receptor - 6 ( 5 - Htr6 ) expression or pharmacologic inhibition of 5 - Htr6 activity rescued the P21397 knockdown phenotype and restored apoptotic activity in the developing brain . Our data suggest that excessive 5 - Htr6 activation reduces activation of caspase - 3 and - 9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl - 2 and Bcl - XL . Moreover , we found that elevated 5 - HT levels in P21397 knockdown embryos coincided with an enhanced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) and a reduction of proliferating cell numbers . In summary , our findings suggest that excessive 5 - HT in P21397 - deficient mouse embryos triggers cellular signaling cascades via 5 - Htr6 , which suppresses developmental apoptosis in the brain and thus induces developmental retardations .", "P98164 is downregulated via LPS - P01375 - α - P27361 / 2 signaling pathway in proximal tubule cells . Expression and function of megalin , an endocytic receptor in proximal tubule cells ( PTCs ) , are reduced in diabetic nephropathy , involved in the development of proteinuria / albuminuria . Lipopolysaccharide ( LPS ) is chronically increased in diabetic sera , by the mechanism called metabolic endotoxemia . We investigated low - level LPS - mediated signaling that regulates megalin expression in immortalized rat PTCs ( IRPTCs ) . Incubation of the cells with LPS ( 10 ng / ml ) for 48 h suppressed megalin protein expression and its endocytic function . P01375 - α mRNA expression was increased by LPS treatment , and knockdown of the mRNA with siRNA inhibited LPS - mediated downregulation of megalin mRNA expression at the 24 - h time point . Incubation of IRPTCs with exogenous P01375 - α also suppressed megalin mRNA and protein expression at the 24 - and 48 - h time points , respectively . Q02750 inhibitor PD98059 competed partially but significantly P01375 - α - mediated downregulation of megalin mRNA expression . Collectively , low - level LPS - mediated P01375 - α - P27361 / 2 signaling pathway is involved in downregulation of megalin expression in IRPTCs .", "Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 gene activity is DB00136 itself , which down - regulates the gene . The down - regulation of the O15528 gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 - binding regions in the distal promoter , 2 . 6 and 3 . 2 kb upstream from the TSS , that bind vitamin D receptor - retinoid X receptor complexes . Since the down regulation of the O15528 gene is tissue - and cell - type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non - permissive to the phenomenon of DB00136 - mediated down - regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 gene is repressed in P29320 - 293 but not in MCF - 7 cells .", "Imatinib induces P16104 phosphorylation and apoptosis in chronic myelogenous leukemia cells in vitro via caspase - 3 / Mst1 pathway . AIM : P16104 is a novel tumor suppressor and its phosphorylation at the C terminus ( Ser139 and Tyr142 ) is required for tumor cell apoptosis . The aim of the present study was to elucidate the mechanisms underlying imatinib - induced C - terminal phosphorylation of P16104 in chronic myelogenous leukemia cells in vitro . METHODS : P11274 - P00519 - positive K562 cells were used . Microscopy , Western blotting and flow cytometry were used to study the signaling pathways that regulate imatinib - induced P16104 phosphorylation and the apoptotic mechanisms . RESULTS : Treatment of K562 cells with imatinib ( 1 - 8 μmol / L ) induced phosphorylation of P16104 at Ser139 and Tyr142 in time - and dose - dependent manners . In contrast , imatinib at the same concentrations did not affect P16104 acetylation at Lys 5 , and the acetylated P16104 maintained a higher level in the cells . Meanwhile , imatinib ( 1 - 8 μmol / L ) activated caspase - 3 and its downstream mammalian Q9H2G2 1 ( Mst1 ) , and induced apoptosis of K562 cells . The caspase - 3 inhibitor Z - VAD ( 40 μmol / L ) reduced imatinib - induced P16104 phosphorylation at Ser139 and Tyr142 and blocked imatinib - induced apoptosis of K562 cells . Imatinib ( 4 μmol / L ) induced expression of Williams - Beuren syndrome transcription factor ( Q9UIG0 ) , but not wild - type p53 - induced phosphatase 1 ( Wip1 ) in K562 cells . CONCLUSION : The caspase - 3 / Mst1 pathway is required for P16104 C - terminal phosphorylation at Ser139 and Tyr142 and subsequent apoptosis in Bcr - Abl - positive K562 cells induced by imatinib .", "P98164 - mediated endocytosis of vitamin D binding protein correlates with DB00146 actions in human mammary cells . The major circulating form of vitamin D is DB00146 [ DB00146 ] , which is delivered to target tissues in complex with the serum vitamin D binding protein ( DBP ) . We recently observed that mammary cells can metabolize DB00146 to DB00136 [ 1 , 25 ( OH )( 2 ) D3 ] , the vitamin D receptor ( P11473 ) ligand , and the objective of our study was to elucidate the mechanisms by which the DB00146 - DBP complex is internalized by mammary cells prior to metabolism . Using fluorescent microscopy and temperature - shift techniques , we found that T - 47D breast cancer cells rapidly internalize DBP via endocytosis , which is blunted by receptor - associated protein , a specific inhibitor of megalin - mediated endocytosis . Endocytosis of DBP was associated with activation of P11473 by DB00146 but not 1 , 25 ( OH )( 2 ) D3 ( as measured by induction of the P11473 target gene , Q07973 ) . We also found that megalin and its endocytic partner , cubilin , are coexpressed in normal murine mammary tissue , in nontransformed human mammary epithelial cell lines , and in some established human breast cancer cell lines . To our knowledge , our studies are the first to demonstrate that mammary - derived cells express megalin and cubilin , which contribute to the endocytic uptake of DB00146 - DBP and activation of the P11473 pathway .", "O60603 signaling protects mice from tumor development in a mouse model of colitis - induced cancer . Inflammatory bowel disease ( Q9UKU7 ) is a disorder of chronic inflammation with increased susceptibility to colorectal cancer . The etiology of Q9UKU7 is unclear but thought to result from a dysregulated adaptive and innate immune response to microbial products in a genetically susceptible host . Toll - like receptor ( TLR ) signaling induced by intestinal commensal bacteria plays a crucial role in maintaining intestinal homeostasis , innate immunity and the enhancement of intestinal epithelial cell ( IEC ) integrity . However , the role of O60603 in the development of colorectal cancer has not been studied . We utilized the AOM - DSS model for colitis - associated colorectal cancer ( CAC ) in wild type ( WT ) and O60603 (-/-) mice . Colons harvested from WT and O60603 (-/-) mice were used for histopathology , immunohistochemistry , immunofluorescence and cytokine analysis . Mice deficient in O60603 developed significantly more and larger colorectal tumors than their WT controls . We provide evidence that colonic epithelium of O60603 (-/-) mice have altered immune responses and dysregulated proliferation under steady - state conditions and during colitis , which lead to inflammatory growth signals and predisposition to accelerated neoplastic growth . At the earliest time - points assessed , O60603 (-/-) colons exhibited a significant increase in aberrant crypt foci ( Q9NQ94 ) , resulting in tumors that developed earlier and grew larger . In addition , the intestinal microenvironment revealed significantly higher levels of P05231 and Q16552 concomitant with increased phospho - P40763 within Q9NQ94 . These observations indicate that in colitis , O60603 plays a protective role against the development of CAC .", "Expression of vitamin D receptor and 25 - hydroxyvitamin D3 - 1 { alpha }- hydroxylase in normal and malignant human colon . Considerable evidence exists to support the use of vitamin D to prevent and / or treat colorectal cancer . However , the routine use of bioactive vitamin D , 1 , 25 - dihydroxyvitamin D3 , is limited by the side effect of toxic hypercalcemia . Recent studies , however , suggest that colonic epithelial cells express 25 - hydroxyvitamin D3 - 1alpha - hydroxylase , an enzyme that converts nontoxic pro - vitamin D , DB00146 [ DB00146 ] , to its bioactive form . Yet , nothing is known as to the cellular expression of 1alpha - hydroxylase and the vitamin D receptor ( P11473 ) in the earliest histopathologic structures associated with malignant transformation such as aberrant crypt foci ( Q9NQ94 ) and polyps [ addressing the possibility of using nontoxic DB00146 for chemoprevention ] , nor is anything known as to the expression of these proteins in colorectal cancer as a function of tumor cell differentiation or metastasis [ relevant to using DB00146 for chemotherapy ] . In this study , we show that 1alpha - hydroxylase is present at equal high levels in normal colonic epithelium as in ACFs , polyps , and colorectal cancer irrespective of tumor cell differentiation . In contrast , P11473 levels were low in normal colonic epithelial cells ; were increased in ACFs , polyps , and well - differentiated tumor cells ; and then declined as a function of tumor cell de - differentiation . Both 1alpha - hydroxylase and P11473 levels were negligible in tumor cells metastasizing to regional lymph nodes . Overall , these data support using DB00146 for colorectal cancer chemoprevention but suggest that pro - vitamin D is less likely to be useful for colorectal cancer chemotherapy .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ( ___MASK100___ , ZD1839 ) and the antioestrogen fulvestrant ( Faslodex , DB00947 ) in breast cancer cells . A high expression level of epidermal growth factor receptor ( P00533 ) / P00533 has been suggested to lead to a shorter survival time and resistance to endocrine therapy in patients with breast cancer . To test the hypothesis that inhibition of the P00533 signalling pathway affects the antitumour effect of endocrine therapy , an P00533 tyrosine kinase inhibitor ( P00533 - TKI ) , gefitinib , and an oestrogen receptor ( ER ) antagonist , fulvestrant , were administered to human breast cancer cells . A total of five human breast cancer cell lines were used . The effects of single or combined treatments with gefitinib and / or fulvestrant on cell growth , cell cycle progression and apoptosis were analysed . Changes in the expression levels of cyclin - dependent kinase inhibitors , P38936 and p27 , an antiapoptotic factor , Bcl - 2 , and a proapoptotic factor , Bax , were also investigated . All cell lines tested were sensitive to gefitinib ( 50 % growth inhibitory concentration , 10 - 28 . 5 microM ) . Breast cancer cell lines with a high expression level of P00533 or P04626 were more sensitive to gefitinib than the others . Gefitinib induced a significant P55008 - S blockade in ER - positive KPL - 3C cells . Gefitinib induced significant apoptosis in P00533 - overexpressing MDA - MB - 231 cells . Gefitinib additively increased the antitumour effect of fulvestrant in all three ER - positive cell lines in a medium supplemented with 17beta - oestradiol . The combined treatment promoted cell cycle retardation in KPL - 3C cells , which is associated with an upregulation of P38936 by fulvestrant and gefitinib , respectively . Apoptosis was associated with downregulation of Bcl - 2 by gefitinib in MDA - MB - 231 cells . These results suggest an additive interaction between the P00533 - TKI gefitinib and the antioestrogen fulvestrant in ER - positive breast cancer cells .", "Transorbital endoscopic repair of cerebrospinal fluid leaks . OBJECTIVES : To describe an anatomic and clinical outcome study of transorbital neuroendoscopic surgical ( TONES ) for the repair of complex anterior cranial fossa ( Q9NQ94 ) cerebrospinal fluid ( P04141 ) leaks . DESIGN : Anatomic cadaver investigation and clinical outcomes evaluation . METHODS : An anatomic cadaver study was undertaken to determine the anatomic feasibility of the TONES approaches for repair of P04141 leaks , and determine the optimal approaches for these repairs . A targeted outcome analysis was performed on 10 consecutive patients who underwent 12 Q9NQ94 P04141 leak repairs by TONES . RESULTS : The cadaver study demonstrated that the entire Q9NQ94 can be accessed by TONES . Due to the rise and angulation of the orbital roof above the interorbital Q9NQ94 , the precaruncular ( PC ) approach optimal for a coplanar target approach in the interorbital Q9NQ94 , and the superior lid crease ( O00585 ) trajectory is preferable for procedures involving the supraorbital Q9NQ94 . There were no complications in the 12 clinical procedures . Fifty percent of the cases were revisions , referred after up to five previous craniotomies and endoscopic procedures ; all TONES repairs were successful with a single operation . CONCLUSIONS : The use of TONES to repair Q9NQ94 P04141 leaks was demonstrated to be technically feasible in cadaver and clinical studies . The O00585 approach was optimal for supraorbital Q9NQ94 leaks ; the PC approach was preferable for interorbital Q9NQ94 pathology . TONES was shown to be highly effective for treating complex pathology that was refractory to correction through frontal craniotomy and / or transnasal endoscopy , providing safe , minimally disruptive direct coplanar routes for target approach and manipulation .", "___MASK8___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK8___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .", "Cloning , expression , and regulation of rabbit cyclooxygenase - 2 in renal medullary interstitial cells . Prostaglandin synthesis requires cyclooxygenase - 1 ( P23219 ) or - 2 ( P35354 ) , which mediate the conversion of arachidonate to prostaglandin H2 . P23219 is the predominant constitutive isoform , whereas P35354 expression is typically low . In the present studies we cloned rabbit P35354 and determined its distribution in unstimulated tissues . Screening rabbit eye and uterine libraries yielded two cDNAs containing identical inserts with a 1 , 812 - nucleotide open - reading frame . This encoded a 604 - amino acid polypeptide , 90 % identical to human , rat , and mouse P35354 . Expression of the rabbit P35354 in P29320 - 293 cells enhanced prostanoid synthesis . Constitutive P35354 mRNA expression was highest in kidney and urinary bladder . P35354 expression was primarily in renal outer medullary interstitial cells with cortical expression in macula densa . In cultured medullary interstitial cells , P35354 mRNA predominated , with little P23219 expression . Interstitial cell P35354 mRNA but not P23219 was induced by phorbol ester and epidermal growth factor but suppressed by dexamethasone . Phorbol ester also upregulated immunoreactive P35354 . Constitutive P35354 in these tissues has important implications for side effects of P35354 - selective inhibitors .", "P12004 - dependent kinase 5 is associated with risk for Alzheimer ' s disease in a Dutch population - based study . Although the role of the Cdk5 protein in Alzheimer ' s disease ( AD ) is well recognized , there have been relatively few studies investigating genetic variants in the Q00535 gene in AD . In this study , we assessed the association between five previously described single nucleotide polymorphisms ( SNPs ) in the Q00535 gene and late onset AD by means of logistic regression and haplotype association analyses . Including all prevalent and incident AD cases , we found a significantly increased risk of AD for carriers of the GG genotype of SNP rs2069442 ( OR = 1 . 79 , 95 % CI 1 . 16 - 2 . 79 , p = 0 . 001 ) in those without P02649 * 4 . When limiting the analysis to incident cases without P02649 * 4 , carriers of the GG genotype showed a 1 . 9 - fold increased risk of AD ( 95 % CI 1 . 16 - 3 . 10 , p = 0 . 003 ) . Variations in the Q00535 gene can be described in 5 haplotype blocks . In our analysis , the haplotype tagged by the G allele of SNP rs2069442 was significantly associated with AD ( p = 0 . 05 ) . In conclusion , our study suggests that Q00535 may be associated with AD .", "[ The mechanisms of the resistance to molecular targeting agents ] . Increasing knowledge of the mechanism of the initiation and progression of various cancers is the catalyst for developing new anticancer therapeutics that target specific molecules expressed in cancer cells . STI571 ( imatinib mesylate ) is an example of the successful development of a rationally designed and targeted agent . Its target is the constitutively active tyrosine kinase , P11274 - P00519 in chronic myelogenous leukemia ( CML ) . Clinical studies with STI571 in CML demonstrated that many patients with advanced stage disease respond initially but then relapse . Drug resistance is associated with the reactivation of P11274 - P00519 signal transduction . Another targeted protein - tyrosine kinase inhibitor that was approved for clinical use is ZD1839 ( ___MASK100___ ) . ZD1839 is an orally active and selective inhibitor for epidermal growth factor receptor ( P00533 ) tyrosine kinase . P04626 is overexpressed in 25 - 30 % of breast cancers and associated with shorter time to relapse and lower survival rate . Specific targeting of these cancers can be accomplished with Herceptin directed against the extracellular domain of the P04626 protein . However , even in the selected group of patients with high levels of P04626 , the response to Herceptin is limited in magnitude and duration . The mechanisms of the resistance to these targeted agents were reviewed .", "Membrane receptors for vitamin D metabolites . Membrane - initiated signaling by steroid hormones is now widely accepted . Current debate is centered upon which protein moieties act as membrane - associated receptors . In this review , we consider evidence for the classical vitamin D receptor ( P11473 ) in this role , as well as the more recently identified 1 , 25D3 - MARRS ( membrane - associated , rapid response steroid binding ) receptor , also known as P30101 / GRp58 . The structure of the 1 , 25D3 - MARRS receptor is discussed , with emphasis on two thioredoxin domains that promote dimerization and ligand binding . We then summarize recent studies on a 24 , 25 ( OH ) 2D3 binding protein -- catalase -- and how ligand - induced decreases in enzymatic activity produce increased reactive oxygen species that target both the 1 , 25D3 - MARRS receptor -- but not the P11473 -- and the protein kinase C signaling pathway . Finally , we briefly discuss the available literature suggesting that the metabolite DB00146 may also be biologically active .", "Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .", "Vitamin D receptor - mediated suppression of RelB in antigen presenting cells : a paradigm for ligand - augmented negative transcriptional regulation . The immunological effects of vitamin D receptor ( P11473 ) ligands include inhibition of dendritic cell ( DC ) maturation , suppression of T - helper type 1 ( Th1 ) T - cell responses and facilitation of antigen - specific immune tolerance in vivo . While studying the molecular profile of DCs cultured in the presence of 1alpha , DB00146 or synthetic D3 analogs we observed that expression of the NF - kappaB family member RelB , which plays an essential role in DC differentiation and maturation , is selectively suppressed by P11473 ligands . Further in vitro and in vivo studies of P11473 - mediated RelB suppression indicated that the mechanism for this effect involves direct binding of P11473 / RXR alpha to a defined region of the relB promoter and assembly of a negative regulatory complex containing O15379 , Q13547 , Q9Y618 and , most likely , other factors . Interestingly , promoter engagement by P11473 and O15379 , but not the other identified components , is enhanced by addition of a P11473 ligand and inhibited by a pro - maturational stimulus ( LPS ) that results in RelB upregulation . Promoter assays in a panel of cell lines suggest that the P11473 ligand - dependent component of relB suppression may occur selectively in antigen presenting cells . Cell type - specific , ligand - enhanced negative transcriptional regulation represents a potentially novel paradigm for P11473 - controlled genes . In this report we review the experimental data to support such a mechanism for relB regulation in DCs and present a model for the process .", "First report of warfarin dose requirements in patients possessing the P11712 * 12 allele . BACKGROUND : ___MASK58___ is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S - warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S - warfarin . Numerous variant alleles of P11712 have been identified . The P11712 * 12 ( rs9332239 ) allele harbors a P489S substitution in P11712 which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 , Q9BQB6 and P02649 variant alleles . None of the four patients carried the common P11712 variant alleles ( * 2 , * 3 , * 5 , * 6 , * 7 , * 8 , * 9 , * 11 , * 13 ) despite a relatively low MWWD ( 23 . 4 ± 7 . 94 mg ) compared to 208 patients carrying the CYP29C9 * 1 genotype ( 32 . 2 ± 12 . 65 mg ) . Given that P11712 * 12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 * 12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 genotypes also demonstrated lower dose requirements in the patients that possessed P11712 * 12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 substrates . This is the first report of patients with the rare P11712 * 12 genotype and lower warfarin dose requirements .", "___MASK26___ binding to human and rat dopamine and 5 - HT receptors . ___MASK26___ ( ___MASK26___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK26___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK26___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK26___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .", "Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .", "P12004 D1 : mechanism and consequence of androgen receptor co - repressor activity . P10275 regulation is pivotal for prostate growth and development . Activation of the receptor is dictated by association with androgen ( ligand ) and through interaction with co - activators and co - repressors . We have shown previously that cyclin D1 functions as a co - repressor to inhibit ligand - dependent androgen receptor activation . We demonstrate that cyclin D1 directly binds the N terminus of the androgen receptor and that this interaction is independent of ligand . Furthermore , we show that the interaction occurs in the nucleus and does not require the LXXLL motif of cyclin D1 . Although two distinct transactivation domains exist in the N terminus ( P38484 and AF - 5 ) , the data shown support the hypothesis that cyclin D1 targets the P38484 transactivation function . The constitutively active AF - 5 domain was refractory to cyclin D1 inhibition . By contrast , cyclin D1 completely abolished androgen receptor activity , even in the presence of potent androgen receptor co - activators . This action of cyclin D1 at least partially required de - acetylase activity . Finally , we show that transient , ectopic expression of cyclin D1 results in reduced cell cycle progression in androgen - dependent LNCaP cells independent of P11802 association . Collectively , our data support a model wherein cyclin D1 has a mitogenic ( P11802 - dependent ) function and an anti - mitogenic function ( dependent on regulation of the P38484 domain ) that can collectively control the rate of androgen - dependent cellular proliferation . These findings provide insight into the non - cell cycle functions of cyclin D1 and provide the impetus to study its pleiotropic effects in androgen - dependent cells , especially prostatic adenocarcinomas .", "Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .", "Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK58___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .", "Activation of vitamin D receptor promotes P15692 and CuZn - SOD expression in endothelial cells . Endothelial dysfunction associated with vitamin D deficiency has been linked to many chronic vascular diseases . Vitamin D elicits its bioactive actions by binding to its receptor , vitamin D receptor ( P11473 ) , on target cells and organs . In the present study , we investigated the role of P11473 in response to 1 , 25 ( OH ) ₂D₃ stimulation and oxidative stress challenge in endothelial cells . We found that 1 , 25 ( OH ) ₂D₃ not only induced a dose - and time - dependent increase in P11473 expression , but also induced up - regulation of vascular endothelial growth factor ( P15692 ) and its receptors ( Flt - 1 and P35968 ) , as well as antioxidant CuZn - superoxide dismutase ( CuZn - SOD ) expression in endothelial cells . We demonstrated that inhibition of P11473 by P11473 siRNA blocked 1 , 25 ( OH ) ₂D₃ induced increased P15692 and P35968 expression and prevented 1 , 25 ( OH ) ₂D₃ induced endothelial proliferation / migration . Using CoCl₂ , a hypoxic mimicking agent , we found that hypoxia / oxidative stress not only reduced CuZn - SOD expression , but also down - regulated P11473 expression in endothelial cells , which could be prevented by addition of 1 , 25 ( OH ) ₂D3 in culture . These findings are important indicating that P11473 expression is inducible in endothelial cells and oxidative stress down - regulates P11473 expression in endothelial cells . We conclude that sufficient vitamin D levels and proper P11473 expression are fundamental for angiogenic and oxidative defense function in endothelial cells .", "Increased vitamin D - driven signalling and expression of the vitamin D receptor , P35548 , and O14788 in tooth resorption in cats . Tooth resorption occurs in 20 - 75 % of cats ( Felis catus ) . The aetiology is not known , but vitamin D is suggested to be involved . Vitamin D acts through a nuclear receptor ( P11473 ) and increases the expression of receptor activator of nuclear factor - kappaB ligand ( rankl ) and muscle segment homeobox 2 ( msx2 ) genes . Mice lacking the muscle segment homeobox 2 ( msx2 ) gene show decreased levels of rankl , suggesting an interaction among P11473 , P35548 , and O14788 . Here , we investigated the expression of P11473 , P35548 , and O14788 proteins , and the activity of the P11473 - mediated signalling pathway ( using the quantitative polymerase chain reaction on P11473 target genes ) , in tooth resorption , and measured the serum levels of vitamin D metabolites in cats . Tooth resorption was categorized into either resorptive or reparative stages . In the resorptive stage , odontoclasts expressed P35548 and O14788 ( 100 % and 88 % , respectively ) and fibroblasts expressed P11473 and P35548 ( both at 100 % ) , whereas fibroblasts expressed O14788 in only 29 % of the sites analysed . In the reparative stage , cementoblasts expressed P11473 , P35548 , and O14788 , whereas fibroblasts expressed P11473 and P35548 , but not O14788 . The vitamin D status did not differ between the groups , based on the serum levels of DB00146 . However , increased expression of P11473 protein , and the relative gene expression levels of 1alpha - hydroxylase and the P11473 - target gene , 24 - hydroxylase , indicated the involvement of an active vitamin D signalling in the pathophysiology of tooth resorption in cats .", "Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte / macrophage progenitor lineage commitment towards dendritic cell differentiation through down - regulation of receptor activator of nuclear factor - kappaB and c - Fos . Activated T lymphocytes either stimulate or inhibit osteoclastogenesis from haematopoietic progenitors in different experimental models . To address this controversy , we used several modes of T lymphocyte activation in osteoclast differentiation -- mitogen - pulse , anti - CD3 / P10747 stimulation and in vivo and in vitro alloactivation . Osteoclast - like cells were generated from non - adherent immature haematopoietic monocyte / macrophage progenitors in murine bone - marrow in the presence of receptor activator of nuclear factor ( NF ) - kappaB ligand ( O14788 ) and monocyte - macrophage colony - stimulating factor ( P09603 ) . All modes of in vivo and in vitro T lymphocyte activation and both P01730 (+) and CD8 (+) subpopulations produced similar inhibitory effects on osteoclastogenesis paralleled by enhanced dendritic cell ( DC ) differentiation . Osteoclast - inhibitory effect was associated with T lymphocyte activation and not proliferation , and could be replaced by their culture supernatants . The stage of osteoclast differentiation was crucial for the inhibitory action of activated T lymphocytes on osteoclastogenesis , because the suppressive effect was visible only on early osteoclast progenitors but not on committed osteoclasts . Inhibition was associated specifically with increased granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) expression by the mechanism of progenitor commitment toward lineages other than osteoclast because activated T lymphocytes down - regulated Q9Y6Q6 , CD115 , c - Fos and calcitonin receptor expression , and increased differentiation towards CD11c - positive DC . An activated T lymphocyte inhibitory role in osteoclastogenesis , confirmed in vitro and in vivo , mediated through GM - P04141 release , may be used to counteract activated bone resorption mediated by T lymphocyte - derived cytokines in inflammatory and immune disorders . We also demonstrated the importance of alloactivation in osteoclast differentiation and the ability of cyclosporin A to abrogate T lymphocyte inhibition of osteoclastogenesis , thereby confirming the functional link between alloreaction and bone metabolism .", "___MASK4___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK4___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .", "Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK7___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .", "Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK58___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .", "Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK61___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK61___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK61___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK61___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK61___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK61___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK61___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK61___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK61___ in the treatment of changes in hypervigilance following severe stress .", "The role of cubilin gene polymorphisms and their influence on DB00146 and 1 , 25 ( OH ) 2D3 plasma levels in type 1 diabetes patients . BACKGROUND : P98164 and cubilin bind and internalize the DB00146 - DBP complex in the kidney . Once the complex is internalized , DB00146 is released and activated to 1 , 25 ( OH ) 2D3 the ligand for the vitamin D receptor ( P11473 ) . Supporting the important role of cubilin in this process recent findings showed that cubilin deficiency results in decrease of DB00146 and 1 , 25 ( OH ) 2D3 plasma levels . METHODS : Two hundred T1D patients and healthy controls ( n = 200 ) were genotyped for five polymorphisms ( rs3740168 , rs3740165 , rs1801233 , rs1801229 and rs2796835 ) within the cubilin gene . The polymorphisms were analyzed by RFLP or real time PCR . Statistic analyses were performed by using allele - wise and genotype - wise chi2 testing by using BiAS software . A p - value < 0 . 05 was considered as significant . RESULTS : We found that the genotype \" AA \" of the rs3740165 was more frequent in T1D patients compared to healthy controls ( 26 . 7 % vs . 5 . 1 % , p = 4x10 (- 7 ) ) . Nevertheless no association between the rs3740165 polymorphism and the DB00146 or 1 , 25 ( OH ) 2D3 plasma levels was found . No association with the other studied polymorphisms was observed . CONCLUSION : Thus our findings reveal a novel association of the cubilin rs3740165 polymorphism with type 1 diabetes . Nevertheless how exactly this polymorphism could increase the risk to develop type 1 diabetes is subject for further investigations .", "A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK36___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK36___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .", "O14788 induces components of the extrinsic coagulation pathway in osteoclasts . P00734 is converted to thrombin by factor Xa in the cell - associated prothrombinase complex . P00734 is present in calcified bone matrix and thrombin exerts effects on osteoblasts as well as on bone resorption by osteoclasts . We investigated whether ( 1 ) osteoclasts display factor Xa - dependent prothrombinase activity and ( 2 ) osteoclasts express critical regulatory components upstream of the prothrombinase complex . The osteoclast differentiation factor O14788 induced formation of multinucleated TRAP positive cells concomitant with induction of prothrombinase activity in cultures of RAW 264 . 7 cells and bone marrow osteoclast progenitors . Expression analysis of extrinsic coagulation factors revealed that O14788 enhanced protein levels of factor Xa as well as of coagulation factor III ( tissue factor ) . Inhibition assays indicated that factor Xa and tissue factor were involved in the control of prothrombinase activity in O14788 - differentiated osteoclasts , presumably at two stages ( 1 ) conversion of prothrombin to thrombin and ( 2 ) conversion of factor X to factor Xa , respectively . Activation of the extrinsic coagulation pathway during osteoclast differentiation through induction of tissue factor and factor Xa by a O14788 - dependent pathway indicates a novel role for osteoclasts in converting prothrombin to thrombin .", "Tumor progression in the LPB - Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status . Previous studies have suggested that 1 , 25 dihydroxyvitamin D ( 3 ) ( 1 , 25 ( OH ) 2D3 ) induces cell cycle arrest and / or apoptosis in prostate cancer cells in vitro , suggesting that vitamin D may be a useful adjuvant therapy for prostate cancer and a chemopreventive agent . Most epidemiological data however shows a weak link between serum DB00146 and risk of prostate cancer . To explore this dichotomy we have compared tumor progression in the LPB - Tag model of prostate in P11473 knock out ( VDRKO ) and wild type ( VDRWT ) mice . On the C57BL / 6 background LPB - Tag tumors progress significantly more rapidly in the VDRKO mice . VDRKO tumors show significantly higher levels of cell proliferation than VDRWT tumors . In mice supplemented with testosterone to restore the serum levels to the normal range , these differences in tumor progression , and proliferation are abrogated , suggesting that there is considerable cross - talk between the androgen receptor ( AR ) and the vitamin D axis which is reflected in significant changes in steady state mRNA levels of the AR , P12004 , cdk2 survivin and P12314 and 2 genes . These alterations may explain the differences between the in vitro data and the epidemiological studies .", "Vitamin D up - regulates the vitamin D receptor by protecting it from proteasomal degradation in human P01730 + T cells . The active form of vitamin D3 , 1 , 25 ( OH ) 2D3 , has significant immunomodulatory properties and is an important determinant in the differentiation of P01730 + effector T cells . The biological actions of 1 , 25 ( OH ) 2D3 are mediated by the vitamin D receptor ( P11473 ) and are believed to correlate with the P11473 protein expression level in a given cell . The aim of this study was to determine if and how 1 , 25 ( OH ) 2D3 by itself regulates P11473 expression in human P01730 + T cells . We found that activated P01730 + T cells have the capacity to convert the inactive DB00146 to the active 1 , 25 ( OH ) 2D3 that subsequently up - regulates P11473 protein expression approximately 2 - fold . 1 , 25 ( OH ) 2D3 does not increase P11473 mRNA expression but increases the half - life of the P11473 protein in activated P01730 + T cells . Furthermore , 1 , 25 ( OH ) 2D3 induces a significant intracellular redistribution of the P11473 . We show that 1 , 25 ( OH ) 2D3 stabilizes the P11473 by protecting it from proteasomal degradation . Finally , we demonstrate that proteasome inhibition leads to up - regulation of P11473 protein expression and increases 1 , 25 ( OH ) 2D3 - induced gene activation . In conclusion , our study shows that activated P01730 + T cells can produce 1 , 25 ( OH ) 2D3 , and that 1 , 25 ( OH ) 2D3 induces a 2 - fold up - regulation of the P11473 protein expression in activated P01730 + T cells by protecting the P11473 against proteasomal degradation .", "In cerebrospinal fluid ER chaperones P30101 and calreticulin bind beta - amyloid . The beta - amyloids ( abetas ) are the major components of the plaque observed in the brains of patients with Alzheimer ' s disease . The conundrum is that although they are produced in everyone during the posttranslational processing in the endoplasmic reticulum ( ER ) of the amyloid precursor protein ( P05067 ) , deposits are only observed in the elderly . Our work suggests that normals have a carrier protein ( s ) keeping them in solution . Based on immunoblotting studies of cerebrospinal fluid ( P04141 ) from normals , we find that the bulk of the abetas are bound to the ER chaperones , P30101 and calreticulin , suggesting that these may be carrier proteins which prevent aggregation of the abetas and that the deposits are due to faulty ER posttranslational processing of P05067 with the failure to form this complex . If membrane protein synthesis is similarly affected , it could explain the neuronal dysfunction characteristic of Alzheimer ' s disease .", "Plasma membrane rafts and chaperones in cytokine / P35610 signaling . We and others have recently obtained data suggesting that cytokine - P35610 signaling in many different cell - types is a chaperoned pathway initiated at the level of specialized plasma membrane microdomains called \" rafts \" ( the \" raft - P35610 signaling hypothesis \" ) . These findings are of broad significance in that all cytokines and growth factors initiate signaling in target cells by interacting with respective cell - surface receptors . The new data suggest that raft microdomains represent the units of function at the cell - surface through which ligand - stimulated P35610 signaling is initiated . Moreover , recent evidence shows the involvement of chaperone proteins in regulating the P35610 signaling pathway . These chaperones include the human homolog of the tumorous imaginal disc 1 protein ( hTid1 ) which associates with O60674 ( O60674 ) at the level of the plasma membrane , heat shock protein 90 ( HSP90 ) which associates with P40763 and P42224 proteins in caveolin - 1 - containing raft and cytoplasmic complexes , and glucose regulated protein 58 ( P30101 / ER - 60 / P30101 ) , a thiol dependent protein - disulfide isomerase , found in association with P40763 \" statosome \" complexes in the cytosol and in the raft fraction . We suggest a function of the HSP90 chaperone system in preserving P05231 / P40763 signaling in liver cells in the context of fever . The identification and function of protein partners associated with specific P35610 species in rafts and in cytosolic complexes , and in the efficient departure of cytokine - activated STATs from the cytosolic face of rafts towards the cell nucleus are now areas of active investigation .", "Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .", "P31749 and megalin determine the survival or death of renal proximal tubule cells . Renal proximal tubule cells have a remarkable ability to reabsorb large quantities of albumin through megalin - mediated endocytosis . This is an essential process for overall body homeostasis . Overstressing this endocytic system with a prolonged excess of albumin is injurious to proximal tubule cells . How these cells function and protect themselves from injury is unknown . Here , we show that megalin is the sensor that determines whether cells will be protected or injured by albumin . P98164 , through a novel mechanism , binds P31749 in a D - 3 - phosphorylated phospholipid - insensitive manner , anchoring P31749 in the luminal plasma membrane . Whereas low doses of albumin are protective , an overload of albumin decreases megalin expression followed by a reduction of plasma membrane P31749 , P31749 activity , and Bad phosphorylation induced by P31749 . The result is albumin - induced apoptosis . These results reveal a model for P31749 distribution in the plasma membrane and elucidate mechanisms involved in both the protective and toxic effects of albumin on proximal tubule cells . In addition , our findings suggest a mechanism for the progression of chronic kidney disease to end - stage renal disease .", "Acute effects of sarpogrelate , a 5 - Q13049 receptor antagonist on cytokine production in endotoxin shock model of rats . Serotonin ( 5 - HT ) ( 2A ) receptors are involved in cytokine production in infection or sepsis . Therefore , 5 - HT ( 2A ) receptor antagonist might be useful to treat sepsis . The present study investigates the effects of a 5 - HT ( 2A ) receptor antagonist , sarpogrelate on endotoxin shock . Catheters were inserted into the femoral artery and vein of Sprague - Dawley rats . First , sarpogrelate 0 ( control ) , 3 , or 10 mg / kg dissolved in 0 . 5 ml of distilled water has been given , followed by endotoxin 10 mg / kg in saline 0 . 5 ml 5 min later . Blood pressure , pulse rate and survival rate were monitored in 20 rats per dose . Blood gas and plasma cytokine concentrations were measured in 8 rats per dose . In four rats each of sarpogrelate 0 , 3 , or 10 mg / kg , and sham operation , the lung histology was examined . Zero , 15 , and 12 rats survived for 8 h in the control , 3 mg / kg , and 10 mg / kg groups , respectively . The control group had the lowest blood pressure , pulse rate , pH and arterial oxygen tension , and the highest arterial carbon dioxide tension and plasma IL - 1beta concentration . The increase of P01375 was significantly lower in 3 mg / kg group than in the control group . Pathological changes of the lung were inhibited in 3 and 10 mg / kg groups . In conclusion , sarpogrelate might be effective to decrease production of pro - inflammatory cytokines , to keep hemodynamics , to inhibit lung damage , and to decrease mortality in endotoxin shock .", "Contact sensitization to oxazolone : involvement of both interferon - gamma and interleukin - 4 in oxazolone - specific Ig and T - cell responses . The synthesis and role of several lymphokines were examined during contact sensitization to oxazolone ( OX ) . Application of OX to the skin of mice increased the delayed - type hypersensitivity ( DTH ) response to challenge , serum titres of OX - specific IgG1 and IgG2a , and draining lymph node cell ( LNC ) numbers . At day 3 , LN contained detectable interleukin - 4 ( P05112 ) , interferon - gamma ( P01579 ) and granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) but not P60568 or P08700 mRNAs ; P08700 and higher levels of P05112 , P01579 and GM - P04141 mRNAs were measured after 24 hr culture with anti - CD3 antibody in OX - primed but not unprimed LNC . As a result of sensitization , LNC secreted P08700 constitutively and produced elevated levels of P60568 , P08700 , P05112 and P01579 in response to anti - CD3 antibody ; a similar but weaker lymphokine response was recalled by OX - protein conjugate . P01730 + cells were the major source of the anti - CD3 - induced lymphokines except P01579 , which was derived mainly from CD8 + cells . Since both P05112 and P01579 were synthesized by OX - primed LNC in vivo and in vitro , their role was investigated by administering anti - lymphokine antibodies at the time of sensitization . Anti - P05112 treatment reduced OX - specific serum IgG1 titres without affecting IgG2a titres , whereas anti - P01579 treatment reduced IgG2a but not IgG1 titres . Although neither antibody altered DTH responsiveness , anti - P01579 treatment markedly increased P05112 production by P01730 + LNC and reduced P01579 production in vitro , particularly by P01730 + cells . We conclude that endogenous P05112 and P01579 reciprocally influence the isotype of the Ig response to OX and that P01579 also affects the relative levels of P05112 and P01579 synthesis by P01730 + LNC .", "Integration of hormone signaling in the regulation of human DB00146 24 - hydroxylase transcription . The current study sought to define the molecular mechanisms involved in the cross talk between 1 , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] and activators of PKC in the regulation of 25 ( OH ) D ( 3 ) 24 - hydroxlyase [ 24 ( OH ) ase ] . Transfection of the h24 ( OH ) ase promoter construct [ - 5 , 500 /- 22 luciferase ; vitamin D response elements at - 294 /- 274 and - 174 /- 151 ; AP - 1 site at - 1 , 167 /- 1 , 160 ] in vitamin D receptor ( P11473 ) - transfected COS - 7 cells resulted in strong activation by 1 , 25 ( OH )( 2 ) D ( 3 ) . In these cells , cotreatment with the PKC activator TPA and 1 , 25 ( OH )( 2 ) D ( 3 ) yielded a 27 - fold increase in luciferase activity , which was 2 - to 3 - fold greater than activation obtained with 1 , 25 ( OH )( 2 ) D ( 3 ) alone ( P < 0 . 05 ) . Similar results were observed using LLCPK - 1 kidney cells , suggesting that the previously observed enhancement of 1 , 25 ( OH )( 2 ) D ( 3 )- induced renal 24 ( OH ) ase mRNA and activity by PKC activation occurs at the level of transcription . The functional cooperation between PKC activation and P11473 was not found to be mediated by the AP - 1 site in the h24 ( OH ) ase promoter or by enhanced binding of GRIP or Q15648 to P11473 and was also not due to PKC - mediated phosphorylation of P11473 on DB00133 ( 51 ) . Our study demonstrates that , in LLCPK - 1 kidney cells , the PKC enhancement of 1 , 25 ( OH )( 2 ) D ( 3 )- stimulated transcription may be due , in part , to an increase in P11473 concentration . In addition , inhibitors of the MAPK pathway were found to decrease the TPA enhancement ( P < 0 . 05 ) . Because activation of MAPK has been reported to result in the phosphorylation of Q15788 and in functional cooperation between Q15788 and CREB binding protein , we propose that the potentiation of P11473 - mediated transcription may also be mediated through changes in the phosphorylation of specific P11473 coregulators .", "Autocrine and paracrine roles of P15692 / P35968 and P49767 / P35916 signaling in angiosarcomas of the scalp and face . Angiosarcoma of the skin is an extremely rare malignant tumor of vascular origin that usually arises in the scalp and face of elderly persons . To clarify its characteristic features and cell cycle kinetics , we quantitatively evaluated the expression of cell cycle - related molecules and vascular endothelial growth factors using immunohistochemical staining , for comparison with 2 benign vascular tumors of the skin , the capillary hemangioma and the cavernous hemangioma . Cell proliferation , determined with reference to the Ki - 67 labeling index , was highest in angiosarcomas and lowest in cavernous hemangiomas ( angiosarcomas versus capillary hemangioma , P = . 014 ; capillary hemangioma versus cavernous hemangiomas , P = 1 . 4 x 10 (- 4 ) ) . Similar differences were also found in cyclin A , cyclin E , and P38936 ( Waf1 ) expression . Expressions of cyclin D1 and p16 ( INK4A ) were also significantly higher in angiosarcoma than in cavernous hemangioma . Expressions of these 5 proteins showed significant positive correlations with Ki - 67 labeling indices ( Spearman rho = 0 . 91 - 0 . 43 ) . Expression levels of vascular endothelial growth factor and its receptor , P35968 , were highest in angiosarcomas . P49767 expression in angiosarcomas was significantly higher than in cavernous hemangiomas , and its receptor P35916 expression was highest in angiosarcomas . Furthermore , significant positive correlations of these protein expression with Ki - 67 labeling indices were noted ( Spearman rho = 0 . 88 - 0 . 40 ) . Among them , P35916 showed the highest correlation coefficient . These results suggest that not only P35968 - mediated signal but also P35916 - mediated signal may contribute to proliferation of vascular tumor cells as autocrine and paracrine signaling factors .", "Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .", "Molecular mechanisms for transcriptional regulation of human high - affinity IgE receptor beta - chain gene induced by GM - P04141 . The beta - chain of the high - affinity receptor for IgE ( FcepsilonRI ) plays an important role in regulating activation of FcepsilonRI - expressing cells such as mast cells in allergic reactions . We already reported that the transcription factor myeloid zinc finger ( P28698 ) 1 which formed a high m . w . complex including four and a half LIM - only protein ( FHL ) 3 in the nucleus repressed human beta - chain gene expression through an element in the fourth intron . We also found that GM - P04141 induced expression of P28698 and nuclear translocation of Q13643 . We screened a human cDNA library and identified NFY which was reported to bind histone deacetylases ( HDACs ) as a constituent of the complex . The C - subunit of NFY was demonstrated to form a ternary complex with P28698 / Q13643 and interact with a beta - chain gene region including the element in the fourth intron . Q13547 and Q92769 were also shown to interact with the fourth intron region of the beta - chain gene . In a human mast cell line HMC - 1 cultured with GM - P04141 , both beta - chain expression and acetylation of histones interacting with the fourth intron region of the beta - chain gene were decreased . Collectively , these results indicated that HDACs , which were recruited to the beta - chain gene through the element in the fourth intron by P28698 / Q13643 / NFY , repressed beta - chain gene transcription by deacetylation of histones in the presence of GM - P04141 . These mechanisms will be involved in not only the cell type - specific repression of beta - chain gene expression in differentiating hemopoietic cells but also the repression of beta - chain gene expression in the peripheral cells under specific circumstances .", "Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK89___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK89___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .", "Simultaneous inhibition of epidermal growth factor receptor ( P00533 ) signaling and enhanced activation of tumor necrosis factor - related apoptosis - inducing ligand ( P50591 ) receptor - mediated apoptosis induction by an scFv : sTRAIL fusion protein with specificity for human P00533 . P00533 ( P00533 ) signaling inhibition by monoclonal antibodies and P00533 - specific tyrosine kinase inhibitors has shown clinical efficacy in cancer by restoring susceptibility of tumor cells to therapeutic apoptosis induction . P01375 - related apoptosis - inducing ligand ( P50591 ) is a promising anti - cancer agent with tumor - selective apoptotic activity . Here we present a novel approach that combines P00533 - signaling inhibition with target cell - restricted apoptosis induction using a P50591 fusion protein with engineered specificity for P00533 . This fusion protein , scFv425 : sTRAIL , comprises the P00533 - blocking antibody fragment scFv425 genetically fused to soluble P50591 ( sTRAIL ) . Treatment with scFv425 : sTRAIL resulted in the specific accretion to the cell surface of P00533 - positive cells only . P00533 - specific binding rapidly induced a dephosphorylation of P00533 and down - stream mitogenic signaling , which was accompanied by cFLIP ( L ) down - regulation and Bad dephosphorylation . P00533 - specific binding converted soluble scFv425 : sTRAIL into a membrane - bound form of P50591 that cross - linked agonistic P50591 receptors in a paracrine manner , resulting in potent apoptosis induction in a series of P00533 - positive tumor cell lines . Co - treatment of P00533 - positive tumor cells with the P00533 - tyrosine kinase inhibitor ___MASK100___ resulted in a potent synergistic pro - apoptotic effect , caused by the specific down - regulation of O15519 . Furthermore , in mixed culture experiments binding ( L ) of scFv425 : sTRAIL to P00533 - positive target cells conveyed a potent apoptotic effect toward P00533 - negative bystander tumor cells . The favorable characteristics of scFv425 : sTRAIL , alone and in combination with ___MASK100___ , as well as its potent anti - tumor bystander activity indicate its potential value for treatment of P00533 - expressing cancers .", "Autoantibodies to low - density - lipoprotein - receptor - related protein 2 ( P98164 ) in systemic autoimmune diseases . We previously reported that autoantibodies ( autoAbs ) to the main epitope on Q07108 reacted to its homologous amino acid sequence in low - density - lipoprotein - receptor - related protein 2 ( LPR2 ) , a multiligand receptor for protein reabsorption . In this study , we have investigated the prevalence , autoepitope distribution , and clinical significance of the autoAbs to P98164 in patients with systemic autoimmune diseases . Using six recombinant proteins ( F2 - P08709 ) for P98164 and one for Q07108 , we detected autoAbs to P98164 in sera of patients with rheumatoid arthritis ( RA ) , systemic lupus erythematosus , Behçet ' s disease , systemic sclerosis , and osteoarthritis and then mapped autoepitopes by Western blotting . The autoAbs to P98164 were detected in 87 % of the patients with rheumatoid arthritis , 40 % of those with systemic lupus erythematosus , 35 % of those with systemic sclerosis , 15 % of those with osteoarthritis , and 3 % of those with Behçet ' s disease . Multiple epitopes on P98164 were recognized by most of the anti - P98164 + serum samples . All of the tested anti - Q07108 autoAb + samples reacted to P98164 - P13726 containing the homologous sequence to the main epitope of Q07108 ; however , only 38 % of the anti - P98164 - P13726 + samples reacted to Q07108 . Clinically , the existence of the autoAbs to P98164 - F4 , - P12259 , and - F6 correlated with the presence of proteinuria in RA . This study revealed that P98164 is a major autoantigen in RA . The autoAbs to P98164 are probably produced by the antigen - driven mechanism and the autoimmunity to P98164 may spread to include Q07108 . The anti - P98164 autoAbs may play pathological roles by inhibiting the reabsorbing function of P98164 .", "Ligand - induced transrepression by P11473 through association of Q9UIG0 with acetylated histones . We have previously shown that the novel DB00171 - dependent chromatin - remodeling complex WINAC is required for the ligand - bound vitamin D receptor ( P11473 ) - mediated transrepression of the DB00146 1alpha - hydroxylase ( 1alpha ( OH ) ase ) gene . However , the molecular basis for P11473 promoter association , which does not involve its binding to specific DNA sequences , remains unclear . To address this issue , we investigated the function of Q9UIG0 in terms of the association between WINAC and chromatin for ligand - induced transrepression by P11473 . Results of in vitro experiments using chromatin templates showed that the association of unliganded P11473 with the promoter required physical interactions between Q9UIG0 and both P11473 and acetylated histones prior to P11473 association with chromatin . The acetylated histone - interacting region of Q9UIG0 was mapped to the bromodomain , and a Q9UIG0 mutant lacking the bromodomain served as a dominant - negative mutant in terms of ligand - induced transrepression of the 1alpha ( OH ) ase gene . Thus , our findings indicate that WINAC associates with chromatin through a physical interaction between the Q9UIG0 bromodomain and acetylated his tones , which appears to be indispensable for P11473 / promoter association for ligand - induced transrepression of 1alpha ( OH ) ase gene expression ." ]

[ "___MASK100___", "___MASK26___", "___MASK36___", "___MASK4___", "___MASK58___", "___MASK61___", "___MASK7___", "___MASK89___", "___MASK8___" ]

[ "[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK33___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .", "Q07869 gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease . BACKGROUND : Q07869 ( PPARalpha ) regulates the expression of genes involved in lipid metabolism and inflammation , making it a candidate gene for atherosclerosis and ischemic heart disease ( IHD ) . METHODS AND RESULTS : We investigated the association between the leucine 162 to valine ( L162V ) polymorphism and a G to C transversion in intron 7 of the PPARalpha gene and progression of atherosclerosis in the DB01241 Coronary Angiography Trial ( LOCAT ) , a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study ( Q9NP85 ) , a prospective study of healthy middle - aged men in the United Kingdom . There was no association with plasma lipid concentrations in either study . Both polymorphisms influenced progression of atherosclerosis and risk of IHD . V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis . Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes . The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele . Homozygotes for the intron 7 C allele had increased risk of IHD , an effect modulated by the L162V polymorphism CONCLUSIONS : The PPARalpha gene affects progression of atherosclerosis and risk of IHD . Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall .", "DB00197 , a peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) ligand , selectively induces the early growth response - 1 gene independently of Q07869 gamma . A novel mechanism for its anti - tumorigenic activity . DB00197 ( Q96PF1 ) is a peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) ligand that has pro - apoptotic activity in human colon cancer . Although Q96PF1 binds to Q07869 gamma transcription factors as an agonist , emerging evidence suggests that Q96PF1 acts independently of Q07869 gamma in many functions , including apoptosis . Early growth response - 1 ( Egr - 1 ) transcription factor has been linked to apoptosis and shown to be activated by extracellular signal - regulated kinase ( P29323 ) . We investigated whether Q96PF1 - induced apoptosis may be related to Egr - 1 induction , because Q96PF1 has been known to induce P29323 activity . Our results show that Egr - 1 is induced dramatically by Q96PF1 but not by other Q07869 gamma ligands . Q96PF1 affects Egr - 1 induction at least by two mechanisms ; Q96PF1 increases Egr - 1 promoter activity by 2 - fold and prolongs Egr - 1 mRNA stability by 3 - fold . Inhibition of P29323 phosphorylation in HCT - 116 cells abolishes the Egr - 1 induction by Q96PF1 , suggesting its P29323 - dependent manner . Further , the Q96PF1 - induced Egr - 1 expression results in increased promoter activity using a reporter system containing four copies of Egr - 1 binding sites , and Q96PF1 induces Egr - 1 binding activity to Egr - 1 consensus sites as assessed by gel shift assay . In addition , Q96PF1 induces P29323 - dependent phosphorylation of Q07869 gamma , resulting in the down - regulation of Q07869 gamma activity . The fact that Q96PF1 - induced apoptosis is accompanied by the biosynthesis of Egr - 1 suggests that Egr - 1 plays a pivotal role in Q96PF1 - induced apoptosis in HCT - 116 cells . Our results suggest that Egr - 1 induction is a unique property of Q96PF1 compared with other Q07869 gamma ligands and is independent of Q07869 gamma activation . Thus , the up - regulation of Egr - 1 may provide an explanation for the anti - tumorigenic properties of Q96PF1 .", "[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK93___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .", "Q07869 gamma ligands , rosiglitazone and pioglitazone , inhibit P09038 - and P15692 - mediated angiogenesis . OBJECTIVE : To study the effect of peroxisome proliferator - activated receptor - gamma ( Q07869 gamma ) agonists , pioglitazone and rosiglitazone , on vascular endothelial growth factor ( P15692 ) - and basic fibroblast growth factor ( P09038 ) - induced angiogenesis and on endothelial cell migration . METHODS : Chick chorioallantoic membrane ( P62158 ) model was used to evaluate the efficacy of pioglitazone and rosiglitazone on P15692 - and P09038 - induced angiogenesis . In addition , the effect of pioglitazone and rosiglitazone on endothelial cell migration was evaluated using 8 mm pore filter to a feeder layer containing vitronectin as chemoattractant . RESULTS : Pioglitazone and rosiglitazone inhibited the pro - angiogenic effects of P09038 and P15692 in the P62158 model significantly ( P < 0 . 001 ) to the same extent . Endothelial cell migration was also inhibited by both pioglitazone and rosiglitazone ( P < 0 . 001 ) . CONCLUSIONS : These results suggest that Q07869 gamma ligands , pioglitazone and rosiglitazone , in addition to their important regulatory role in adipogenesis and inflammation , possess anti - angiogenic properties . Thus , Q07869 gamma ligands may be useful in the treatment of diabetic retinopathy , macular degeneration , and other ocular disorders and may lower the risk to develop cancer in diabetic patients .", "Activation of MEK / P29323 signaling promotes adipogenesis by enhancing peroxisome proliferator - activated receptor gamma ( PPARgamma ) and C / EBPalpha gene expression during the differentiation of 3T3 - Q9NUQ9 preadipocytes . We demonstrate that exposure of post - confluent 3T3 - Q9NUQ9 preadipocytes to insulin , isobutylmethylxanthine ( MIX ) , dexamethasone ( DEX ) , and fetal bovine serum induces a rapid but transient activation of Q02750 as indicated by extensive phosphorylation of P27361 and P28482 during the initial 2 h of adipogenesis . Inhibition of this activity by treating the cells with a Q02750 - specific inhibitor ( U0126 or PD98059 ) prior to the induction of differentiation significantly attenuated the expression of peroxisome proliferator - activated receptor ( Q07869 ) gamma , CCAAT / enhancer - binding protein ( C / EBP ) alpha , perilipin , and adipocyte - specific fatty acid - binding protein ( aP2 ) . Treating the preadipocytes with troglitazone , a potent PPARgamma ligand , could circumvent the inhibition of adipogenic gene expression by U0126 . Fibroblast growth factor - 2 ( P09038 ) , in the presence of dexamethasone , isobutylmethylxanthine , and insulin , induces a prolonged activation of the MEK / P29323 signaling pathway , which lasts for at least 12 h post - induction , and this activity is less sensitive to the MEK inhibitors . Consequently , preadipocytes treated with U0126 in the presence of fibroblast growth factor - 2 ( P09038 ) express normal post - induction levels of MEK activity , and , in so doing , are capable of undergoing adipogenesis . We further show that activation of Q02750 significantly enhances the transactivation of the C / EBPalpha minimal promoter during the early phase of the differentiation process . Our results suggest that activation of the MEK / P29323 signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C / EBPalpha and PPARgamma expression .", "Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK76___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .", "Effect of the IkBα mutant gene delivery to DB05914 on rat chronic pancreatitis . This study aimed to investigate the effect of inhibitors of the NF - kΒ alpha mutant gene ( IkBaM ) delivery to mensenchymal stem cells ( MSCs ) on rat chronic pancreatitis ( CP ) . A total of 120 Sprague - Dawley rats were randomly divided into 6 groups of 20 : Group A was injected with sterile saline solution , Group B was injected with allogenic MSCs , Group C1 was injected with allogenic IkBαM - MSCs cultured in vitro 4 h before CP modeling , Group P06681 was injected with allogenic IkBαM - MSCs cultured in vitro during CP modeling , Group P01024 was cultured with allogenic IkBαM - MSCs cultured in vitro 4 h after CP modeling , and Group D was injected with rAAV2 - MSCs . Cytokine levels of P05362 , P29279 , IL - 1 , P05231 , P10145 , P01375 - α , P01033 , P16035 , P22301 , FN , P03956 , P08253 , P08254 , and P14780 were examined . The results indicated that allogenic IκBαM - MSCs could reduce pro - inflammatory cytokine levels and increase anti - inflammatory cytokine levels in CP . The allogenic IkBαM - MSCs reduced the activation and promoted the apoptosis of pancreatic stellate cells in the rat model of CP . IkBαM - MSCs influenced the proliferation and apoptosis of pancreatic stellate cells by regulating the activation of the Q07869 , MAPK , P42345 , TGF - β , NOD - like receptor , Notch , WNT , TGF - β1 - SMAD - 2 / 3 , and P04637 signal transduction pathways .", "Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .", "___MASK43___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .", "[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .", "P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK25___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .", "Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK65___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "___MASK40___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK40___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK40___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK40___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .", "Atheroprotective effect of oleoylethanolamide ( OEA ) targeting oxidized LDL . Dietary fat - derived lipid oleoylethanolamide ( OEA ) has shown to modulate lipid metabolism through a peroxisome proliferator - activated receptor - alpha ( Q07869 - α ) - mediated mechanism . In our study , we further demonstrated that OEA , as an atheroprotective agent , modulated the atherosclerotic plaques development . In vitro studies showed that OEA antagonized oxidized LDL ( ox - LDL ) - induced vascular endothelial cell proliferation and vascular smooth muscle cell migration , and suppressed lipopolysaccharide ( LPS ) - induced LDL modification and inflammation . In vivo studies , atherosclerosis animals were established using balloon - aortic denudation ( Q92934 ) rats and ApoE (-/-) mice fed with high - caloric diet ( HCD ) for 17 or 14 weeks respectively , and atherosclerotic plaques were evaluated by oil red staining . The administration of OEA ( 5 mg / kg / day , intraperitoneal injection , i . p . ) prevented or attenuated the formation of atherosclerotic plaques in HCD - Q92934 rats or HCD - ApoE (-/-) mice . Gene expression analysis of vessel tissues from these animals showed that OEA induced the mRNA expressions of Q07869 - α and downregulated the expression of M - CFS , an atherosclerotic marker , and genes involved in oxidation and inflammation , including P35228 , P35354 , P01375 - α and P05231 . Collectively , our results suggested that OEA exerted a pharmacological effect on modulating atherosclerotic plaque formation through the inhibition of LDL modification in vascular system and therefore be a potential candidate for anti - atherosclerosis drug .", "Synergism between bosutinib ( ___MASK9___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .", "[ ___MASK24___ : A new drug of B - cell malignancies ] . ___MASK24___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK24___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK24___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .", "Targeting mitochondrial 18 kDa translocator protein ( TSPO ) regulates macrophage cholesterol efflux and lipid phenotype . The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein ( TSPO ) as a potential therapeutic target , capable of increasing macrophage cholesterol efflux to ( apo ) lipoprotein acceptors . Expression and activity of TSPO in human ( THP - 1 ) macrophages were manipulated genetically and by the use of selective TSPO ligands . Cellular responses were analysed by quantitative PCR ( Q - PCR ) , immunoblotting and radiolabelling , including [ 3H ] cholesterol efflux to ( apo ) lipoprotein A - I ( apoA - I ) , high - density lipoprotein ( HDL ) and human serum . Induction of macrophage cholesterol deposition by acetylated low - density lipoprotein ( AcLDL ) increased expression of TSPO mRNA and protein , reflecting findings in human carotid atherosclerosis . Transient overexpression of TSPO enhanced efflux ( E % ) of [ 3H ] cholesterol to apoA - I , HDL and human serum compared with empty vector ( EV ) controls , whereas gene knockdown of TSPO achieved the converse . Ligation of TSPO ( using PK11195 , FGIN - 1 - 27 and flunitrazepam ) triggered increases in [ 3H ] cholesterol efflux , an effect that was amplified in TSPO - overexpressing macrophages . Overexpression of TSPO induced the expression of genes [ Q07869 ( peroxisome - proliferator - activated receptor α ) , Q13133 ( nuclear receptor 1H3 / liver X receptor α ) , O95477 ( DB00171 - binding cassette A1 ) , Q9H172 ( DB00171 - binding cassette G4 ) and P02649 ( apolipoprotein E ) ] and proteins ( O95477 and PPARα ) involved in cholesterol efflux , reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL . Thus , targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation , via enhanced cholesterol efflux to ( apo ) lipoprotein acceptors .", "Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator - activated receptor / retinoid X receptor heterodimers in the absence and presence of ligand . In a global approach combining fluorescence recovery after photobleaching ( P42345 ) , fluorescence correlation spectroscopy ( FCS ) , and fluorescence resonance energy transfer ( FRET ) , we address the behavior in living cells of the peroxisome proliferator - activated receptors ( PPARs ) , a family of nuclear receptors involved in lipid and glucose metabolism , inflammation control , and wound healing . We first demonstrate that unlike several other nuclear receptors , PPARs do not form speckles upon ligand activation . The subnuclear structures that may be observed under some experimental conditions result from overexpression of the protein and our immunolabeling experiments suggest that these structures are subjected to degradation by the proteasome . Interestingly and in contrast to a general assumption , PPARs readily heterodimerize with retinoid X receptor ( RXR ) in the absence of ligand in living cells . Q07869 diffusion coefficients indicate that all the receptors are engaged in complexes of very high molecular masses and / or interact with relatively immobile nuclear components . PPARs are not immobilized by ligand binding . However , they exhibit a ligand - induced reduction of mobility , probably due to enhanced interactions with cofactors and / or chromatin . Our study draws attention to the limitations and pitfalls of fluorescent chimera imaging and demonstrates the usefulness of the combination of FCS , P42345 , and FRET to assess the behavior of nuclear receptors and their mode of action in living cells ." ]

[ "___MASK24___", "___MASK25___", "___MASK33___", "___MASK40___", "___MASK43___", "___MASK65___", "___MASK76___", "___MASK93___", "___MASK9___" ]

[ "Thrombin - induced DB00171 release from human umbilical vein endothelial cells . DB00171 and its degradation products play an important role as signaling molecules in the vascular system , and endothelial cells are considered to be an important source of nucleotide release . To investigate the mechanism and physiological significance of endothelial DB00171 release , we compared different pharmacological stimuli for their ability to evoke DB00171 release from first passage cultivated human umbilical vein endothelial cells ( HUVECs ) . Agonists known to increase intracellular Ca ( 2 +) levels ( A23187 , histamine , thrombin ) induced a stable , non - lytic DB00171 release . Since thrombin proved to be the most robust and reproducible stimulus , the molecular mechanism of thrombin - mediated DB00171 release from HUVECs was further investigated . DB00171 rapidly increased with thrombin ( 1 U / ml ) and reached a steady - state level after 4 min . Loading the cells with BAPTA - AM to capture intracellular calcium suppressed DB00171 release . The thrombin - specific , protease - activated receptor 1 ( P25116 ) - specific agonist peptide TFLLRN ( 10 μM ) fully mimicked thrombin action on DB00171 release . To identify the nature of the DB00171 - permeable pathway , we tested various inhibitors of potential DB00171 channels for their ability to inhibit the thrombin response . DB02329 , an inhibitor of connexin hemichannels and pannexin channels , as well as Gd ( 3 +) were highly effective in blocking the thrombin - mediated DB00171 release . Specifically targeting connexin43 ( P17302 ) and pannexin1 ( Panx1 ) revealed that reducing Panx1 expression significantly reduced DB00171 release , while downregulating P17302 was ineffective . Our study demonstrates that thrombin at physiological concentrations is a potent stimulus of endothelial DB00171 release involving P25116 receptor activation and intracellular calcium mobilization . DB00171 is released by a carbenoxolone - and Gd ( 3 +)- sensitive pathway , most likely involving Panx1 channels .", "Pharmacodynamics and pharmacokinetics of the novel P25116 antagonist vorapaxar ( formerly P35240 530348 ) in healthy subjects . PURPOSE : The aim of our study was to evaluate the pharmacology of vorapaxar ( P35240 530348 ) , an oral P25116 antagonist , in healthy volunteers . METHODS AND RESULTS : In two randomized , placebo - controlled studies , subjects received either single ascending doses of vorapaxar ( 0 . 25 , 1 , 5 , 10 , 20 , or 40 mg ; n = 50 ) , multiple ascending doses of vorapaxar ( 1 , 3 , or 5 mg / day for 28 days ; n = 36 ) , a loading dose ( 10 or 20 mg ) followed by daily maintenance doses ( 1 mg ) for 6 days ( n = 12 ) , or placebo . Single 20 - and 40 - mg doses of vorapaxar completely inhibited thrombin receptor activating peptide ( TRAP ) - induced platelet aggregation ( > 80 % inhibition ) at 1 h and sustained this level of inhibition for ≥ 72 h . Multiple doses yielded complete inhibition on Day 1 ( 5 mg / day ) and Day 7 ( 1 and 3 mg / day ) . Adverse events were generally mild , transient , and unrelated to dose . CONCLUSION : DB09030 provided rapid and sustained dose - related inhibition of platelet aggregation without affecting bleeding or clotting times .", "Porphyromonas gingivalis selectively up - regulates the HIV - 1 coreceptor P51681 in oral keratinocytes . Primary infection of oral epithelial cells by HIV - 1 , if it occurs , could promote systemic infection . Most primary systemic infections are associated with R5 - type HIV - 1 targeting the R5 - specific coreceptor P51681 , which is not usually expressed on oral keratinocytes . Because coinfection with other microbes has been suggested to modulate cellular infection by HIV - 1 , we hypothesized that oral keratinocytes may up - regulate P51681 in response to the oral endogenous pathogen Porphyromonas gingivalis by cysteine - protease ( gingipains ) activation of the protease - activated receptors ( PARs ) or LPS signaling through the TLRs . The OKF6 / O14746 - 2 - immortalized normal human oral keratinocyte line expressed P61073 , whereas P51681 was not detectable . When exposed to P . gingivalis ATCC 33277 , O14746 - 2 cells induced greater time - dependent expression of P51681 - specific mRNA and surface coreceptors than P61073 . By comparing arg - ( Rgp ) and lys - gingipain ( Kgp ) mutants , a mutant deficient in both proteases , and the action of trypsin , P . gingivalis Rgp was strongly suggested to cleave P25116 and P55085 to up - regulate P51681 . P51681 was also slightly up - regulated by an isogenic gingipain - deficient mutant , suggesting the presence of a nongingipain - mediated mechanism . Purified P . gingivalis LPS also up - regulated P51681 . Blocking O60603 and O00206 receptors with Abs attenuated induction of P51681 , suggesting LPS signaling through TLRs . P . gingivalis , therefore , selectively up - regulated P51681 by two independent signaling pathways , Rgp acting on P25116 and P55085 , and LPS on O60603 and O00206 . By inducing P51681 expression , P . gingivalis coinfection could promote selective R5 - type HIV - 1 infection of oral keratinocytes .", "Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK19___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided .", "Pharmacokinetics of the novel P25116 antagonist vorapaxar in patients with hepatic impairment . PURPOSE : To determine whether hepatic impairment has an effect on the pharmacokinetics ( PK ) of vorapaxar or M20 , its main pharmacologically active metabolite . METHODS : This was an open - label study in which a single 40 - mg oral dose of vorapaxar was administered to patients with mild ( n = 6 ) , moderate ( n = 6 ) , and severe ( n = 4 ) hepatic impairment and healthy controls ( n = 16 ) matched for age , gender , weight , and height . Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose . RESULTS : Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls . Group mean values for vorapaxar C ( max ) and AUC ( tf ) were 206 - 279 ng / mL and 14 , 200 - 18 , 200 ng · h / mL , respectively , with the lowest values observed in patients with severe impairment . DB09030 median T ( max ) and mean t ( 1 / 2 ) values were 1 . 00 - 1 . 75 h and 298 - 366 h , respectively . There was no apparent correlation between vorapaxar or M20 exposure or t ( 1 / 2 ) values and disease severity . DB09030 was generally well tolerated ; one serious adverse event ( gastrointestinal bleeding secondary to ruptured esophageal varices ) was reported in a patient with severe hepatic impairment . CONCLUSIONS : Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20 . No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment . Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment , administration of vorapaxar to such patients is not recommended given their bleeding diathesis .", "___MASK59___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK59___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .", "Q03135 interacts with 5 - Q13049 serotonin receptors and profoundly modulates the signaling of selected Galphaq - coupled protein receptors . 5 - Hydroxytryptamine 2A ( 5 - HT ( 2A ) ) serotonin receptors are important for a variety of functions including vascular smooth muscle contraction , platelet aggregation , and the modulation of perception , cognition , and emotion . In a search for 5 - HT ( 2A ) receptor - interacting proteins , we discovered that caveolin - 1 ( Cav - 1 ) , a scaffolding protein enriched in caveolae , complexes with 5 - HT ( 2A ) receptors in a number of cell types including P13671 glioma cells , transfected P29320 - 293 cells , and rat brain synaptic membrane preparations . To address the functional significance of this interaction , we performed RNA interference - mediated knockdown of Cav - 1 in P13671 glioma cells , a cell type that endogenously expresses both 5 - HT ( 2A ) receptors and Cav - 1 . We discovered that the in vitro knockdown of Cav - 1 in P13671 glioma cells nearly abolished 5 - HT ( 2A ) receptor - mediated signal transduction as measured by calcium flux assays . RNA interference - mediated knockdown of Cav - 1 also greatly attenuated endogenous Galpha ( q )- coupled P2Y purinergic receptor - mediated signaling without altering the signaling of P25116 thrombin receptors . Cav - 1 appeared to modulate 5 - HT ( 2A ) signaling by facilitating the interaction of 5 - HT ( 2A ) receptors with Galpha ( q ) . These studies provide compelling evidence for a prominent role of Cav - 1 in regulating the functional activity of not only 5 - HT ( 2A ) serotonin receptors but also selected Galpha ( q )- coupled receptors .", "DB09030 : first global approval . DB09030 [ DB09030 (®) ( US ) ] , an orally active protease - activated receptor - 1 ( P25116 ) receptor antagonist , has been developed by Merck & Co for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction ( MI ) or peripheral arterial disease ( PAD ) . DB09030 has received its first global approval for this indication in the US . This article summarizes the milestones in the development of vorapaxar leading to this first approval for the reduction of thrombotic cardiovascular events in patients with a prior MI or PAD .", "Clinical potential of vorapaxar in cardiovascular risk reduction in patients with atherosclerosis . DB09030 ( ZONTIVITY ™ , formerly known as P35240 530348 ) is a specific , orally active antagonist of the protease - activated receptor - 1 ( P25116 ) on platelets . It inhibits thrombin - induced platelet activation by binding to the ectodomain of P25116 . After animal studies and Phase II studies showed that vorapaxar sufficiently inhibits platelet activation without significantly increasing bleeding complications , safety and efficacy of vorapaxar were assessed in two large multicenter trials in patients with coronary artery disease and atherosclerosis . The Thrombin - Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndromes ( TRACER ) trial investigated safety and efficacy of vorapaxar in patients with an acute coronary syndrome without ST - segment elevation . The Trial to Assess the Effects of DB09030 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis - Thrombolysis In Myocardial Infarction 50 ( TRA 2 ° P - TIMI 50 ) investigated atherothrombotic events in patients with stable atherosclerosis . Results of both studies suggested that vorapaxar given in addition to standard antiplatelet therapy can reduce atherothrombotic events , but increases the risk of mild and moderate bleeding complications . This review article summarizes the main results of TRACER and TRA 2 ° P - TIMI 50 and suggests patient cohorts that might benefit from treatment with vorapaxar in addition to standard antiplatelet therapy .", "P06401 - mediated up - regulation of transthyretin in preimplantation mouse uterus . P02766 ( P02766 ) , a carrier for thyroxine and retinol , has its messenger RNA ( mRNA ) expressed in the glandular endometrial epithelium and its protein detected in the glandular endometrial epithelium and the uterine lumen . P02766 mRNA is dramatically up - regulated in the preimplantation mouse uterus as well as the P - treated ovariectomized mouse uterus , and in both situations the up - regulation of P02766 is blocked by treatment with the P receptor antagonist ___MASK76___ .", "P25116 antagonists : current state of evidence . DB09030 ( P35240 530348 ) and atopaxar ( E5555 ) are oral protease - activated receptor - 1 ( P25116 ) antagonists with high bioavailability . They inhibits thrombin induced platelet aggregation by competitively inhibiting P25116 . We systematically evaluated the evidence for the efficacy and safety of all P25116 antagonists as well as for the individual drugs vorapaxar and atopaxar in different databases - PubMed , EMBASE , Scopus , and Cochrane register of Controlled Clinical Trials ( CENTRAL ). We selected randomized controlled trials of P25116 antagonists that reported on cardiovascular mortality as a clinical outcome . The random - effects Mantel - Haenszel model was used to evaluate the effect of P25116 antagonists on cardiovascular mortality . Seven trials were selected ( N = 42 , 355 ) for analysis . P25116 antagonists as a class , as well as individually , were associated with a non - significant numerically lower risk of cardiovascular mortality than that seen with agents used in the control group ; RR , 0 . 93 ; 95 % CI , 0 . 83 - 1 . 04 ; P = 0 . 20 ) . No heterogeneity was noted . However , P25116 antagonists also appeared to increase the risk of bleeding significantly . P25116 antagonists appear to be associated with some reduction in the risk of cardiovascular mortality ; however the significantly higher bleeding risk noted with P25116 antagonists appear to mandate a very careful selection of patients that may benefit without a substantially increased risk of bleeds .", "DB09030 expands antiplatelet options . Which patients may benefit from thrombin receptor antagonism ? DB09030 is the first substance of a new class of antiplatelet drugs that has been tested in large clinical trials . The protease - activated receptor 1 ( P25116 ) antagonist inhibits thrombin - induced platelet activation to prevent atherothrombosis . In the phase 3 trials TRACER ( acute coronary syndrome ) and TRA 2P - TIMI 50 ( stable atherosclerosis ) reducing ischemic events with vorapaxar came at the cost of bleeding . TRACER compared vorapaxar to placebo in 12 , 944 patients who had non - ST - segment elevation acute coronary syndromes on top of contemporary treatment including dual antiplatelet therapy ( aspirin and clopidogrel ) . DB09030 reduced ischemic events non - significantly , but increased bleeding significantly , therefore not justifying triple antiplatelet therapy in this setting . Follow - up was stopped early because of bleeding . TRA 2P - TIMI 50 examined 26 , 449 patients who had a history of myocardial infarction , ischemic stroke , or peripheral arterial disease . DB09030 reduced ischemic events and increased bleeding both significantly . Recruitment of patients with prior stroke was stopped early . Net clinical outcome and subgroup analyses suggested that vorapaxar could be beneficial for patients with prior myocardial infarction - but no history of stroke .", "DB09030 , an oral P25116 receptor antagonist , does not affect the pharmacokinetics and pharmacodynamics of warfarin . PURPOSE : DB09030 is an orally active protease - activated receptor 1 ( P25116 ) antagonist that inhibits thrombin - induced platelet aggregation . This open - label study assessed the pharmacokinetics and pharmacodynamics of single - dose warfarin in the presence / absence of multiple - dose vorapaxar in 12 healthy men . METHODS : Subjects received two treatments separated by ≥ 7 - day washout : Treatment A warfarin 25 mg ( Day 1 ) ; Treatment B vorapaxar 2 . 5 mg / day on Days 1 - 6 and vorapaxar 40 mg coadministered with warfarin 25 mg ( Day 7 ) . R - warfarin , S - warfarin , and prothrombin time ( PT ) were assayed predose and up to 120 h postdose . RESULTS : The geometric mean ratio ( GMR ) as a percentage ( warfarin + vorapaxar / warfarin ) was calculated . The GMR ( 90 % CIs ) estimates of C ( max ) were 105 ( 99 , 111 ) and 105 ( 99 , 112 ) for R - and S - warfarin , respectively . The GMR ( 90 % CIs ) estimates of AUC ( 0 -∞) were 108 ( 101 , 116 ) and 105 ( 96 , 115 ) for R - and S - warfarin , respectively . The GMR ( 95 % CIs ) estimates of AUC ( 0 - 120 h ) for PT and INR were 97 ( 95 , 98 ) and 96 ( 94 , 98 ) , respectively . CONCLUSION : Results of this study indicate that vorapaxar has no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin , suggesting that the coadministration of these two drugs or vorapaxar coadministered with other P11712 / P33261 substrates is unlikely to cause a clinically significant pharmacokinetic drug interaction .", "___MASK80___ block of cloned human T - type voltage - gated calcium channels . ___MASK80___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .", "Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma . BACKGROUND : Angiogenesis has been attributed to be a well - recognized aspect of human cancer biology . As such , proteinase - activated receptor ( PAR ) - 1 , endostatin ( ES ) and interleukin - 8 ( P10145 ) mediate the regulation of early - onset angiogenesis and in turn impact the process of tumor - growth and disease progression . PATIENTS AND METHODS : DB03843 - fixed paraffin - embedded tissues were obtained from 137 patients with localized gastric cancer at University of Southern California and Memorial Sloan - Kettering Cancer Center medical facilities . DNA was extracted and genotyping was carried out using PCR - restriction fragment length polymorphism - based protocols . RESULTS : In false discovery rate - adjusted univariate analysis , P25116 - 506 ins / del ( P < 0 . 001 ) , ES + 4349 G > A ( P = 0 . 004 ) , and P10145 - 251 T > A ( P < 0 . 0001 ) were associated with time to tumor recurrence ( P02766 ) . Further , P25116 - 506 ins / del and P10145 - 251 were associated with overall survival ( OS ) . After adjusting for covariates , P10145 remained significantly associated with P02766 ( adjusted P = 0 . 003 ) and OS ( adjusted P = 0 . 049 ) , whereas ES was significantly associated with P02766 ( adjusted P = 0 . 026 ) . CONCLUSIONS : Polymorphisms in P25116 , ES , and P10145 may serve as independent molecular prognostic markers in patients with localized gastric adenocarcinoma . The assessment of the patients ' individual risk on the basis of interindividual genotypes may therefore help to identify patient subgroups at high risk for poor clinical outcome .", "Thrombin regulates vascular smooth muscle cell growth and heat shock proteins via the JAK - P35610 pathway . The growth - stimulating effects of thrombin are mediated primarily via activation of a G protein - coupled receptor , P25116 . Because P25116 has no intrinsic tyrosine kinase activity , yet requires tyrosine phosphorylation events to induce mitogenesis , we investigated the role of the Janus tyrosine kinases ( JAKs ) in thrombin - mediated signaling . O60674 was activated rapidly in rat vascular smooth muscle cells ( VSMC ) treated with thrombin , and signal transducers and activators of transcription ( P42224 and P40763 ) were phosphorylated and translocated to the nucleus in a O60674 - dependent manner . AG - 490 , a O60674 - specific inhibitor , and a dominant negative O60674 mutant inhibited thrombin - induced P28482 activity and VSMC proliferation suggesting that O60674 is upstream of the Ras / Raf / MEK / P29323 pathway . To elucidate the functional significance of JAK - P35610 activation , we studied the effect of thrombin on heat shock protein ( Hsp ) expression , based upon the following : 1 ) reports that thrombin stimulates reactive oxygen species production in VSMC ; 2 ) the putative role of Hsps in modulating cellular responses to reactive oxygen species ; and 3 ) the presence of functional P42224 / 3 - binding sites in Hsp70 and Hsp90beta promoters . Indeed , thrombin up - regulated Hsp70 and Hsp90 protein expression via enhanced binding of STATs to cognate binding sites in the Hsp70 and Hsp90 promoters . Together , these results suggest that JAK - P35610 pathway activation is necessary for thrombin - induced VSMC growth and Hsp gene expression .", "Safety of the novel protease - activated receptor - 1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke . BACKGROUND : DB09030 , formerly P35240 530348 , is a novel , orally active , potent thrombin receptor inhibitor selective for the protease - activated receptor - 1 ( P25116 ) . Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events , particularly myocardial infarction , without increasing bleeding risk . The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin . METHODS : Ninety patients with previous ischemic stroke ( ≥ 14 days to < 1 year before randomization ) were randomized to receive vorapaxar ( 1 or 2 . 5 mg ) or placebo once daily for 60 days . All patients received aspirin ( 75 - 150 mg / day ) . The primary endpoint was overall incidence of adverse events during the protocol - defined treatment phase ( 60 days ) . RESULTS : Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events , including serious adverse events . None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo . Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar . CONCLUSIONS : DB09030 used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke .", "___MASK2___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .", "Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK93___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .", "5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK71___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .", "DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK52___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .", "Distinct PKC isoforms mediate cell survival and DNA synthesis in thrombin - induced myofibroblasts . Thrombin activates protease - activated receptor ( PAR ) - 1 and induces a myofibroblast phenotype in normal lung fibroblasts that resembles the phenotype of scleroderma lung fibroblasts . We now demonstrate that P25116 expression is dramatically increased in lung tissue from scleroderma patients , where it is associated with inflammatory and fibroproliferative foci . We also observe that thrombin induces resistance to apoptosis in normal lung fibroblasts , and this process is regulated by protein kinase C ( PKC ) - epsilon but not by P17252 . Overexpression of a constitutively active ( c - a ) form of P25116 or PKC - epsilon significantly inhibits P48023 - induced apoptosis in lung fibroblasts , whereas scleroderma lung fibroblasts are resistant to apoptosis de novo . Thrombin translocates p21Cip1 / P38936 , a signaling molecule downstream of PKC , from the nucleus to cytoplasm in normal lung fibroblasts mimicking the localization of p21Cip1 / P38936 in scleroderma lung fibroblasts . Overexpression of c - a P17252 or PKC - epsilon results in accumulation of p21Cip1 / P38936 in the cytoplasm . Depletion of P17252 or inhibition of mitogen - activated protein kinase ( MAPK ) blocks thrombin - induced DNA synthesis in lung fibroblasts . Inhibition of PKC by calphostin or P17252 , but not PKC - epsilon , by antisense oligonucleotides prevents thrombin - induced MAPK phosphorylation and accumulation of G ( 1 ) phase regulatory protein cyclin D1 , suggesting that P17252 , MAPK , and cyclin D1 mediate lung fibroblast proliferation . These data demonstrate that two distinct PKC isoforms mediate thrombin - induced resistance to apoptosis and proliferation and suggest that p21Cip1 / P38936 promotes both phenomena .", "No differences in the pharmacodynamics and pharmacokinetics of the thrombin receptor antagonist vorapaxar between healthy Japanese and Caucasian subjects . BACKGROUND : DB09030 , a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease , is a potent , orally bioavailable thrombin receptor antagonist selective for the protease - activated receptor 1 ( P25116 ) . METHODS : Since race / ethnicity may affect the safety , efficacy and dosage of drugs , this study was conducted to evaluate potential differences in the pharmacodynamics , pharmacokinetics and safety of vorapaxar after single ( 5 , 10 , 20 , or 40 mg ) or multiple ( 0 . 5 , 1 , or 2 . 5 mg once daily ) doses in healthy Japanese and matched ( gender , age , height , and weight ) Caucasian volunteers . RESULTS : DB09030 was well tolerated in both Japanese and Caucasian subjects . Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial / ethnic groups were similar . In both racial groups , complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40 mg and was consistently achieved and maintained with a 2 . 5 mg daily maintenance dose . CONCLUSION : There were no substantial differences in the safety , pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects .", "Connexin36 knockout mice display increased sensitivity to pentylenetetrazol - induced seizure - like behaviors . OBJECTIVE : Large - scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions . To explore roles for connexin36 ( Q9UKL4 ) gap junctions in seizures , we examined the seizure threshold of connexin36 knockout ( Cx36KO ) mice using a pentylenetetrazol ( PTZ ) model . METHODS : Mice ( 2 - 3months old ) with Q9UKL4 wildtype ( WT ) or Cx36KO genotype were treated with vehicle or 10 - 40mg / kg of the convulsant PTZ by intraperitoneal injection . Seizure and seizure - like behaviors were scored by examination of video collected for 20min . Quantitative real - time PCR ( QPCR ) was performed to measure potential compensatory neuronal connexin ( Q8NFK1 , P35212 , P17302 and P36383 ) , pannexin ( Q96RD7 and Q96RD6 ) and gamma - aminobutyric acid type A ( GABA ( A ) ) receptor α1 subunit gene expression . RESULTS : Cx36KO animals exhibited considerably more severe seizures ; 40mg / kg of PTZ caused severe generalized ( ≥ grade III ) seizures in 78 % of KO , but just 5 % of WT mice . A lower dose of PTZ ( 20mg / kg ) induced grade II seizure - like behaviors in 40 % KO vs . 0 % of WT animals . There was no significant difference in either connexin , pannexin or GABA ( A ) α1 gene expression between WT and KO animals . CONCLUSION : Increased sensitivity of Cx36KO animals to PTZ - induced seizure suggests that Q9UKL4 gap junctional communication functions as a physiological anti - convulsant mechanism , and identifies the Q9UKL4 gap junction as a potential therapeutic target in epilepsy .", "DB09030 : a novel protease - activated receptor - 1 inhibitor . INTRODUCTION : Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences . AREAS COVERED : Only 20 % relative risk ( ∼ 2 % absolute risk ) reduction associated with newer P2Y ( 12 ) receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet - mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy . Therefore , inhibition of the thrombin - protease - activated receptor ( PAR ) - 1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients . There are two major P25116 blockers are under investigations - vorapaxar and atopaxar . In preclinical and Phase I - II studies , inhibition of thrombin - mediated platelet activation by a P25116 inhibitor , in general , has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding . However , intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns . EXPERT OPINION : At this time , the specific role of P25116 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome , both during the acute setting and as a long - term therapeutic agent , is not clear . Although the P25116 inhibitors are associated with less bleeding , its effectiveness as an antithrombotic agent and also side effects are major concerns . Future large - scale trials with goals addressing these concerns are needed to define the specific role of P25116 receptor inhibitor .", "Modulation of Q8IVT5 activity in Caenorhabditis elegans by Zn ions , P25116 kinase and PP2A phosphatase . Vulval differentiation in Caenorhabditis elegans is controlled by a conserved signal transduction pathway mediated by Ras and a kinase cascade that includes Raf , Mek and MAPK . Activation of this cascade is positively regulated by a number of proteins such as Q8IVT5 ( kinase suppressor of Ras ) , Q09428 - 8 / Q5T124 - 2 , Q09428 - 6 / PP2A - B and P05231 - 1 . We describe the functional characterization of sur - 7 and several genes that regulate signaling downstream of ras . We identified sur - 7 by isolating a mutation that suppresses an activated ras allele , and showed that Q09428 - 7 is a divergent member of the cation diffusion facilitator family of heavy metal ion transporters that is probably localized to the endoplosmic recticulum membrane and regulates cellular Zn ( 2 +) concentrations . Genetic double mutant analyses suggest that the Q09428 - 7 - mediated effect is not a general toxic response . Instead , Zn ( 2 +) ions target a specific step of the pathway , probably regulation of the scaffolding protein Q8IVT5 . Biochemical analysis in mammalian cells indicates that high Zn ( 2 +) concentration causes a dramatic increase of Q8IVT5 phosphorylation . Genetic analysis also indicates that PP2A phosphatase and P25116 kinase act downstream of Raf to positively and negatively regulate Q8IVT5 activity , respectively .", "Investigation of P25116 - type thrombin receptors in rat glioma P13671 cells with a novel monoclonal anti - P25116 antibody ( Mab COR7 - 6H9 ) . Rat glioma P13671 cells have been demonstrated to be a suitable model in the investigation of P25116 - type thrombin receptors in brain . However , anti - P25116 antibodies , which should be very helpful tools in studying P25116 in rat cells , have not been available up until now . Therefore , we prepared a monoclonal anti - thrombin receptor antibody ( Mab COR7 - 6H9 ) directed against the peptide sequence GRAVYLNKSRFPPMPPPPFISEDASG in the N - terminus below the thrombin cleavage site of the rat P25116 - type thrombin receptor . Using this antibody , we demonstrated the presence of P25116 binding sites on the plasma membrane of rat glioma P13671 cells both with confocal laser fluorescence and with scanning electron microscopy . In addition , Mab COR7 - 6H9 was shown to block P25116 - mediated transmembranal signaling as demonstrated by measurement of free intracellular calcium and cyclic AMP . This novel anti - P25116 antibody is therefore likely to be a very helpful tool in studying P25116 - type thrombin receptors in rat brain .", "Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK46___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK46___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK46___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK46___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK46___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively ." ]

[ "___MASK19___", "___MASK2___", "___MASK46___", "___MASK52___", "___MASK59___", "___MASK71___", "___MASK76___", "___MASK80___", "___MASK93___" ]

[ "___MASK87___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK87___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .", "mu - Opioid receptor agonists differentially regulate the expression of miR - 190 and Q13562 . The agonists of mu - opioid receptor ( P35372 ) induce extracellular signal - regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) - pathway , whereas fentanyl functions in a beta - arrestin2 - dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR - 190 , was down - regulated by fentanyl but not by morphine . This down - regulation was attenuated by 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( methylthio ) butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl - induced but not morphine - induced P29323 phosphorylation was blocked in the primary cultures from beta - arrestin2 (-/-) mouse , fentanyl did not decrease the expression of miR - 190 . However , a PKC inhibitor that blocked morphine - induced P29323 phosphorylation specifically had no effect on the miR - 190 down - regulation . Therefore the decrease in miR - 190 expression resulted from the agonist - selective P29323 phosphorylation . In addition , the expressional changes in one of the miR - 190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR - 190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR - 190 expression .", "A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK89___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .", "A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .", "Lack of evidence for the mu - opioid receptor splice variant MOR1C in rats . We previously reported the existence of P35372 ( C ) mRNA and P35372 ( C )- immunoreactivity ( - ir ) in rats . However , the sequence that we reported for rat P35372 ( C ) appears not to be present in the rat genome . We have therefore reexamined whether P35372 ( C ) mRNA or P35372 ( C )- ir exist in rats . We used reverse - transcription polymerase chain reaction ( RT - PCR ) to attempt to amplify P35372 , P35372 ( A ) , P35372 ( B ) , the rat P35372 ( C ) sequence we previously reported , and P35372 ( C1 ) and P35372 ( P06681 ) ( which have recently been reported to exist in rats ) . In RNA extracted from rats , we were able to demonstrate PCR products representing P35372 , P35372 ( A ) , and P35372 ( B ) splice variants . All three products were confirmed as related to P35372 by Southern blot . However , we were unable to detect either the P35372 ( C ) product reported previously by us or the P35372 ( C )- like products reported to exist in rats by others . In RNA extracted from mice we were able to detect P35372 , P35372 ( A ) , P35372 ( B ) , and P35372 ( D )- like products . To test the specificity of our P35372 ( C ) antiserum , we examined P35372 ( C )- ir in control and knockout mice . P35372 ( C )- ir had a distribution in control mice similar to that previously reported in rats , including coexisting with vGLUT2 . However , although P35372 - ir was absent in P35372 knockout mice , the density and distribution of P35372 ( C )- ir were unchanged , suggesting that the antiserum crossreacts with another molecule in tissue . We find no evidence for P35372 ( C ) mRNA in rats . Furthermore , we conclude that P35372 ( C )- ir represents crossreactivity .", "Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .", "P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist - dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist - induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D - Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l - alpha - acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta - endorphin ( 1 - 31 ) , enkephalins , and dynorphin A ( 1 - 17 ) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor - mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor / agonist / G - protein complexes and / or receptor conformational changes induced by agonists are required for agonist - induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies .", "Comparative cytotoxicity of folate - based inhibitors of thymidylate synthase and 5 - fluorouracil +/- leucovorin in MGH - U1 cells . P04818 ( TS ) is a critical enzyme in the synthesis of DNA and an important target for cancer chemotherapy . ___MASK48___ ( 5FU ) combined with leucovorin ( LV ) has been used to inhibit TS , and inhibition is dependent on the formation of a ternary complex between a folate cofactor , TS , and 5 - fluorodeoxyuridine monophosphate ( FdUMP ) , a metabolite of FU . The folate - based TS inhibitors CB3717 , its analogs , and BW1843U89 have been synthesized as specific inhibitors of TS that do not require activation or the presence of a cofactor . We have compared the cytotoxicity of 5FU +/- LV with that of these folate - based TS inhibitors in human bladder cancer MGH - U1 cells using a colony - forming assay . After a 6 - h exposure , FU + LV , CB3717 , dCB3717 , or P06681 methyl dideazafolate analogs demonstrated similar cytotoxic potency that was 0 . 96 to 2 . 9 times that of 5FU alone . A 24 - h exposure did not increase the potency of 5FU + LV relative to 5FU alone , but there was a marked increase in the cytotoxicity of the dideazafolates as compared with 5FU + LV . Similarly , BW1843U89 was more cytotoxic than 5FU / LV . This was reflected in a 3 . 2 - to 1333 - fold decrease in the 50 % inhibitory concentration ( IC50 ) . Simultaneous exposure to LV and thymidine ( TdR ) protected MGH - U1 cells from the cytotoxicity of CB3717 , its analogs , and BW1843U89 . We conclude that ( a ) the folate - based TS inhibitors are more potent than 5FU + LV after a 24 - h exposure , ( b ) protection by LV and TdR indicates that TS inhibition is the primary site of action , and ( c ) BW1843U89 is more potent than D1694 in MGH - U1 cells .", "Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .", "P11387 is a cofactor for c - Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation . P11387 ( Topo I ) is a molecular target for the anticancer agent topotecan in the treatment of small cell lung cancer and ovarian carcinomas . However , the molecular mechanisms by which topotecan treatment inhibits cancer cell proliferation are unclear . We describe here the identification of Topo I as a novel endogenous interaction partner for transcription factor c - Jun . Reciprocal coimmunoprecipitation analysis showed that Topo I and c - Jun interact in transformed human cells in a manner that is dependent on JNK activity . c - Jun target gene epidermal growth factor receptor ( P00533 ) was identified as a novel gene whose expression was specifically inhibited by topotecan . Moreover , Topo I overexpression supported c - Jun - mediated reporter gene activation and both genetic and chemical inhibition of c - Jun converted cells resistant to topotecan - elicited P00533 downregulation . ___MASK57___ - elicited suppression of proliferation was rescued by exogenously expressed P00533 . Furthermore , we demonstrate the cooperation of the JNK - c - Jun pathway , Topo I , and P00533 in the positive regulation of O75794 cell proliferation . Together , these results have identified transcriptional coactivator Topo I as a first endogenous cofactor for c - Jun in the regulation of cell proliferation . In addition , the results of the present study strongly suggest that inhibition of P00533 expression is a novel mechanism by which topotecan inhibits cell proliferation in cancer therapy .", "The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK78___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .", "P35372 activation of P27361 / 2 is P35626 and arrestin dependent in striatal neurons . In this study we investigated the mechanisms responsible for Q96HU1 kinase P27361 / 2 activation following agonist activation of endogenous mu opioid receptors ( MOR ) normally expressed in cultured striatal neurons . Treatment with the MOR agonist fentanyl caused significant activation of P27361 / 2 in neurons derived from wild type mice . Fentanyl effects were blocked by the opioid antagonist naloxone and were not evident in neurons derived from MOR knock - out ( -/- ) mice . In contrast , P27361 / 2 activation by fentanyl was not evident in neurons from P35626 -/- mice or neurons pretreated with small inhibitory RNA for arrestin3 . Consistent with this observation , treatment with the opiate morphine ( which is less able to activate arrestin ) did not elicit P27361 / 2 activation in wild type neurons ; however , transfection of arrestin3 -( R170E ) ( a dominant positive form of arrestin that does not require receptor phosphorylation for activation ) enabled morphine activation of P27361 / 2 . In addition , activation of P27361 / 2 by fentanyl and morphine was rescued in P35626 -/- neurons following transfection with dominant positive arrestin3 -( R170E ) . The activation of P27361 / 2 appeared to be selective as p38 Q96HU1 kinase activation was not increased by either fentanyl or morphine treatment in neurons from wild type , MOR -/- , or P35626 -/- mice . In addition , U0126 ( a selective inhibitor of MEK kinase responsible for P29323 phosphorylation ) blocked P27361 / 2 activation by fentanyl . These results support the hypothesis that MOR activation of P27361 / 2 requires opioid receptor phosphorylation by P35626 and association of arrestin3 to initiate the cascade resulting in P27361 / 2 phosphorylation in striatal neurons .", "Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK92___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .", "Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK3___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .", "P35372 expression is increased in inflammatory bowel diseases : implications for homeostatic intestinal inflammation . BACKGROUND AND AIMS : Recent studies with mu opioid receptor ( MOR ) deficient mice support a physiological anti - inflammatory effect of MOR at the colon interface . To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases ( Q9UKU7 ) , we ( 1 ) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation ; and ( 2 ) tested the potential anti - inflammatory function of a specific opiate ( DALDA ) in inflamed and resting human mucosa . PATIENTS AND METHODS : Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues , isolated peripheral blood mononuclear cells and purified monocytes , and P01730 + and CD8 + T cells from healthy donors and Q9UKU7 patients . The effect of cytokines and nuclear factor kappaB ( NFkappaB ) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed . Finally , DALDA induced anti - inflammatory effect was investigated in mucosal explants from controls and Q9UKU7 patients . RESULTS : MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and P01730 + and CD8 + T cells . Overexpressed in active Q9UKU7 mucosa , MOR was significantly enhanced by cytokines and repressed by NFkappaB inhibitor in myeloid and lymphocytic cell lines . Furthermore , ex vivo DALDA treatment dampened tumour necrosis factor alpha mRNA expression in the colon of active Q9UKU7 patients . CONCLUSIONS : Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active Q9UKU7 , natural and / or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation .", "Expression of two variants of the human mu opioid receptor mRNA in SK - N - SH cells and human brain . A partial mu opioid receptor gene was isolated from a human genomic library using a mouse delta opioid receptor cDNA as a probe . Using information from this genomic clone and the published human mu receptor , P35372 , a cDNA was isolated from SK - N - SH mRNA that codes for a variant of the P35372 mRNA , MOR1A . The presence of MOR1A is also shown in human brain using RT - PCR . MOR1A differs from P35372 in that the 3 ' terminal intron has not been removed . An in - frame termination codon is found four amino acids after the 5 ' consensus splice site , making MOR1A eight amino acids shorter than P35372 . Both receptors show similar ligand binding and coupling to DB02527 in CHO - P04264 cells . The C - terminal differences between P35372 and MOR1A could have effects on receptor coupling or receptor transport and localization .", "Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK97___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK97___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK97___ .", "AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK50___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .", "Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .", "P35372 and P00533 contribute to skin pigmentation differences between Indigenous Americans and Europeans . Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments . Previous studies have identified several genes involved in skin pigmentation differences among African , Asian , and European populations . However , none have examined skin pigmentation variation among Indigenous American populations , creating a critical gap in our understanding of skin pigmentation variation . This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans . Analysis was performed on two samples of Indigenous Americans genotyped on genome - wide SNP arrays . Using four tests for natural selection -- locus - specific branch length ( LSBL ) , ratio of heterozygosities ( lnRH ) , Tajima ' s D difference , and extended haplotype homozygosity ( EHH ) -- we identified 14 selection - nominated candidate genes ( SNCGs ) . SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground - level ultraviolet radiation . In addition to Q71RS6 and Q9UMX9 , genes previously associated with European / non - European differences in skin pigmentation , P35372 and P00533 were associated with variation in skin pigmentation in New World populations for the first time ." ]

[ "___MASK3___", "___MASK48___", "___MASK50___", "___MASK57___", "___MASK78___", "___MASK87___", "___MASK89___", "___MASK92___", "___MASK97___" ]

[ "Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co - delivery of anticancer drugs and siRNA . We developed , synthesized , and tested a multifunctional nanostructured lipid nanocarrier - based system ( NLCS ) for efficient delivery of an anticancer drug and siRNA directly into the lungs by inhalation . The system contains : ( 1 ) nanostructured lipid carriers ( NLC ) ; ( 2 ) anticancer drug ( doxorubicin or paclitaxel ) ; ( 3 ) siRNA targeted to MRP1 mRNA as a suppressor of pump drug resistance ; ( 4 ) siRNA targeted to P10415 mRNA as a suppressor of nonpump cellular resistance and ( 5 ) a modified synthetic analog of luteinizing hormone - releasing hormone ( P01148 ) as a targeting moiety specific to the receptors that are overexpressed in the plasma membrane of lung cancer cells . The NLCS was tested in vitro using human lung cancer cells and in vivo utilizing mouse orthotopic model of human lung cancer . After inhalation , the proposed NLCS effectively delivered its payload into lung cancer cells leaving healthy lung tissues intact and also significantly decreasing the exposure of healthy organs when compared with intravenous injection . The NLCS showed enhanced antitumor activity when compared with intravenous treatment . The data obtained demonstrated high efficiency of proposed NLCS for tumor - targeted local delivery by inhalation of anticancer drugs and mixture of siRNAs specifically to lung cancer cells and , as a result , efficient suppression of tumor growth and prevention of adverse side effects on healthy organs .", "cDNA array analysis of cytobrush - collected normal and malignant cervical epithelial cells : a feasibility study . Analysis of gene expression pattern is a useful approach to evaluating the biological behavior and clinical outcome of several human malignancies . Differentially expressed genes in malignant squamous cervical cells and the feasibility of gene expression profiling on squamous cervical cells obtained from cervical swabs were investigated . Cervical squamous cells from three women with high - risk human papilloma virus ( HR - HPV ) positive invasive squamous cervical carcinoma and from three HPV - negative women with normal ectocervical smears were analyzed with cDNA array . Immunoblot analysis was performed to detect the proteins corresponding to the highest upregulated genes with cDNA array . mRNA expression of P04626 , P10721 , P17948 , P04198 , DB01367 , CDKN2A , P24385 , P15531 , P22392 , MET , P21781 , P21802 , and P42224 was increased in malignant samples . Several expressed genes associated with antiapoptosis ( such as P10415 ) , cell structuring , or cell attachment were also upregulated in carcinoma cells . Decreased gene expression was observed for members of the transforming growth factor receptor superfamily ( TGF ) and integrin family , interleukin 1 ( IL1 ) , and insulin - like growth factor binding proteins ( IGFBPs ) . This study shows the feasibility of gene expression profiling of cervical squamous cells obtained with cytobrushes by identifying a characteristic gene expression pattern that clearly distinguishes between malignant and normal cervical epithelia of squamous type . We hypothesize that this noninvasive technique could be used in the evaluation of ambiguous Papanicolaou ( PAP ) smears .", "Aberrant microRNA expression likely controls DB01367 oncogene activation during malignant transformation of human prostate epithelial and stem cells by arsenic . Inorganic arsenic ( iAs ) , a human carcinogen , potentially targets the prostate . iAs malignantly transforms the RWPE - 1 human prostate epithelial line to CAsE - PE cells , and a derivative normal stem cell ( SC ) line , WPE - stem , to As - Cancer SC ( As - CSC ) line . MicroRNAs ( miRNA ) are noncoding but exert negative control on expression by degradation or translational repression of target mRNAs . Aberrant miRNA expression is important in carcinogenesis . A miRNA array of CAsE - PE and As - CSC revealed common altered expression in both for pathways concerning oncogenesis , miRNA biogenesis , cell signaling , proliferation , and tumor metastasis and invasion . The P01116 oncogene is overexpressed in CAsE - PE cells but not by mutation or promoter hypomethylation , and is intensely overexpressed in As - CSC cells . In both transformants , decreased miRNAs targeting P01116 and DB01367 superfamily members occurred . Reduced miR - 134 , miR - 373 , miR - 155 , miR - 138 , miR - 205 , miR - 181d , miR - 181c , and let - 7 in CAsE - PE cells correlated with increased target DB01367 oncogenes , RAN , P51159 , Q9UL26 mRNAs , and P01116 protein . Reduced miR - 143 , miR - 34c - 5p , and miR - 205 in As - CSC correlated with increased target RAN mRNA , and P01116 , P01111 , and P10301 proteins . The DB01367 / P29323 and PI3K / P60484 / AKT pathways control cell survival , differentiation , and proliferation , and when dysregulated promote a cancer phenotype . iAs transformation increased expression of activated P29323 kinase in both transformants and altered components of the PI3K / P60484 / AKT pathway including decreased P60484 and increases in P10415 , BCL - XL , and P15692 in the absence of AKT activation . Thus , dysregulated miRNA expression may be linked to DB01367 activation in both transformants .", "Overexpression of SnoN / SkiL , amplified at the 3q26 . 2 locus , in ovarian cancers : a role in ovarian pathogenesis . High - resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26 . 2 encompassing SnoN / SkiL , a coregulator of SMAD / TGFbeta signaling . SnoN RNA transcripts were elevated in approximately 80 % of advanced stage serous epithelial ovarian cancers . In both immortalized normal ( TIOSE ) and ovarian carcinoma cell lines ( OVCA ) , SnoN RNA levels were increased by TGFbeta stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGFbeta - induced increases in SnoN RNA . In TIOSE , SnoN protein levels were reduced 15min post TGFbeta - stimulation , likely by proteosome - mediated degradation . In contrast , in OVCA , SnoN levels were elevated 3h post - stimulation potentially as a result of inhibition of the proteosome . To elucidate the role of SnoN in ovarian tumorigenesis , we explored the effects of both increasing and decreasing SnoN levels . In both TIOSE and OVCA , SnoN siRNA decreased cell growth between 20 and 50 % concurrent with increased P38936 levels . In TIOSE , transient expression of SnoN repressed TGFbeta induction of P05121 promoters with little effect on the P38936 promoter or resultant cell growth . In contrast to the effects of transient expression , stable expression of SnoN in TIOSE led to growth arrest through induction of senescence . Collectively , these results implicate SnoN levels in multiple roles during ovarian carcinogenesis : promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non - transformed ovarian epithelial cells .", "Reactive oxygen species , DNA damage , and error - prone repair : a model for genomic instability with progression in myeloid leukemia ? Myelodysplastic syndromes ( P43034 ) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis , with an increased propensity to develop acute myelogenous leukemia ( AML ) . The molecular basis for P43034 progression is unknown , but a key element in P43034 disease progression is loss of chromosomal material ( genomic instability ) . Using our two - step mouse model for myeloid leukemic disease progression involving overexpression of human mutant P01111 and P10415 genes , we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error - prone repair of double - strand breaks ( DSB ) by nonhomologous end - joining . There is a concomitant increase in reactive oxygen species ( ROS ) in these transgenic mice with disease progression . Importantly , P63000 , an essential component of the ROS - producing NADPH oxidase , is downstream of DB01367 , and we show that ROS production in P01111 / P10415 mice is in part dependent on P63000 activity . DNA damage and error - prone repair can be decreased or reversed in vivo by N - acetyl cysteine antioxidant treatment . Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with P43034 disease progression . These data suggest treatment strategies that target DB01367 / P31749 pathways and ROS production in human P43034 / AML .", "Frequent Q9UM73 rearrangement and Q15669 - 1 / p63 co - expression in lung adenocarcinoma with signet - ring cell component . Primary adenocarcinoma with signet - ring cell component ( Ad - SRCC ) of the lung has been well characterized clinicopathologically and histologically , but their genetics has rarely been investigated . A recent report suggesting an association between Ad - SRCC and Q9HC35 - Q9UM73 fusion prompted us to undertake a histological , immunohistochemical , and molecular analysis of 10 cases of primary Ad - SRCC identified out of 699 lung adenocarcinomas ( 1 . 4 % ) . Most of the Ad - SRCCs showed characteristic architectural as well as cytological features including cohesive clustering of signet - ring cells , a solid / acinar growth pattern , and alveolar filling at the tumor periphery . Diffuse co - expression of Q15669 - 1 and p63 was observed in half of the Ad - SRCCs , and this immunoprofile has not been recognized previously . Four Ad - SRCCs ( 40 % ) harbored Q9UM73 translocations detected by reverse - transcriptase polymerase chain reaction , fluorescence in situ hybridization , and immunohistochemistry . One new Q9HC35 - Q9UM73 fusion variant was identified . One Q9UM73 - rearranged tumor showed focal squamous differentiation . None of the present Ad - SRCCs had P00533 or P01116 mutations , regardless of Q9UM73 status . This study successfully utilized tumor histology alone to identify a subset of adenocarcinomas showing a high rate of Q9UM73 translocation . The characteristic histology , immunoprofile , frequent Q9UM73 translocation , and total lack of P00533 or P01116 mutations , may suggest that Ad - SRCC forms a histologically / molecularly coherent subgroup of adenocarcinoma .", "Repression of P10415 by the tumor suppressor activity of the lysyl oxidase propeptide inhibits transformed phenotype of lung and pancreatic cancer cells . The gene encoding lysyl oxidase ( P28300 ) was identified as the ras recision gene ( rrg ) , with the ability to revert Ras - mediated transformation of NIH 3T3 fibroblasts . Mutations in DB01367 genes have been found in approximately 25 % of lung cancers and in 85 % of pancreatic cancers . In microarray analysis , these cancers were found to display reduced P28300 gene expression . Thus , the ability of the P28300 gene to repress the transformed phenotype of these cancer cells was tested . P28300 is synthesized as a 50 - kDa secreted precursor Pro - P28300 that is processed to the 32 - kDa active enzyme ( P28300 ) and to an 18 - kDa propeptide ( P28300 - PP ) . Recently , we mapped the rrg activity of Pro - P28300 to the P28300 - PP in Ras - transformed NIH 3T3 cells . Ectopic Pro - P28300 and P28300 - PP expression in H1299 lung cancer cells inhibited growth in soft agar and invasive colony formation in Matrigel and reduced activation of extracellular signal - regulated kinase ( P29323 ) and Akt , with P28300 - PP showing substantially higher activity . Similarly , P28300 - PP expression in PANC - 1 pancreatic cancer cells effectively reduced P29323 and Akt activity and inhibited growth in soft agar and ability of these cells to migrate . Nuclear Factor - kappaB ( NF - kappaB ) and its target gene P10415 , which are overexpressed in 70 % to 75 % of pancreatic cancers , have recently been implicated in invasive phenotype . P28300 - PP substantially reduced NF - kappaB and Bcl - 2 levels . Reintroduction of Bcl - 2 into PANC - 1 or H1299 cells expressing P28300 - PP restored the transformed phenotype , suggesting that Bcl - 2 is an essential target . Thus , P28300 - PP potently inhibits invasive phenotype of lung and pancreatic cancer cells , suggesting potential therapeutic applications in treatment of these cancers .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK50___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "Linkage of cytokine genes to rheumatoid arthritis . Evidence of genetic heterogeneity . OBJECTIVE : To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis ( RA ) in affected sibling pair families stratified for specific clinical features . METHOD : Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from : P27352 alpha , P27352 gamma , P27352 beta , IL1 alpha , IL1 beta , P14778 , P60568 , P05231 , Q01344 , IL8R , P10415 , P29965 , NOS3 , P49279 , alpha 1 anti - trypsin , and alpha 1 anti - chymotrypsin , using fluorescence based automated technology . Linkage was examined by defining allele sharing sibling pairs . This was assessed by maximum likelihood - inheritance by descent methods . RESULTS : An increase in allele sharing was seen for Q01344 in female sibling pairs ( LOD 0 . 91 , p = 0 . 03 ) , for P27352 gamma in sibling pairs with an affected male ( LOD 0 . 96 , p = 0 . 03 ) and most significantly for P60568 in sibling pairs where one or both were persistently seronegative ( LOD 1 . 05 , p = 0 . 02 ) . CONCLUSION : Weak evidence of linkage of RA to Q01344 , IFN gamma , and P60568 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease .", "P05121 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma . The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma ( SCC ) often reflects increased autocrine / paracrine TGF - beta synthesis and epidermal growth factor receptor ( P00533 ) amplification . Cooperative TGF - beta / P00533 signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype . In one physiologically relevant model of human cutaneous SCC progression , TGF - beta1 + P01133 stimulation increases the production of several matrix metalloproteinases ( MMPs ) , among the most prominent of which is P09238 - an MMP known to be elevated in SCC in situ . Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity . Paradoxically , P05121 , the major physiological inhibitor of plasmin generation , is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC . One testable hypothesis proposes that TGF - beta1 + P01133 - dependent P09238 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion . Increased P05121 expression serves to temporally and spatially modulate plasmin - initiated pericellular proteolysis , further facilitating epithelial invasive potential . Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies .", "Molecular pathways : the basis for rational combination using MEK inhibitors in P01116 - mutant cancers . Mutations in DB01367 oncogenes are frequently observed in human cancers , and the mutations result in activation of the DB01367 - RAF - MEK - P29323 pathway , leading to cell proliferation and survival . The pathway is , therefore , a potent therapeutic target in the DB01367 - mutant cancers . MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the DB01367 - mutant cancers . As DB01367 proteins activate other downstream signaling proteins in addition to the DB01367 - RAF - MEK - P29323 pathway , combination therapeutic approaches with MEK inhibitors are also being evaluated . Moreover , MEK inhibitors can arrest cancer cells in P55008 phase and repress prosurvival Bcl2 family proteins such as Q07820 and P10415 / BCLXL , and increase expression of Bim , a proapoptotic BH3 - only family protein . This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors . A better understanding of the pathway will help us with development of rational combinations for the treatment of the DB01367 - mutant cancers .", "Phorbol ester - mediated inhibition of growth and regulation of proto - oncogene expression in the human T cell leukemia line JURKAT . The expression and function of several proto - oncogenes were examined in a human acute T cell leukemia line , JURKAT , during phorbol ester - induced terminal differentiation . Treating JURKAT cells with the phorbol ester tetradecanoyl phorbol acetate ( TPA ) inhibited their proliferation and induced expression of the gene for the interleukin 2 receptor alpha chain ( IL2R - alpha ) , consistent with previous reports . In unstimulated proliferating JURKAT cells , high levels of C - MYC , N - DB01367 , and P10415 mRNAs were found that diminished rapidly following TPA - induced cessation of growth . In contrast , accumulation of mRNAs for the C - P01100 , C - P05412 , and P18146 genes increased markedly in TPA - treated cells and preceded the induction of IL2R - alpha mRNA . Expression of C - P10242 , C - RAF - 1 , C - P06239 , C - P06241 , and C - P09769 proto - oncogenes was relatively unchanged . To explore directly the function of two of these protooncogenes in regulating the growth of JURKAT T cells , we stably transferred C - MYC and P10415 expression plasmids into these cells . Despite sustained expression of C - MYC , P10415 , or the combination of these protooncogenes , TPA continued to inhibit JURKAT cell growth and to induce IL2R expression . Thus , although C - MYC and P10415 proto - oncogene expression correlated with proliferation in TPA - treated JURKAT cells , continuous over - expression of even the combination of these oncogenes was insufficient for abrogating the effects of TPA in these leukemic T cells . Because human lymphoid malignancies frequently contain chromosomal translocations that deregulate the expression of C - MYC and P10415 , our findings could have relevance for attempts to induce terminal differentiation of leukemic cells by in vitro exposure of patients ' bone marrow cells to phorbol esters .", "___MASK30___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .", "EAP1 / Q9UER7 interacts with P14921 and represses transcriptional activation of P14921 target genes . P14921 is a member of the evolutionarily conserved family of ets genes , which are transcription factors that bind to unique DNA sequences , either alone or by association with other proteins . In this study , we have used the yeast two - hybrid system to identify an P14921 interacting protein . The P14921 N - terminal amino acid region was used as bait and an interaction was identified with the Q9UER7 protein , referred to as EAP1 ( P14921 Associated Protein 1 ) / Q9UER7 . This interactin has been shown to exist in yeast and in vitro . EAP1 / Q9UER7 and P14921 are co - localized in the nucleus of mammalian cells . The region in EAP1 / Q9UER7 which specifically binds to P14921 is located within its carboxy terminal 173 amino acid region . The P14921 interaction region is located within its N - terminal 139 amino acids and is referred as the Q9UER7 Interaction Domain ( DID ) . The DID appears to be conserved in several other ets family members , as well as in other proteins known to interact with Q9UER7 . The EAP1 / Q9UER7 interacts with both isoforms of P14921 , Q9H3D4 - P14921 and Q8NFH3 - P14921 . Interaction of EAP1 / Q9UER7 with P14921 causes the repression of transcriptional activation of the P03956 and P10415 genes . The interaction domains of both P14921 and EAP1 / Q9UER7 are required for this repression and deletion of either domain abolishes this activity .", "Distinct signalling pathways of murine histamine H1 - and H4 - receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G - protein - coupled receptors , referred to as histamine H1 - receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro - inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre - clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse ( m ) P35367 or mH4R at similar levels and analyzed HA - induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen - activated protein kinases ( MAPKs ) P29323 1 / 2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA - induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA - induced P18146 gene expression only in Q9H3N8 - expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA - induced gene expression . In summary , using this system which allows a direct comparison of mH1R - and mH4R - induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident .", "Optimized protocols for generation of cord blood - derived cytokine - induced killer / natural killer cells . The efficacy of various combinations of stem cell factor ( P21583 ) , P36888 ligand , interleukin ( IL ) - 2 , P13232 and P40933 to induce and expand cord blood - derived cytokine - induced killer ( CIK ) cells was investigated . There were three treatment groups : group A : P21583 combined with P60568 , P13232 and P40933 ; group B : P21583 , P36888 ligand combined with P60568 , P13232 and P40933 , and group C : P60568 , P13232 and P40933 , the control group . Proliferation rates of CD3 (+) CD56 (+) CIK cells and CD3 (-) CD56 (+) natural killer ( NK ) cells were highest in group B ; expansion of CIK cells increased 796 . 1 ± 278 . 5 - fold , and that of NK cells increased 36 . 6 ± 3 . 5 - fold . All expanded cord blood - derived CIK / NK cells showed cytotoxic activity against the K562 cell line . Interestingly , the cytotoxicity of group A was highest and significantly higher than that of other groups . These protocols might provide an alternative choice for CIK / NK cell expansion .", "Risk stratification of intermediate - risk acute myeloid leukemia : integrative analysis of a multitude of gene mutation and gene expression markers . Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia ( AML ) . It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance . Gene expression profiling was conducted in a well - characterized cohort of 439 AML patients ( age < 60 years ) to determine expression levels of EVI1 , P19544 , P10415 , P08183 , Q8WXS3 , P36888 , P28906 , P14902 , ERG and Q10571 . A variety of AML - specific mutations were evaluated , that is , P36888 , P06748 , N - DB01367 , K - DB01367 , O75874 , P48735 , and P49715 ( DM / SM ) ( double / single ) . Univariable survival analysis shows that ( 1 ) patients with P36888 ( ITD ) mutations have inferior overall survival ( OS ) and event - free survival ( O43281 ) , whereas P49715 ( DM ) and P06748 mutations indicate favorable OS and O43281 in intermediate - risk AML , and ( 2 ) high transcript levels of Q8WXS3 , P28906 , Q10571 , EVl1 , and ERG predict inferior OS and O43281 . In multivariable survival analysis , P28906 , ERG , and P49715 ( DM ) remain significant . Using survival tree and regression methodologies , we show that P49715 ( DM ) , P28906 , and P48735 mutations are capable of separating the intermediate group into 2 AML subgroups with highly distinctive survival characteristics ( OS at 60 months : 51 . 9 % vs 14 . 9 % ) . The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate - risk AML .", "JTT - 705 blocks cell proliferation and angiogenesis through p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways . The excessive proliferation and migration of vascular smooth muscle cells ( SMCs ) participate in the growth and instability of atherosclerotic plaque . We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein , JTT - 705 , on SMC proliferation and angiogenesis in endothelial cells ( ECs ) . JTT - 705 inhibited human coronary artery SMC proliferation . JTT - 705 induced the phosphorylation of p38 mitogen - activated protein kinase ( MAPK ) and extracellular - signal - regulated kinases ( P29323 ) in SMCs . In addition , the anti - proliferative effects of JTT - 705 in SMCs were blocked by p38 MAPK inhibitor . JTT - 705 induced the upregulation of p - P38936 ( waf1 ) , and this effect was blocked by dominant - negative Ras ( N17 ) , but not by inhibitors of p38 MAPK or P29323 . In addition , JTT - 705 also induced the upregulation of p27 ( kip1 ) , and this effect was blocked by p38 MAPK inhibitor . Interestingly , culture medium from JTT - 705 - treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor ( P15692 ) from SMCs and directly via an anti - proliferative effect in ECs . JTT - 705 blocked the proliferation of SMCs through the activation of p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways , and simultaneously blocked EC tube formation associated with a decrease in P15692 production from SMCs and an anti - proliferative effect in ECs . Our results indicate that JTT - 705 may induce a direct anti - atherogenic effect in addition to its inhibitory effect of P11597 activity .", "The BH3 mimetic DB05764 synergizes with the Q02750 / 2 inhibitor selumetinib / AZD6244 to promote O43521 - dependent tumour cell death and inhibit acquired resistance . Tumour cells typically exhibit a G ( 1 ) cell cycle arrest in response to the Q02750 / 2 [ mitogen - activated protein kinase / P29323 ( extracellular - signal - regulated kinase ) kinase 1 / 2 ] inhibitor selumetinib , but do not die , and thus they acquire resistance . In the present study we examined the effect of combining selumetinib with the BH3 [ P10415 ( B - cell lymphoma 2 ) homology domain 3 ] - mimetic P10415 inhibitor DB05764 . Although either drug alone caused little tumour cell death , the two agents combined to cause substantial caspase - dependent cell death and inhibit long - term clonogenic survival of colorectal cancer and melanoma cell lines with P15056 ( V600E ) or DB01367 mutations . This cell death absolutely required Q07812 ( P10415 - associated X protein ) and was inhibited by RNAi ( RNA interference ) - mediated knockdown of O43521 ( P10415 - interacting mediator of cell death ) in the P15056 ( V600E )- positive COLO205 cell line . When colorectal cancer cell lines were treated with selumetinib plus DB05764 we observed a striking reduction in the incidence of cells emerging with acquired resistance to selumetinib . Similar results were observed when we combined DB05764 with the P15056 ( V600E )- selective inhibitor PLX4720 , but only in cells expressing P15056 ( V600E ) . Finally , cancer cells in which acquired resistance to selumetinib arises through P15056 ( V600E ) amplification remained sensitive to DB05764 , whereas selumetinib - resistant HCT116 cells ( P01116 ( G13D ) amplification ) were cross - resistant to DB05764 . Thus the combination of a P10415 inhibitor and an P27361 / 2 pathway inhibitor is synthetic lethal in P27361 / 2 - addicted tumour cells , delays the onset of acquired resistance and in some cases overcomes acquired resistance to selumetinib .", "Oleocanthal inhibits proliferation and MIP - 1α expression in human multiple myeloma cells . Multiple myeloma ( MM ) is a plasma cell malignancy that causes devastating bone destruction by activating osteoclasts in the bone marrow milieu . MM is the second of all hematological malignancies . Thus , the search for new pharmacological weapons is under intensive investigation being MM a critically important public health goal . Recently , it has been demonstrated that macrophage inflammatory protein 1 - alpha ( MIP - 1 α ) is crucially involved in the development of osteolytic bone lesions in MM . Phenolic components of extra virgin olive oil are reported to have anti tumor activity . However , the underlying mechanisms and specific targets of extra virgin olive oil remain to be elucidated . In the present study , we investigated the effects of a recently isolated novel extra virgin olive oil polyphenol , oleocanthal , on the human multiple myeloma cell line Q5SW96 - 77 . Here we report that this natural compound has a remarkable in vitro activity by inhibiting MIP - 1 α expression and secretion in MM cells . In addition , we also demonstrated that oleocanthal inhibits MM cells proliferation by inducing the activation of apoptosis mechanisms and by down - regulating P27361 / 2 and AKT signal transduction pathways . This in vitro study suggests a therapeutic potential of oleocanthal in treating multiple myeloma .", "That which does not kill me makes me stronger ; combining P27361 / 2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance . Oncogenic mutations in DB01367 or P15056 can drive the inappropriate activation of the P27361 / 2 . In many cases , tumour cells adapt to become addicted to this deregulated P27361 / 2 signalling for their proliferation , providing a therapeutic window for tumour - selective growth inhibition . As a result , inhibition of P27361 / 2 signalling by P15056 or Q02750 / 2 inhibitors is an attractive therapeutic strategy . Indeed , the first P15056 inhibitor , vemurafenib , has now been approved for clinical use , while clinical evaluation of Q02750 / 2 inhibitors is at an advanced stage . Despite this progress , it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6 - 9 months of primary treatment . One of the major reasons for this is that tumour cells typically respond to P15056 or Q02750 / 2 inhibitors by undergoing a P55008 cell cycle arrest rather than dying . Indeed , although inhibition of P27361 / 2 invariably increases the expression of pro - apoptotic P10415 family proteins , tumour cells undergo minimal apoptosis . This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance . Here we discuss recent studies that demonstrate that combination of P15056 or Q02750 / 2 inhibitors with inhibitors of pro - survival P10415 proteins is synthetic lethal for P27361 / 2 - addicted tumour cells . This combination effectively transforms the cytostatic response of P15056 and Q02750 / 2 inhibitors into a striking apoptotic cell death response . This not only augments the primary efficacy of P15056 and Q02750 / 2 inhibitors but delays the onset of acquired resistance to these agents , validating their combination in the clinic . LINKED ARTICLES : This article is part of a themed section on Emerging Therapeutic Aspects in Oncology . To view the other articles in this section visit http :// dx . doi . org / 10 . 1111 / bph . 2013 . 169 . issue - 8 .", "Role of nitrative and oxidative DNA damage in inflammation - related carcinogenesis . Chronic inflammation induced by biological , chemical , and physical factors has been found to be associated with the increased risk of cancer in various organs . We revealed that infectious agents including liver fluke , Helicobacter pylori , and human papilloma virus and noninfectious agents such as asbestos fiber induced P35228 - dependent formation of 8 - nitroguanine and 8 - oxo - 7 , 8 - dihydro - 2 '- deoxyguanosine ( 8 - oxodG ) in cancer tissues and precancerous regions . Our results with the colocalization of phosphorylated Q13315 and γ - P16104 with 8 - oxodG and 8 - nitroguanine in inflammation - related cancer tissues suggest that DNA base damage leads to double - stranded breaks . It is interesting from the aspect of genetic instability . We also demonstrated P05231 - modulated P35228 expression via P40763 and P00533 in Epstein - Barr - virus - associated nasopharyngeal carcinoma and found promoter hypermethylation in several tumor suppressor genes . Such epigenetic alteration may occur by controlling the DNA methylation through P05231 - mediated JAK / P40763 pathways . Collectively , 8 - nitroguanine would be a useful biomarker for predicting the risk of inflammation - related cancers .", "Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK78___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .", "Transforming growth factor alpha - induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity . Although transforming growth factor ( TGF ) - alpha , a member of the epidermal growth factor ( P01133 ) family , has been shown to protect neurons against excitotoxic and ischemic brain injuries , its mechanism of action remains unknown . In the present study , we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF - alpha rescues neurons from N - methyl - D - aspartate ( DB01221 ) - induced excitotoxic death , with the obligatory presence of astrocytes . Because neuronal tissue - type plasminogen activator ( t - PA ) release was shown to potentiate DB01221 - induced excitotoxicity , we observed that TGF - alpha treatment reduced DB01221 - induced increase of t - PA activity in mixed cultures of neurons and astrocytes . In addition , we showed that although TGF - alpha induces activation of the extracellular signal - regulated kinases ( ERKs ) in astrocytes , it failed to activate Q8NFH3 / Q8TCB0 in neurons . Finally , we showed that TGF - alpha , by an P29323 - dependent mechanism , stimulates the astrocytic expression of P05121 , a t - PA inhibitor , which mediates the neuroprotective activity of TGF - alpha against DB01221 - mediated excitotoxic neuronal death . Taken together , we indicate that TGF - alpha rescues neurons from DB01221 - induced excitotoxicity in mixed cultures through inhibition of t - PA activity , involving P05121 overexpression by an P29323 - dependent pathway in astrocytes .", "The MAPK pathway and Q9BYW2 are involved in the induction of the human P05121 gene expression by insulin in the human hepatoma cell line HepG2 . Enhanced levels of plasminogen activator inhibitor - 1 ( P05121 ) are considered to be a risk factor for pathological conditions associated with hypoxia or hyperinsulinemia . The expression of the P05121 gene is increased by insulin in different cells , although , the molecular mechanisms behind insulin - induced P05121 expression are not fully known yet . Here , we show that insulin upregulates human P05121 gene expression and promoter activity in HepG2 cells and that mutation of the hypoxia - responsive element ( HRE ) - binding hypoxia - inducible factor - 1 ( Q9BYW2 ) abolished the insulin effects . Mutation of E - boxes E4 and O94989 abolished the insulin - dependent activation of the P05121 promoter only under normoxia , but did not affect it under hypoxia . Furthermore , the insulin effect was associated with activation of HIF - 1alpha via mitogen - activated protein kinases ( MAPKs ) but not PDK1 and P31749 in HepG2 cells . Furthermore , mutation of a putative FoxO1 binding site which was supposed to be involved in insulin - dependent P05121 gene expression influenced the insulin - dependent activation only under normoxia . Thus , insulin - dependent P05121 gene expression might be regulated by the action of both Q9BYW2 and FoxO1 transcription factors .", "Initial responses of osteoblasts derived from human alveolar bone to various compressive forces . Mechanical stress generated by orthodontic force is recognized as a major factor in the modulation of alveolar bone remodeling . During this process , osteoblasts play a crucial role , not only by participating in bone formation but also by promoting osteoclastogenesis . The aim of this study was to investigate how continuous compressive force ( CF ) affects human primary osteoblasts ( HOBs ) in terms of cell proliferation , apoptosis , and expression of interleukin - 6 ( P05231 ) and chemokine CXC ligand 8 ( P10145 ) . Human primary osteoblasts , isolated from human mandibular bone pieces , were cultured with or without CF ( 1 - 4 g cm (- 2 ) ) for up to 72 h . Cell viability and proliferation were evaluated using the MTT assay . RT - PCR was used to determine the levels of expression of KI67 ( a proliferation marker ) , Q07812 ( a pro - apoptotic marker ) , P10415 ( an apoptotic inhibitor ) , P05231 , and P10145 mRNAs , while a multiplexed bead immunoassay was used to measure the release of P05231 and P10145 . The results revealed that CF decreased cell viability and proliferation in a time - and force - dependent manner . After applying CF for 24 h , the mRNA expression of KI67 was markedly inhibited , whereas the mRNA expression of Q07812 and P10415 was unaltered . In addition , CF enhanced the levels of P05231 and P10145 mRNAs in a force - dependent manner , whereas the levels of the corresponding proteins were reduced in the compressed HOBs .", "Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK35___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .", "Expression of lung surfactant proteins P07988 and P11686 and their modulating factors in fetal lung of P09769 rats . This study investigated the expression of lung surfactant proteins P07988 and P11686 , and their modulating factors Q15669 - 1 and Q9UPG8 in the fetal lung of rats with fetal growth restriction ( P09769 ) . The rat P09769 model was established by prenatal hypoxia in the first stage of pregnancy , 180 rats for experiment served as hypoxia group , and 197 healthy rats served as normal control group . The P09769 incidence in hypoxia was compared with that in normal control group . The histological changes in the fetal lung were observed under the light microscope and electronic microscope in two groups . The P07988 , P11686 , Q15669 - 1 and Q9UPG8 proteins were determined in the fetal lung of two groups immunohistochemically . The expression levels of P07988 , P11686 , Q15669 - 1 and Q9UPG8 protein and mRNA in the fetal lung of two groups were detected by using Western blotting and RT - PCR respectively . The P09769 rat model was successfully established by using hypoxia . Pathologically the fetal lung developed slowly , and the expression levels of P07988 , P11686 , Q15669 - 1 and Q9UPG8 protein and mRNA in the fetal lung were significantly reduced in hypoxia group as compared with those in normal control group . It was suggested that maternal hypoxia in the first stage of pregnancy could induce P09769 , and reduce the expression of P07988 and P11686 , resulting in the disorder of fetal lung development and maturation .", "Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .", "The potential role of PD0332991 ( ___MASK1___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK1___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .", "Luteinizing Hormone - Releasing Hormone ( P01148 ) - I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo . The objective of this study was to determine the effects of an luteinizing hormone - releasing hormone ( P01148 ) - I antagonist , DB00050 , on human multiple myeloma ( MM ) cells and to elucidate the mechanisms of action . We showed that P01148 - I and P22888 - I genes were expressed in MM cell lines and primary MM cells . Treatment with DB00050 inhibited growth and colony - forming ability of myeloma cells , including cell lines resistant to arsenic trioxide , bortezomib , or lenalidomide . DB00050 induced apoptosis in myeloma cells including primary myeloma cells . In addition , DB00050 inhibited the growth of human myeloma cells xenografted into mice without any apparent side effects . DB00050 downregulated the nuclear factor - kappa B ( NF - κB ) pathway activity and the expression of cytokines , including interleukin 6 , insulin - like growth factor 1 , P15692 , and stromal - derived factor 1 , important for myeloma cell growth and survival in myeloma cells and / or marrow stromal cells from myeloma patients . DB00050 decreased the phosphorylation of extracellular signal regulated kinase 1 / 2 and P40763 in myeloma cells , two crucial pathways for myeloma cells growth and survival . Moreover , the expression of P38936 and p53 was increased , whereas that of antiapoptotic proteins Bcl - 2 and Bcl - x ( L ) was reduced by DB00050 . Our findings indicate that DB00050 induces cytotoxicity in myeloma cells through various mechanisms and provide a rationale for investigating DB00050 for the treatment of MM .", "P40763 regulates proliferation and survival of CD8 + T cells : enhances effector responses to HSV - 1 infection , and inhibits P22301 + regulatory CD8 + T cells in autoimmune uveitis . P40763 regulates P01730 + T cell survival and differentiation . However , its effects on CD8 + T cells are not well understood . Here , we show that in comparison to WT CD8 + T cells , P40763 - deficient CD8 + T cells exhibit a preactivated memory - like phenotype , produce more P60568 , proliferate faster , and are more sensitive to activation - induced cell death ( AICD ) . The enhanced proliferation and sensitivity to AICD correlated with downregulation of class - O forkhead transcription factors ( FoxO1 , FoxO3A ) , P38936 ( waf1 ) , p27 ( P46527 ) , Bcl - 2 , OX - 40 , and upregulation of P48023 , Bax , and Bad . We examined whether P40763 - deficient CD8 + T cells can mount effective response during herpes simplex virus ( HSV - 1 ) infection and experimental autoimmune uveitis ( EAU ) . Compared to WT mice , HSV - 1 - infected P40763 - deficient mice ( STAT3KO ) produced less IFN - γ and virus - specific KLRG - 1 + CD8 + T cells . STAT3KO mice are also resistant to EAU and produced less Q16552 - producing Tc17 cells . Resistance of STAT3KO to EAU correlated with marked expansion of P22301 - producing regulatory CD8 + T cells ( CD8 - Treg ) implicated in recovery from autoimmune encephalomyelitis . Thus , increases of P05231 - induced P40763 activation observed during inflammation may inhibit expansion of CD8 - Tregs , thereby impeding recovery from uveitis . These results suggest that P40763 is a potential therapeutic target for upregulating CD8 + T cell - mediated responses to viruses and suggest the successful therapeutic targeting of P40763 as treatment for uveitis , derived , in part , from promoting CD8 - Treg expansion .", "Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large - scale Genome - Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2 , 047 subjects of European descent ( 1 , 062 cases and 985 controls ) . ___MASK82___ dependence was assessed with multiple smoking measures , including the Fagerström Test for ___MASK82___ Dependence , the Diagnostic and Statistical Manual for Mental Disorders - IV ( DSM - IV ) nicotine dependence , the ___MASK82___ Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single - item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM - V .", "DB11194 dehydrogenase kinase 4 induces bone loss at unloading by promoting osteoclastogenesis . Disuse osteoporosis , which occurs commonly in prolonged bed rest and immobilization , is becoming a major problem in modern societies ; however , the molecular mechanisms underlying unloading - driven bone loss have not been fully elucidated . The osteocyte network is considered to be an ideal mechanosensor and mechanotransduction system . We searched for the molecules responsible for disuse osteoporosis using P10415 transgenic mice , in which the osteocyte network was disrupted . DB11194 dehydrogenase kinase 4 ( Pdk4 ) , which inactivates pyruvate dehydrogenase complex ( P20941 ) , was upregulated in femurs and tibiae of wild - type mice but not of P10415 transgenic mice after tail suspension . Bone in Pdk4 (-/-) mice developed normally and was maintained . At unloading , however , bone mass was reduced due to enhanced osteoclastogenesis and Rankl expression in wild - type mice but not in Pdk4 (-/-) mice . Osteoclast differentiation of Pdk4 (-/-) bone marrow - derived monocyte / macrophage lineage cells ( BMMs ) in the presence of P09603 and O14788 was suppressed , and osteoclastogenesis was impaired in the coculture of wild - type BMMs and Pdk4 (-/-) osteoblasts , in which Rankl expression and promoter activity were reduced . Further , introduction of Pdk4 into Pdk4 (-/-) BMMs and osteoblasts enhanced osteoclastogenesis and Rankl expression and activated Rankl promoter . These findings indicate that Pdk4 plays an important role in bone loss at unloading by promoting osteoclastogenesis .", "P35354 induction and prostaglandin E2 accumulation in squamous cell carcinoma as a consequence of epidermal growth factor receptor activation by imatinib mesylate . Imatinib mesylate is a novel anti - tumor agent useful in the clinical management of chronic myelogenous leukemia and gastrointestinal stromal tumors with minimal toxicity relative to other forms of cancer therapy . Its clinical activity and minimal toxicity are related to specific inhibition of cellular targets including P11274 - P00519 , platelet - derived growth factor receptor and c - kit kinases , resulting in the collapse of downstream signaling cascades important for transformation . In some patients , unexpected toxicities arise that are not associated with inhibition of any known cellular imatinib target . In this report , we investigated the effects of imatinib on squamous carcinoma cell signaling . Imatinib induced expression of P35354 in a dose - dependent manner with concomitant accumulation of prostaglandin E2 . P35354 induction by imatinib was initiated through epidermal growth factor ( P01133 ) receptor kinase activation and downstream signaling through mitogenic - activated protein kinase . P35354 induction by imatinib was blocked by Q02750 or P01133 receptor inhibition . Imatinib did not activate stressor cytokine - signaling pathways ( p38 kinase , nuclear factor - kB nuclear translocation ) or affect P23219 expression . Imatinib failed to activate P01133 receptor signals in other tumor types , suggesting that P35354 induction in imatinib - treated cells is mediated through release of autocrine factors expressed or activated in squamous tumors . P35354 induction by imatinib in squamous tumors derived from the head and neck region is unique with respect to other target - specific agents and may represent one of the unintended toxic effects of imatinib described in some patients .", "___MASK1___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK1___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .", "Prevention of neuron and oligodendrocyte degeneration by interleukin - 6 ( P05231 ) and P05231 receptor / P05231 fusion protein in organotypic hippocampal slices . We investigated the effects of P05231 and a chimeric derivative of P05231 and soluble P05231 receptor ( IL6RIL6 chimera ) on excitotoxic injury in rat organotypic hippocampal slices . Brief application of N - methyl - d - aspartate ( DB01221 ) induced astrocyte reactivity , neuron cell death , and oligodendrocyte degeneration , the latter caused by secondary activation of AMPA / kainate receptors . Both these cytokines rescued neurons and oligodendrocytes , albeit the chimeric compound was much more potent and efficient than P05231 . No change was produced on reactive astrocytosis . The cytokines preserved myelin basic protein ( MBP ) production in slices exposed to excitotoxic insult , and when applied singularly for a week , they also enhanced both MBP and proteolipid protein expression . These effects occurred through activating the signal transducer P40189 and were associated with stimulation of transcription factors P42224 and P40763 . Our results suggest that P05231 and IL6RIL6 may prove to be valuable in treating neurodegenerative and demyelinating diseases .", "Complementation by P10415 and C - HA - DB01367 oncogenes in malignant transformation of rat embryo fibroblasts . The P10415 ( B cell lymphoma / leukemia - 2 ) and C - HA - DB01367 oncogenes encode membrane - associated proteins of 26 and 21 kilodaltons , respectively . Although DB01367 proteins have long been known for their ability to bind and hydrolyze GTP , recent investigations suggest that P10415 encodes a novel GTP - binding protein ( S . Haldar , C . Beatty , Y . Tsujimoto , and C . M . Croce , Nature [ London ] 342 : 195 - 198 , 1989 ) . Cotransfection of P10415 and HA - DB01367 oncogenes resulted in morphological transformation of early - passage rodent fibroblasts , rendering these cells tumorigenic in animals and enabling them to grow in semisolid medium . In contrast , cotransfection of P10415 with oncogenes that encode nuclear proteins ( E1A and C - MYC ) did not produce malignant transformation , whereas HA - DB01367 did complement with these genes . These findings suggest that proteins encoded by oncogenes such as P10415 and HA - DB01367 , although having similar subcellular locations and perhaps similar biochemical properties , can regulate distinct complementary pathways involved in cellular transformation .", "Transformed 3T3 cells have reduced levels and altered subcellular distribution of the major PKC substrate protein P29966 . The P29966 ( myristylated alanine - rich C - kinase substrate ) protein is an abundant calmodulin - binding protein that is a major and specific endogenous substrate of protein kinase C ( PKC ) . Stimulation of cells with phorbol esters or other activators of PKC has been shown previously to result in rapid phosphorylation of P29966 proteins and redistribution of these myristylated C - kinase substrates from membrane to cytosol . Here we show that NIH3T3 murine fibroblasts transformed by P38936 - HA - C - DB01367 or pp60 - V - P12931 oncoproteins have markedly reduced levels of p68 - P29966 and that most of the remaining P29966 protein is found in the cytosol . 3T3 cells containing a nontransforming oncoprotein Q9Y3Q3 - P10415 , in contrast , exhibited normal levels and distribution of p68 - P29966 . When taken together with recent evidence that P29966 proteins are involved in regulating organization of the membrane cytoskeleton , our findings suggest that oncoprotein - mediated alterations in P29966 protein levels and subcellular distribution may contribute to the development or maintenance of the transformed phenotype .", "Q16552 stimulates the production of inflammatory mediators via Erk1 / 2 , p38 MAPK , PI3K / Akt , and NF - κB pathways in ARPE - 19 cells . PURPOSE : To investigate the signaling pathways involved in interleukin ( IL ) - 17A - mediated production of interleukin 8 ( P10145 ) , chemokine ( C - C motif ) ligand 2 ( P13500 ) , and interleukin 6 ( P05231 ) by ARPE - 19 cells , a spontaneously arisen cell line of retinal pigment epithelium ( Q96AT9 ) . METHODS : Flow cytometry analysis and western blot were used to detect the phosphorylation of extracellular signal - regulated kinases 1 / 2 ( Erk1 / 2 ) , p38 mitogen activated protein kinase ( MAPK ) and protein kinase B ( P31749 ; Akt ) in ARPE - 19 cells stimulated with Q16552 . These cells were further pretreated with a series of kinase inhibitors and followed by incubation with Q16552 . P10145 , P13500 , and P05231 in the supernatant were quantified by enzyme - linked immunosorbent assay ( ELISA ) . RESULTS : Coculture of ARPE - 19 cells with Q16552 resulted in significant increases in Erk1 / 2 , p38 MAPK , and Akt phosphorylation . Inhibition of p38MAPK , phosphoinositide 3 - kinase ( PI3K ) - Akt and nuclear factor - kappaB ( NF - κB ) , with the inhibitors SB203580 , LY294002 and pyrrolydine dithiocarbamate ( PDTC ) respectively , reduced Q16552 ( 100 ng / ml ) mediated production of P10145 , P13500 , and P05231 in a concentration dependent manner . Inhibition of Erk1 / 2 with PD98059 decreased the expression of the tested three inflammatory mediators when using low doses of Q16552 ( 0 - 10 ng / ml ) but not at higher concentrations . CONCLUSIONS : Q16552 - induced production of inflammatory mediators by ARPE - 19 cells involves Erk1 / 2 , p38MAPK , PI3K - Akt and NF - κB pathways .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "Unbiased screen for interactors of leucine - rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease . Mutations in leucine - rich repeat kinase 2 ( Q5S007 ) cause inherited Parkinson disease ( PD ) , and common variants around Q5S007 are a risk factor for sporadic PD . Using protein - protein interaction arrays , we identified P10415 - associated athanogene 5 , Rab7L1 ( P51149 , member DB01367 oncogene family - like 1 ) , and O14976 as binding partners of Q5S007 . The latter two genes are candidate genes for risk for sporadic PD identified by genome - wide association studies . These proteins form a complex that promotes clearance of Golgi - derived vesicles through the autophagy - lysosome system both in vitro and in vivo . We propose that three different genes for PD have a common biological function . More generally , data integration from multiple unbiased screens can provide insight into human disease mechanisms .", "Splenic marginal zone lymphoma : proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis . Splenic marginal zone lymphoma ( SMZL ) is a newly recognized lymphoma type whose precise molecular pathogenesis is still essentially unknown . This hampers differential diagnosis with other small B - cell malignancies . With the aim of characterizing this tumor more comprehensively , and of identifying new diagnostic and prognostic markers , we performed cDNA microarray expression profiling and tissue microarray ( TMA ) immunohistochemical studies in a relatively large series of 44 SMZLs . The results were related to immunoglobulin heavy chain variable region ( IgV ( H ) ) mutational status and clinical outcome . SMZLs display a largely homogenous signature , implying the existence of a single molecular entity . Of the genes deregulated in SMZLs , special mention may be made of the genes involved in B - cell receptor ( P11274 ) signaling , tumor necrosis factor ( P01375 ) signaling and nuclear factor - kappaB ( NF - kappaB ) activation , such as P43405 , Q06187 , Q13489 , Q13114 , and Q06643 . Other genes observed were P14151 and O60711 , which were highly expressed in spleen , and lymphoma oncogenes , such as Q15669 and TCL1 . In contrast , the genes Q03135 , P51636 , and P61952 located in 7q31 , a commonly deleted area , were down - regulated in the entire series . A comparison with the genes comprising the signature of other small B - cell lymphomas identified 3 genes whose expression distinguishes SMZL , namely Q01167 , SENATAXIN , and P25942 . Shorter survival was associated with P28907 expression , naive IgV ( H ) genes , and the expression of a set of NF - kappaB pathway genes , including O00463 , Q04864 , and P17252 .", "Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK35___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .", "Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK22___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .", "Inhibitory effects of a luteinizing hormone - releasing hormone agonist on basal and epidermal growth factor - induced cell proliferation and metastasis - associated properties in human epidermoid carcinoma A431 cells . The purpose of this study was to investigate the effects of a potent P01148 agonist , [ D - DB00150 ( 6 )] P01148 on the basal and P01133 - induced cell proliferation and the metastasis - associated properties in A431 human epidermoid carcinoma . [ D - DB00150 ( 6 )] P01148 time - dependently inhibited the basal and P01133 - stimulated growth of A431 cancer cells . It is assumed that phosphorylation / dephosphorylation of cellular proteins is highly related to cell growth . This study demonstrates that [ D - DB00150 ( 6 )] P01148 decreased the basal and P01133 - induced total cellular kinase activity , particularly the tyrosine phosphorylation of several cellular proteins including the P00533 . In contrast , [ D - DB00150 ( 6 )] P01148 did not cause detectable changes in basal and P01133 - stimulated serine / threonine phosphorylation of A431 cellular proteins . The inhibitory effect of [ D - DB00150 ( 6 )] P01148 on A431 cell proliferation was associated with apoptosis as evidenced by the cell morphology and DNA integrity ( ladder pattern ) , the expression of interleukin 1beta - converting enzyme ( ICE ) and activation of caspase . Furthermore , P01133 could rescue the remaining attached A431 cells following [ D - DB00150 ( 6 )] P01148 treatment for 48 hr , which suggests that limited exposure to [ D - DB00150 ( 6 )] P01148 did not channel all cells to irreversible apoptotic process . We also determined the effects of [ D - DB00150 ( 6 )] P01148 on metastasis - associated properties in A431 cells . [ D - DB00150 ( 6 )] P01148 reduced both basal and P01133 - stimulated secretion of P14780 and P08253 . In addition , [ D - DB00150 ( 6 )] P01148 suppressed the basal and P01133 - induced invasive activity of A431 cells based on an in vitro invasion assay . In conclusion , this study indicates that [ D - DB00150 ( 6 )] P01148 may act partly through activating tyrosine phosphatase activity to inhibit cell proliferation and the metastasis - associated properties of A431 cancer cells . Our work suggests that [ D - DB00150 ( 6 )] P01148 may be therapeutically useful in limiting the tumor growth and metastasis of some neoplasms .", "Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes : evidence for in situ t - cell activation and therapeutic efficacy . After adoptive transfer of pre - activated lymphocytes into the operation cavity of glioma patients , tumor regression and improved survival have been reported in some patients . Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied . In this study , we attempted to avoid time - consuming pre - activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the P01133 receptor ( P00533 ) on tumor cells and to CD3 and P10747 on T cells . Eleven patients with high - grade malignant glioma received 3 injections of 2 bispecific antibody fragments ( P00533 x CD3 and P00533 x P10747 ) together with freshly isolated autologous lymphocytes via an Ommaya reservoir . Intracavitary fluid aspirated during immunotherapy was examined for markers of T - cell activation . Increased levels of soluble P60568 receptor and P01375 were detected in the intracavitary fluid of all patients tested . Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent Q9BWK5 scans and prolonged survival . Side effects were transient and consisted of fever , nausea , headache and aggravation of pre - existing neurologic deficits . These adverse effects were most likely due to the antibody construct containing anti - CD3 specificity . Two patients developed cerebral edema and required steroid treatment .", "Gene clustering analysis in human osteoporosis disease and modifications of the jawbone . OBJECTIVE : An analysis of the genes involved in both osteoporosis and modifications of the jawbone , through text mining , using a web search tool , of information regarding gene / protein interaction . DESIGN : The final set of genes involved in the present phenomenon was obtained by expansion - filtering loop . Using a web - available software ( STRING ) , interactions among all genes were searched for , and a clustering procedure was performed in which only high - confidence predicted associations were considered . RESULTS : Two hundred forty - two genes potentially involved in osteoporosis and in modifications of the jawbone were recorded . Seven \" leader genes \" were identified ( P35222 , P01584 , P05231 , P05412 , Q13950 , P10451 , P01137 ) , while another 10 genes formed the cluster B group ( P12643 , P18075 , P02452 , P05362 , IGF1 , P22301 , P14780 , P19838 , O14788 , P15692 ) . Ninety - eight genes had no interactions , and were defined as \" orphan genes \" . CONCLUSIONS : The expansion of knowledge regarding the molecular basis causing osteoporotic traits has been brought about with the help of a de novo identification , based on the data mining of genes involved in osteoporosis and in modification of the jawbone . A comparison of the present data , in which no role was verified for 98 genes that had been previously supposed to have a role , with that of the literature , in which another 81 genes , as obtained from GWAS reviews and meta - analyses , appeared to be strongly associated with osteoporosis , probably attests to a lack of information on osteoporotic disease .", "Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen - induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( ___MASK30___ ) - induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 - Px , MDA , NO and P35228 , and the activities of serum ALT and Q9NRA2 caused by ___MASK30___ . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT - mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 ) , pro - inflammatory mediators ( IL - 1β , P05112 , P05231 , P01375 - α , P35228 , Bax , HMGB - 1 and P35354 ) , pro - inflammatory transcription factors ( NF - κB and AP - 1 ) , pro - apoptotic proteins ( cytochrome C , p53 , caspase - 3 , caspase - 9 , p - JNK , p - p38 and p - P29323 ) , and increased the protein expressions of Bcl - 2 and Bcl - xL . Moreover , the gene expression of P22301 , and the proteins including LC3 , Q14457 and Atg5 induced by ___MASK30___ were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat ___MASK30___ - induced liver damage in the future .", "Connexin 43 and P29323 regulate tension - induced signal transduction in human periodontal ligament fibroblasts . Periodontal ligament ( PDL ) fibroblasts play an important role in preserving periodontal homeostasis and transmitting mechanical signals to alveolar bone . Connexin 43 ( P17302 ) , a gap junction protein , is essential for bone homeostasis and regulates bone remodeling . However , the function of P17302 in human PDL fibroblast - regulated bone remodeling has not yet been elucidated . In this study , human PDL fibroblasts were exposed to cyclic mechanical tension with a maximum 5 % elongation for different durations . We then examined the expression of signaling molecules related to osteogenesis and osteoclastogenesis at both the mRNA and protein levels as well as the activity of extracellular signal - regulated kinase ( P29323 ) in human PDL fibroblasts after loading . We found that mechanical tension increased P17302 , which further upregulated osteogenic ( e . g . , Q13950 , Osterix , and O00300 ) and down - regulated osteoclastogenic ( e . g . , O14788 ) signaling molecules . Suppressing P17302 gene ( Gja1 ) by siRNA inhibited the increase in osteogenesis - related molecules but enhanced O14788 expression . Similar to P17302 , activated P27361 / 2 was also enhanced by mechanical tension and suppressed by P17302 siRNA . Inhibition of P27361 / 2 signaling using PD98059 reduced the tension - regulated increase in osteogenesis - related molecules but enhanced that of osteoclastogenesis - related ones . These findings suggest that cyclic tension may involve into the osteogenic or osteoclastogenetic differentiation potential of human PDL fibroblasts via the P17302 - P27361 / 2 signaling pathway .", "Simultaneous inhibition of MEK and P11802 leads to potent apoptosis in human melanoma cells . ABSTRACT Deregulation of DB01367 - RAF - MEK - P29323 and P42771 - cycylin D : P11802 / 6 - RB pathways is important for melanoma development . Chemotherapeutic agents targeting both pathways were developed but results of clinical studies with monotherapies were disappointing . We examined the effect of co - targeting both pathways with MEK inhibitor PD98059 and P11802 inhibitor 219476 on human melanoma cells lines , and found that combinatorial treatment dramatically increased apoptosis compared to the single agent treatment . The apoptosis was associated with downregulation of P10415 , Q07817 , O15392 , and upregulation of O43521 . Our results indicate that simultaneously targeting P29323 and RB pathways is a promising strategy for melanoma treatment and should encourage further in - depth investigations .", "P00533 regulates osteoclast differentiation and survival through cross - talking with Q9Y6Q6 signaling . The epidermal growth factor receptor ( P00533 ) functions in various cellular physiological processes such as proliferation , differentiation , and motility . Although recent studies have reported that P00533 signaling is involved in osteoclast recruitment and formation , the molecular mechanism of P00533 signaling for the regulation of osteoclastogenesis remains unclear . We investigated the role of the P00533 in osteoclast differentiation and survival and show that the expression of the P00533 was highly up - regulated by receptor activator of nuclear factor - kappaB ligand ( O14788 ) during osteoclast differentiation . P00533 - specific tyrosine kinase inhibitors and P00533 knockdown blocked O14788 - dependent osteoclast formation , suggesting that P00533 signaling plays an important role in osteoclastogenesis . P00533 inhibition impaired the O14788 - mediated activation of osteoclastogenic signaling pathways , including c - Jun N - terminal kinase ( JNK ) , NF - kappaB , and Akt / protein kinase B ( P31749 ) . In addition , P00533 inhibition in differentiated osteoclasts caused apoptosis through caspase activation . Inhibition of the phosphoinositide - 3 kinase ( PI3K ) - Akt / P31749 pathway and subsequent activation of Q92934 and caspases - 9 and - 3 may be responsible for the P00533 inhibition - induced apoptosis . The P00533 physically associated with receptor activator of nuclear factor - kappaB ( Q9Y6Q6 ) and Grb2 - associated binder 2 ( Gab2 ) . Moreover , O14788 transactivated P00533 . These data indicate that P00533 regulates O14788 - activated signaling pathways by cross - talking with Q9Y6Q6 , suggesting that the P00533 may play a crucial role as a Q9Y6Q6 downstream signal and / or a novel type of Q9Y6Q6 co - receptor in osteoclast differentiation and survival .", "Tumor - targeted responsive nanoparticle - based systems for magnetic resonance imaging and therapy . PURPOSE : Design and synthesis of a tumor responsive nanoparticle - based system for imaging and treatment of various cancers . METHODS : DB06757 oxide nanoparticles ( Mn3O4 NPs ) were synthesized and modified with P01148 targeting peptide or anti - melanoma antibodies ( cancer targeting moieties ) and a P08253 cleavable peptide ( a possible chemotactic factor ) . Nanostructured lipid carriers ( NLCs ) were used to entrap the P15056 inhibitor , vemurafenib , and enhance cytotoxicity of the drug . Size distribution , stability , drug entrapment , cytotoxicity and genotoxicity of synthesized nanoparticles were studied in vitro . Enhancement of Q9BWK5 signal by nanoparticles and their body distribution were examined in vivo on mouse models of melanoma , ovarian and lung cancers . RESULTS : Uniform , stable cancer - targeted nanoparticles ( PEGylated water - soluble Mn3O4 NPs and NLCs ) were synthesized . No signs of cyto -, genotoxicity and DNA damage were detected for nanoparticles that do not contain an anticancer drug . Entrapment of vemurafenib into nanoparticles significantly enhanced drug toxicity in cancer cells with targeted V600E mutation . The developed nanoparticles containing P01148 and P08253 peptides showed preferential accumulation in primary and metastatic tumors increasing the Q9BWK5 signal in mice with melanoma , lung and ovarian cancers . CONCLUSIONS : The proposed nanoparticle - based systems provide the foundation for building an integrated Q9BWK5 diagnostic and therapeutic approach for various types of cancer .", "Use of an array technology for profiling and comparing transcription factors activated by TNFalpha and PMA in HeLa cells . Multiple signal transduction pathways are generally triggered simultaneously by a single extracellular stimulus . As a result , multiple transcription factors ( TFs ) can be activated downstream to mediate the inducible expression of target genes . Profiling the activation of all TFs will aid in the dissection of the numerous pathways of signal transduction . P01375 alpha ( TNFalpha ) and phorbol 12 - myristate 13 - acetate ( PMA ) mediate many biological functions , including cell proliferation and apoptosis , by stimulating signaling pathways . Two TFs , nuclear factor kappaB ( NFkappaB ) and activating factor 1 ( P05412 ) , have been identified as targets of both TNFalpha and PMA activation . Here , we describe the use of a protein / DNA array system to identify additional TFs activated by TNFalpha and PMA in HeLa cells . From a total of 150 targeted TFs , six - CREB , E2F , P11597 / CRE , c - Rel , MSP1 , and Pax6 - were identified whose activities , like NFkappaB and P05412 , were regulated by both TNFalpha - and PMA - induced pathways . Interestingly , the TF E47 was shown to be specifically activated by TNFalpha but was not affected by treatment with PMA . In addition , GATA , P25490 , and ISRE were shown to be specifically activated by PMA but not TNFalpha . These findings suggest that TNFalpha and PMA both stimulate unique signaling pathways while mediating transcriptional activation through common pathways .", "P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK59___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK59___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .", "Leptomeningeal carcinomatosis as initial presentation in adenocarcinoma of lung with signet ring cell features : an autopsy case report . Signet ring cell ( P12931 ) features are rare but well - recognized cytological changes of pulmonary adenocarcinoma ( PA ) . PA with P12931 features ( PA - P12931 ) is frequently associated with anaplastic lymphoma kinase ( Q9UM73 ) gene rearrangement , and recognition of PA - P12931 may be important for the administration of targeted treatment . To the authors ' knowledge , leptomeningeal carcinomatosis ( O15467 ) as an initial presentation of PA - P12931 has not yet been reported . We report an autopsy case from a 59 - year - old female who presented with intractable headache for 6 weeks and died of O15467 as a result of metastatic PA - P12931 . Premortem brain Q9BWK5 showed nonspecific leptomeningeal enhancement . At autopsy , a tan rubbery mass was found in the hilar area of the right lung , which also surrounded the lower trachea and carotid arteries . A right posteromedial middle lobe mass was also found . Leptomeninges were slightly thickened , without discrete masses . Microscopic examination of the lung mass and leptomeninges showed solid sheets and nests of malignant cells with pleomorphic nuclei and frequent P12931 features which comprised 50 % of the mass . Immunohistochemically , the tumor cells demonstrated strong diffuse expression of cytokeratin ( CK ) - 7 , Q15669 - 1 , and napsin - A . Immunostains for P35900 and Q9UM73 were negative . These features were consistent with PA - P12931 . It has been reported that approximately 70 % of PAs demonstrate Q9UM73 gene rearrangement when SRCs comprised > 10 % of the tumor cells . The presence of SRCs can be indicative of a lung primary and , because of frequent Q9UM73 gene rearrangement in PA - P12931 , proper recognition of PA - P12931 may be important in determining whether further testing is advisable ( e . g . , Q9UM73 immunostaining and / or Q9UM73 gene rearrangement ) .", "Membrane attack by complement : the assembly and biology of terminal complement complexes . Complement system activation plays an important role in both innate and acquired immunity . Activation of the complement and the subsequent formation of C5b - 9 channels ( the membrane attack complex ) on the cell membranes lead to cell death . However , when the number of channels assembled on the surface of nucleated cells is limited , sublytic C5b - 9 can induce cell cycle progression by activating signal transduction pathways and transcription factors and inhibiting apoptosis . This induction by C5b - 9 is dependent upon the activation of the phosphatidylinositol 3 - kinase / Akt / Q12778 and P27361 pathways in a Gi protein - dependent manner . C5b - 9 induces sequential activation of P11802 and P24941 , enabling the P55008 / S - phase transition and cellular proliferation . In addition , it induces Q9H4X1 , a novel gene that plays a role in cell cycle activation by interacting with Akt and the cyclin B1 - P06493 complex . C5b - 9 also inhibits apoptosis by inducing the phosphorylation of Bad and blocking the activation of FLIP , caspase - 8 , and Bid cleavage . Thus , sublytic C5b - 9 plays an important role in cell activation , proliferation , and differentiation , thereby contributing to the maintenance of cell and tissue homeostasis .", "Traps to catch unwary oncogenes . The MYC proto - oncogene has long been implicated in the control of normal cell growth and its deregulation is associated with the development of neoplasia . The MYC protein has a well - established role as a component of signal - transduction pathways promoting both proliferation and apoptosis . Because signalling pathways that drive cell death and cell proliferation are so tightly coupled , a synergy between genetic lesions leading to suppression of cell death and those promoting cell proliferation is observed during carcinogenesis . We discuss such synergy with respect to the cooperating oncogenes MYC , DB01367 and P10415 .", "___MASK85___ for joints and bones . ___MASK85___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK85___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK85___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .", "Cooperative Hedgehog - P00533 signaling . It has been known for many years that cooperative interactions between oncogenes ( e . g . DB01367 , MYC , P10415 ) can fuel cancer growth ( 1 - 5 ) , but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy . The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy . Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog / P08151 and Epidermal Growth Factor Receptor ( P00533 ) signaling , two clinically relevant oncogenic pathways involved in the development of many human malignancies . We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways .", "Epigenetics of multiple myeloma after treatment with cytostatics and gamma radiation . Genetic and epigenetic changes in multiple myeloma ( MM ) correlate with the stage of the disease . Therefore , we investigated how cytostatics and gamma radiation influence MM - associated histone modifications . ChIP - PCR and ChIP - on - chip technologies were used to quantify H3K9 acetylation and H3K9 dimethylation at select loci in MM patients , lymphoblastoid Q5SW96 - 77 , and myeloma MOLP - 8 cells . Genome - wide analysis revealed that the cytostatic , melphalan , increased H3K9 acetylation at multiple gene promoters in Q5SW96 - 77 cells . DB01042 and gamma radiation also influenced histone modification of prognostically important c - myc and P24385 genes in Q5SW96 - 77 and MOLP - 8 cells . Moreover , H3K9 acetylation at c - myc and P24385 promoters was increased in individual MM patients after melphalan treatment . Western blotting revealed that these effects were accompanied by changes in c - MYC and cyclin D1 protein levels . Taken together , we showed that cytostatics significantly alter histone modification of tumor - related genes which is indispensable for understanding cancer therapies .", "Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .", "___MASK82___ activates P46937 through nAChRs mediated signaling in esophageal squamous cell cancer ( ESCC ) . Cigarette smoking is an established risk factor for esophageal cancers . P46937 ( P46937 ) , the key transcription factor of the mammalian Hippo pathway , has been reported to be an oncogenic factor for many cancers . In this study , we find nicotine administration can induce nuclear translocation and activation of P46937 in ESCC . Consistently , we observed nuclear translocation and activation of P46937 by knockdown of P32297 , which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells . ___MASK82___ administration or P32297 depletion substantially increased proliferation and migration in esophageal cancer cells . Interestingly , we find that P46937 physically interacts with nAChRs , and nAChRs - signaling dissociates P46937 from its negative regulatory complex composed with α - catenin , β - catenin and 14 - 3 - 3 in the cytoplasm , leading to upregulation and nuclear translocation of P46937 . This process likely requires PKC activation , as PKC specific inhibitor Enzastaurin can block nicotine induced P46937 activation . In addition , we find nicotine signaling also inhibits the interaction of P46937 with Q9H3D4 , which contributes to the inhibitory effect of nicotine on apoptosis . Using immunohistochemistry analysis we observed upregulation of P46937 in a significant portion of esophageal cancer samples . Consistently , we have found a significant association between P46937 upregulation and cigarette smoking in the clinical esophageal cancer samples . Together , these findings suggest that the nicotine activated nAChRs signaling pathway which further activates P46937 plays an important role in the development of esophageal cancer , and this mechanism may be of a general significance for the carcinogenesis of smoking related cancers .", "Induction of apoptosis by a dominant negative H - DB01367 mutant ( 116Y ) in K562 cells . Recent extensive work on apoptosis has begun to reveal its molecular mechanisms . Several genes that regulate apoptosis have been identified . Among them , the P10415 gene is considered to be an important gene that inhibits apoptosis . However , there must be other genes , yet to be identified , which suppress apoptosis . It has been suggested that the activation of DB01367 function by P11274 - P00519 fusion protein in chronic myelogenous leukemia may be an important mechanism in the P11274 - P00519 mediated transformation . Therefore , in this study we have investigated whether the suppression of endogenous H - DB01367 function inhibits the P11274 - P00519 mediated transforming activity in a K562 human chronic myelogenous leukemia cell line . The induced expression of a dominant negative v - H - DB01367 mutant ( 116Y ) in K562 cells has resulted in cell death . The morphological characteristics and the detection of fragmented DNA by gel electrophoresis in the dead cells have revealed that this cell death is apoptosis . These results directly indicate that the DB01367 gene as well as the P10415 gene has an ability to suppress apoptosis ." ]

[ "___MASK1___", "___MASK22___", "___MASK30___", "___MASK35___", "___MASK50___", "___MASK59___", "___MASK78___", "___MASK82___", "___MASK85___" ]

[ "Identification of the fused bicyclic 4 - amino - 2 - phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2 - Phenyl - 4 - piperidinyl - 6 , 7 - dihydrothieno [ 3 , 4 - d ] pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50 = 150 nM ) . A number of derivatives with a variety of 4 - amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5 , 5 - dioxo - 7 , 8 - dihydro - 6H - thiopyrano [ 3 , 2 - d ] pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50 = 25 nM ) . Finally , N - propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50 = 7 . 5 nM ) and P01375 - α production in mouse splenocytes ( IC50 = 9 . 8 nM ) and showed good in vivo anti - inflammatory activity in the LPS - induced lung inflammation model in mice ( ID50 = 18 mg / kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X - ray crystal structure of the ligand - enzyme complex .", "Golimumab : in the treatment of rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis . Golimumab is a human anti - tumor necrosis factor ( P01375 ) monoclonal antibody that acts principally by targeting and neutralizing P01375 to prevent inflammation and destruction of cartilage and bone . Large , randomized , double - blind trials in patients with rheumatoid arthritis who were methotrexate - naïve ( GO - BEFORE ) or - experienced ( GO - FORWARD ) have shown that DB06674 50 or 100 mg every 4 weeks , in combination with methotrexate , was more effective than methotrexate alone for improving signs and symptoms of arthritis at weeks 14 and / or 24 , according to American College of Rheumatology ( P10323 ) criteria . In patients with active rheumatoid arthritis despite previous treatment with anti - P01375 agents ( GO - AFTER ) , DB06674 50 or 100 mg every 4 weeks was more effective than placebo for improving P10323 responses at weeks 14 and 24 ; most patients in the study received concomitant methotrexate . In patients with psoriatic arthritis in the GO - REVEAL study , significantly more DB06674 than placebo recipients achieved a > or = 20 % improvement in P10323 criteria at week 14 . Golimumab was also superior to placebo for improving the signs and symptoms of ankylosing spondylitis in the GO - RAISE study ; significantly more DB06674 than placebo recipients achieved a > or = 20 % improvement in the Assessment in Ankylosing Spondylitis ( ASAS ) criteria at week 14 . In the five phase III trials in patients with rheumatoid arthritis , psoriatic arthritis , or ankylosing spondylitis , there was no clear evidence of improved P10323 or ASAS responses with the 100 mg dosage compared with the 50 mg dosage of DB06674 . The tolerability profile of DB06674 was generally consistent with that of other anti - P01375 agents .", "Emerging drugs for the treatment of axial and peripheral spondyloarthritis . INTRODUCTION : The topic under discussion is of strong relevance to the field of spondyloarthritis ( SpA ) because , in addition to established biological , there are new promising compounds . The reason for the review is to put all available data together to allow for an overview on recent developments and to especially inform readers about emerging drugs , biologics and small molecules in the field of SpA . AREAS COVERED : This review on new therapies in axial and peripheral SpA comprising psoriatic arthritis ( PsA ) shows , that , in addition to the established anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , certolizumab and the first biosimilar approved in the EU , there are at least two emerging biologics in the field of SpA : ustekinumab , a compound targeting IL12 / IL - 23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn ' s disease , and the anti - Q16552 antibody secukinumab which has also been shown to work in psoriasis , both compounds seem to also work in ankylosing spondylitis . In addition , the potential of two small molecules , apremilast a phoshodiesterase4 inhibitor and tofacitinib , a januskinase inhibitor is discussed . EXPERT OPINION : Since , in contrast to rheumatoid arthritis , the therapeutic array in SpA is currently limited to P01375 - blockers , and since there is still an unmet need because some patients do not respond to anti - P01375 therapy at all or they loose response , new agents with a different mechanism of action are eagerly awaited .", "Current evidence in the field of the management with P01375 - α inhibitors in psoriatic arthritis and concomitant hepatitis C virus infection . INTRODUCTION : Psoriatic arthritis ( PsA ) is a chronic inflammatory condition involving the spine , enthesis and peripheral joints , which is associated with psoriasis . PsA therapy varies from use of NSAIDs to disease - modifying anti - rheumatic agents ( DMARDs ) . However , their use can represent a limitation in patients with concomitant hepatitis C virus ( HCV ) infection . In the last few decades , anti - P01375 - α therapy has opened new horizons in the treatment of PsA . Hence , the purpose of this review is to explore the efficacy and safety of anti - P01375 - α agents in PsA and concomitant HCV infection . AREAS COVERED : We reviewed the available medical literature to find all cases of PsA and concomitant HCV infection treated with P01375 - α inhibitors . We found a total of 38 cases of patients with PsA and concomitant HCV infection in therapy with anti - P01375 - α agents . EXPERT OPINION : The available literature , summarized in this review , still remains very limited . Data suggest that therapy with the anti - P01375 - α agents , mainly etanercept and adalimumab , at least with short - term use , would appear efficacious and reasonably safe in the management of PsA patients with concomitant HCV infection . With regard to infliximab , efficacy and safety have been scarcely explored , whereas in the case of DB06674 and certolizumab no report was found , may be due to their recent introduction on the market .", "___MASK96___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK96___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .", "Role of DB06674 , a P01375 inhibitor , in the treatment of the psoriatic arthritis . Psoriatic arthritis ( PsA ) is an inflammatory arthritis that affects many psoriasis patients and can often have a debilitating disease progression . Golimumab is a new tumor necrosis factor ( P01375 ) antagonist recently approved by the FDA for controlling signs and symptoms of psoriatic arthritis . In a Phase III clinical trial in patients with PsA , patients receiving DB06674 showed significant improvement in the signs and symptoms of disease . It was usually well tolerated , but adverse events generally occurred more in patients receiving DB06674 compared to placebo . Golimumab has also recently shown efficacy in slowing structural damage in PsA . This new biologic therapy provides physicians with another option in the treatment of this inflammatory arthritis while offering patients certain advantages over other P01375 antagonists .", "Behçet disease - associated uveitis successfully treated with DB06674 . Over the past decade , the off - label use of biologic agents such as P01375 - α antagonists , including infliximab and adalimumab , has improved the treatment armamentarium for refractory immune - mediated uveitis , with particular success in Behçet disease - associated uveitis . Golimumab is a novel fully human anti - P01375 - α monoclonal antibody that has been approved for the treatment of rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis , with very promising results . Herein , the authors present the use of GLM in a case of Behçet uveitis refractory to other P01375 - α blockers . There are only two reports in the literature about the use of GLM in uveitis , describing four patients with JIA - associated uveitis and a case of idiopathic retinal vasculitis . To the authors ' knowledge , this is the first report about the use of GLM in Behçet uveitis .", "Bilateral optic neuropathy associated with the tumor necrosis factor - alpha inhibitor DB06674 . A 62 - year - old man developed bilateral blurred vision associated with bilateral optic disc swelling shortly after receiving his third dose of the tumor necrosis factor - alpha ( P01375 - α ) inhibitor DB06674 , that he took for psoriatic arthritis . An extensive assessment including magnetic resonance imaging , lumbar puncture , and serologies was negative . He was treated with systemic corticosteroids and the DB06674 was stopped , after which his vision improved and his disc swelling resolved . We postulate that the bilateral , simultaneous anterior optic neuropathies in this patient were due to DB06674 , representing a rare but well - documented serious adverse event associated with P01375 - α inhibitors .", "Golimumab in uveitis previously treated with other anti - P01375 drugs : a retrospective study of three cases from a single centre and literature review . OBJECTIVES : The aim of this paper is to assess the clinical response to DB06674 ( GLM ) in patients with non - infectious uveitis from a single centre that had previously been treated with other anti - P01375 - α drugs . METHODS : A retrospective chart review was carried out of patients with immune - mediated uveitis refractory to standard synthetic immunosuppressive drugs who were treated with GLM at Hospital Universitario Marqués de Valdecilla , Santander ( Spain ) . Patients were included in this study if they had previously been treated with other anti - P01375 - α drugs . A literature review of patients with immune - mediated uveitis undergoing GLM therapy was conducted . RESULTS : Three patients ( 2 men and 1 woman ) were included in this study . Two of them were refractory to other anti - P01375 - α drugs . The median age of patients was 26 years ( range 20 - 42 ) . Uveitis was bilateral in two patients . The underlying diseases were uveitis associated with HLA - Q8TCY5 and psoriasis in one case and sarcoidosis in the other two cases . Improvement of the main ocular parameters following GLM therapy was achieved in all cases . After a median follow - up of 3 ( range 1 - 9 ) months using GLM therapy , none of the patients had experienced new relapses of uveitis . None of them had side effects during treatment with this drug . A literature review disclosed that our observations were in keeping with other reports that showed good response to GLM in 13 of 16 patients with immune - mediated uveitis refractory to other biologic agents . CONCLUSIONS : Although the follow - up was too short in our series , GLM could be an effective and safe therapy for the management of patients with uveitis previously treated with other anti - P01375 - α drugs .", "P01375 alpha antagonists in the treatment of axial spondyloarthritis . INTRODUCTION : The introduction of therapy with tumor necrosis factor antagonists ( aTNF ) was a cornerstone of treatment modalities in patients with ankylosing spondylitis ( AS ) . After > 10 years of using aTNF , the introduction of aTNF therapy was a major step forward in the medical management of patients with spondyloarthritis ( SpA ) , but there are still a number of scientific questions that have not been resolved . AREAS COVERED : This review includes both subtypes of axial spondyloarthritis ( axSpA ) , non - radiographic axial SpA ( nr - axSpA ) , and AS . It covers all five aTNF adalimumab , certolizumab , etanercept , DB06674 , and infliximab , which are approved for patients with active AS . EXPERT OPINION : aTNF are efficacious and effective in reducing signs and symptoms of patients with axSpA . While aTNF reduce spinal inflammation , the effects on new bone formation are less clear . There may be a deceleration of radiographic progression in 4 years . The development of fatty lesions in vertebral edges seems to be relevant for that - especially when inflammation also persists . Reduction of aTNF doses seems to be possible in selected patients over time . In case of failure , switching to another aTNF works in the majority of cases . Long - term data suggest a favorable safety profile of aTNF .", "P01375 inhibitors - new and old agents for rheumatoid arthritis . The development of tumor necrosis factor ( P01375 ) inhibitor therapy has revolutionized the treatment of rheumatoid arthritis ( RA ) . Unfortunately , no one single agent is fully effective in every patient ; different patients respond to different therapies in different ways , even to those agents with the same mechanism of action . In this regard , newer P01375 inhibitor agents , such as DB06674 and certolizumab pegol , are a welcome addition to the treatment armamentarium of RA . This article addresses some of the recent advances in P01375 inhibitor therapy for RA , including therapy involving these two newer agents and recent recommendations about well established P01375 inhibitors ( infiximab , etanercept , adalimumab ) that may affect various aspects of RA treatment strategies .", "Q9GZV9 contributes to diminished bone mineral density in childhood inflammatory bowel disease . BACKGROUND : Diminished bone mineral density ( BMD ) is of significant concern in pediatric inflammatory bowel disease ( Q9UKU7 ) . Exact etiology is debatable . The recognition of fibroblast growth factor 23 ( Q9GZV9 ) , a phosphaturic hormone related to tumor necrosis factor alpha ( P01375 - α ) makes it plausible to hypothesize its possible relation to this pathology . METHODS : In this follow up case control study , BMD as well as serum levels of Q9GZV9 , calcium , phosphorus , alkaline phosphatase , creatinine , parathyroid hormone , 25 hydroxy vitamin D3 and 1 , 25 dihydroxy vitamin D3 were measured in 47 children with Q9UKU7 during flare and reassessed in the next remission . RESULTS : Low BMD was frequent during Q9UKU7 flare ( 87 . 2 % ) with significant improvement after remission ( 44 . 7 % ) . During disease flare , only 21 . 3 % of patients had vitamin D deficiency , which was severe in 12 . 8 % . During remission , all patients had normal vitamin D except for two patients with Crohn ' s disease ( CD ) who remained vitamin D deficient . Mean value of serum Q9GZV9 was significantly higher among patients with Q9UKU7 during flare compared to controls . It showed significant improvement during remission but not to the control values . 1 , 25 dihydroxy vitamin D3 , Q9GZV9 , serum calcium and urinary phosphorus were significant determinants of BMD in Q9UKU7 patients . CONCLUSIONS : We can conclude that diminished BMD in childhood Q9UKU7 is a common multifactorial problem . Elevated Q9GZV9 would be a novel addition to the list of factors affecting bone mineral density in this context . Further molecular studies are warranted to display the exact interplay of these factors .", "Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .", "Optimizing outcomes in rheumatoid arthritis patients with inadequate responses to disease - modifying anti - rheumatic drugs . Conventional DMARDs such as MTX are the mainstay of treatment for patients with RA . However , failure to achieve adequate disease control in many patients , even with combination therapy , has spurred the development of agents that target various immune mediators involved in the disease process . In the past decade , biologic agents have proved viable as alternative or add - on therapy to DMARDs in patients whose disease is inadequately controlled . Well - controlled clinical trials have evaluated the effects of these agents not only on disease activity , but also on inhibition of structural change and improvement in physical function . This article reviews phase 3 clinical trial results on biologic agents that inhibit T - and B - cell activation ( abatacept and rituximab , respectively ) , inflammatory cytokines such as P01375 - α ( adalimumab , etanercept , infliximab , DB06674 and certolizumab ) and P05231 ( tocilizumab ) . Although data comparing the efficacy of the various biologic agents are limited , the availability of biologic therapies with differing mechanisms of action expands therapeutic options for patients whose disease is inadequately controlled with DMARDs and allows for greater individualization of treatment .", "Off - label uses of anti - P01375 therapy in three frequent disorders : Behçet ' s disease , sarcoidosis , and noninfectious uveitis . Tumoral necrosis factor α plays a central role in both the inflammatory response and that of the immune system . Thus , its blockade with the so - called anti - P01375 agents ( infliximab , etanercept , adalimumab , certolizumab pegol , and DB06674 ) has turned into the most important tool in the management of a variety of disorders , such as rheumatoid arthritis , spondyloarthropatties , inflammatory bowel disease , and psoriasis . Nonetheless , theoretically , some other autoimmune disorders may benefit from these agents . Our aim is to review these off - label uses of anti - P01375 blockers in three common conditions : Behçet ' s disease , sarcoidosis , and noninfectious uveitis . Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders , this review is mainly based on case reports and case series .", "DB00051 for the treatment of immune - mediated diseases : an update on old and recent indications . Ongoing progress in understanding the pathogenic mechanisms regulating various immune - mediated and inflammatory diseases , as well as the availability of innovative biotechnological approaches , have lead to the development of new drugs that add to conventional treatments . Among these , tumor necrosis factor ( P01375 ) - α inhibitors such as infliximab , adalimumab , etanercept , DB06674 and certolizumab pegol , are now available for clinical use . DB00051 is a fully recombinant human immunoglobulin P55008 monoclonal antibody that specifically binds with high affinity to human P01375 - α and inhibits its binding to P01375 receptors . DB00051 was approved by the U . S . FDA in 2002 and was granted approval from the European Medicines Agency in September 2003 for the treatment of moderate to severe rheumatoid arthritis and subsequently for the treatment of ankylosing spondylitis , chronic plaque psoriasis , psoriatic arthritis , juvenile idiopathic arthritis and Crohn ' s disease . In this paper , we will briefly review the structure and biological effects of P01375 - α , the old and recent indications of adalimumab , the pretreatment considerations , the reported adverse events and finally , the recommendations for its use in pregnancy .", "Golimumab . Inflammatory rheumatism : just another P01375 alpha antagonist , no advantage . In the absence of head - to - head comparisons with other P01375 alpha antagonists , which are perfectly feasible , there is no firm evidence that DB06674 has a better risk - benefit balance than other immunosuppressants .", "Failure of anti - interleukin - 1 therapy in severe hidradenitis suppurativa : a case report . Hidradenitis suppurativa ( HS ) is an inflammatory , debilitating skin disease of follicular origin , characterized by painful deep - seated , inflamed lesions in mainly the inverse areas of the body . HS is notoriously difficult to treat and especially severe disease is often resistant to therapy . New therapeutic options are therefore highly needed . Elevated levels of IL - 1 have been demonstrated in HS lesions . Here we report for the first time on the sequential treatment with anakinra ( an IL - 1 receptor antagonist ) and DB06674 ( a P01375 - α - neutralizing antibody ) of a patient with severe HS and with comorbid psoriatic arthritis . Although adalimumab and DB06674 were efficacious in improving arthritis complaints , both failed in improving the severe HS of our patient . Eventually the patient underwent radical excision of the inflammatory lesions and fistulas .", "Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK8___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .", "Update upon efficacy and safety of P01375 - α inhibitors . The ongoing progresses in the knowledge of the pathogenic mechanisms of various immune - mediated and inflammatory diseases as well as the availability of innovative biotechnological approaches have led to the development of new drugs that add to conventional treatments . Among these , tumor necrosis factor ( P01375 ) - α inhibitors , that is , infliximab , adalimumab , etanercept , DB06674 and certolizumab pegol , are now available for clinical use . This editorial discusses the recent indications of P01375 - α inhibitors , the pretreatment considerations , the reported adverse events and , finally , the recommendations for its use in pregnancy .", "Pharmacogenetics and future therapeutic scenarios : what affects the prediction of response to treatment with etanercept ? There are five tumor necrosis factor alpha ( P01375 - α ) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs ( DMARDs ) in the treatment of immune - mediated diseases . These include the anti - P01375 - α monoclonal antibodies infliximab , adalimumab , DB06674 , and certolizumab pegol , and the fusion protein , etanercept . The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to , or toxicities from , P01375 - α inhibitors , and could be used to individualize therapy . Several studies have reported associations between genetic polymorphisms and the response to etanercept , but most are small and insufficiently powered to detect effect , and markers tend to be more prognostic than predictive of therapeutic response . Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms ( SNPs ) , genes in linkage with other loci , interaction of environmental factors , and cohort heterogeneity , all of which can complicate the relationship between genetic polymorphisms and treatment response . Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice .", "[ Research update of anti - P01375 - α biologic agents in the treatment of uveitis ] . Uveitis is one of the common sight - threatening eye diseases , which is usually recurrent and refractory to treatment . It is generally considered that the development of uveitis is closely related to the autoimmune response of uvea . P01375 ( P01375 ) - α is one of the key cytokines involved in the emergence and progression of uveitis . Blocking the production or inhibiting the activity of P01375 - α can inhibit the development or progression of uveitis . Presently , the commercially available P01375 - α blockers include infliximab , adalimumab , etanercept , and DB06674 . This review describes the clinical studies and adverse effects of P01375 - α blockers in the treatment of uveitis , and discusses the principle for clinical use of P01375 - α blockers in synergy with other immunosuppressive agents .", "An update on disease modifying antirheumatic drugs . Disease modifying antirheumatic drugs ( DMARDs ) is a category of drugs which is used as medication in various arthritic conditions to arrest the progression of disease along with relief from pain . About 83 % of population worldwide uses DMARDs . Withdrawal of P35354 inhibitors because of cardiovascular side effects and short - term action associated with glucocorticoids provided a motivation for development of newer DMARDs . Currently non - biological DMARDs like methotrexate , sulfasalazine , hydroxychloroquine and azathioprine serve the purpose of relieving pain and inhibiting the progression of disease . Biological DMARDs like toclizumab , adalimumab , infliximab , DB06674 and abatacept have shown more efficacy and lesser side effects as compared to non - biological DMARDs but their access to patient is less because of higher cost . DMARDs act by different mechanisms against inflammation like inhibition of tumor necrosis factor , suppression of IL - 1 and P01375 - α , induction of apoptosis of inflammatory cells , by increasing chemotactic factors , inhibition of purine synthesis , pyrimidine metabolism or purine embolism . DMARDs have important applications in diseases like rheumatoid arthritis , Crohn ' s disease , juvenile idiopathic arthritis , psoriatic arthritis and myasthenia gravis . Present review mainly focuses on DMARDs and their clinical applications giving an overview of their mechanism of action , pharmacokinetic properties , advantages over conventional therapies , shortcomings and recent trends .", "Biologic monotherapy as initial treatment in patients with early rheumatoid arthritis . Although biologic agents are most well established as part of combination regimens in patients with RA , biologic monotherapy is common in clinical practice . To date , few double - blind , randomized clinical trials have compared biologic monotherapy with MTX monotherapy . Five randomized double - blind trials evaluating the P01375 antagonists etanercept ( ERA and TEMPO ) , adalimumab ( PREMIER ) and DB06674 ( GO - BEFORE ) and the P05231 receptor antagonist tocilizumab ( AMBITION ) were identified . We noted considerable variation in patient characteristics ( i . e . disease duration and disease severity ) in the five trials . Studies involving monotherapy with P01375 inhibitors found no clear clinical efficacy advantage over MTX monotherapy . In the two trials that included a P01375 inhibitor / MTX combination arm , combination therapy was superior to monotherapy with either agent alone . In contrast , the AMBITION trial demonstrated that tocilizumab monotherapy was superior to MTX in terms of clinical response , disease activity , remission and functionality . Although results can not be compared across clinical trials , tocilizumab was the only biologic agent to demonstrate superiority to MTX as monotherapy in patients with RA with limited / no exposure to MTX .", "Golimumab - a new tool in the armoury against inflammatory arthritis . The development of biological drugs blocking tumour necrosis factor - alpha ( P01375 - α ) has had a dramatic impact on the treatment of inflammatory arthritis in recent years . Golimumab is a fully human monoclonal antibody which inhibits P01375 - α . It is licensed for the treatment of rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis . In this review we evaluate the results of phase III studies using DB06674 and explore the place of DB06674 in the treatment of these diseases .", "Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK82___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .", "An open label study to evaluate the safety and efficacy of intratympanic DB06674 therapy in patients with autoimmune inner ear disease . OBJECTIVE : To evaluate the safety and efficacy of intratympanically injected DB06674 ( GLM ) , a P01375 - α inhibitor , as a steroid - sparing agent for patients with steroid - dependent autoimmune inner ear disease ( AIED ) . STUDY DESIGN : Open label . SETTING : Tertiary referral center . PATIENTS : Ten patients with steroid - dependent AIED were enrolled in Stage 2 . The average patient age at enrollment was 59 , with an average of 12 . 5 years from the start of bilateral hearing loss symptoms . The average dose of daily prednisone at the start of injections was 18 mg . INTERVENTION : Intratympanic injection of GLM . MAIN OUTCOME MEASURE : Hearing loss progression ( treatment failure ) was defined as either an increase in pure - tone thresholds by frequency or a decrease in word recognition score . RESULTS : There were no serious adverse events . Five of seven per - protocol subjects experienced stable pure - tone thresholds in the injected ear , whereas 4 had stable word recognition scores . Two subjects experienced an improvement in word recognition scores . The results support the hypothesis that GLM may be a promising treatment . CONCLUSIONS : The P01375 - α inhibitor GLM stabilized hearing in 3 of 7 per - protocol subjects with AIED and allowed a complete tapering off of prednisone in those 7 subjects . Studies with larger samples sizes are warranted .", "Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK78___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .", "New treatments for inflammatory rheumatic disease . As our understanding of the pathogenesis of autoimmune diseases is growing , new therapies are being developed to target disease - specific pathways . Since the introduction of etanercept in 1998 , several biotechnological agents have been developed , most of them indicated in the treatment of rheumatoid arthritis , but also psoriatic arthritis . Most currently available molecules target P01375 - alfa with different strategies ( i . e . , etanercept , infliximab , adalimumab , DB06674 , and certolizumab pegol ) , P05231 ( tocilizumab ) , P16410 ( abatacept ) , and B cells ( rituximab , belimumab ) as they are key mediators in the cascade of inflammation . Further , small molecules have been recently developed to target intracellular signaling , such as Janus Kinases for tofacitinib , the first FDA - approved small molecule for rheumatoid arthritis . Most novel treatments are being developed for arthritis with specific differences between rheumatoid and psoriatic arthritis , as well as for systemic lupus erythematosus , following the approval of belimumab . Finally , biologic therapies are effective also in gout , mainly targeting interleukin - 1 to block the inflammasome . This review article describes the new and upcoming treatment options for rheumatoid arthritis , psoriatic arthritis , systemic lupus erythematosus , and gout to dissect what we should be aware of when discussing these new and promising molecules .", "Role for macrophage migration inhibitory factor in acute respiratory distress syndrome . The critical role of macrophage migration inhibitory factor ( MIF ) in mediating inflammatory lung injury in acute respiratory distress syndrome ( ARDS ) has been raised recently . The present study has identified enhanced MIF protein expression in alveolar capillary endothelium and infiltrating macrophages in lung tissues from ARDS patients . The possibility that MIF up - regulates its synthesis in an autocrine fashion in ARDS was tested using cultured endothelial cells stimulated with MIF and a murine model of lipopolysaccharide ( LPS ) - induced acute lung injury . MIF induced significant MIF and tumour necrosis factor ( P01375 ) - alpha synthesis in cultured endothelial cells and the effect was blocked by neutralizing anti - MIF antibody . A similar blocking effect was observed when MIF - stimulated endothelial cells were pretreated with neutralizing anti - P01375 antibody or glucocorticoid , supporting the notion that MIF induced P01375 production via an amplifying pro - inflammatory loop . Treatment with anti - MIF or glucocorticoid effectively attenuated pulmonary pathology and the synthesis of MIF or P01375 in mice with LPS - induced acute lung injury . Mildly augmented expression of aquaporin 1 ( P29972 ) was also detected in alveolar capillary endothelium in ARDS . In vitro studies revealed that both MIF and P01375 induced a small increase of P29972 synthesis in cultured endothelial cells . These findings suggest that MIF plays a crucial pathological role leading to alveolar inflammation in ARDS . Anti - MIF and early glucocorticoid therapy may represent a novel therapeutic approach for reducing alveolar inflammation in ARDS .", "Autosomal - dominant hypophosphatemic rickets ( P30518 ) mutations stabilize Q9GZV9 . BACKGROUND : The gene for the renal phosphate wasting disorder autosomal - dominant hypophosphatemic rickets ( P30518 ) is Q9GZV9 , which encodes a secreted protein related to the fibroblast growth factors ( FGFs ) . We previously detected missense mutations R176Q , R179W , and R179Q in Q9GZV9 from P30518 kindreds . The mutations replace R residues within a subtilisin - like proprotein convertase ( Q969E3 ) cleavage site 176RHTR - 179 ( RXXR motif ) . The goal of these studies was to determine if the P30518 mutations lead to protease resistance of Q9GZV9 . METHODS : The P30518 mutations were introduced into human Q9GZV9 cDNA clones with or without an N - terminal FLAG tag by site - directed mutagenesis and were transiently transfected into HEK293 cells . Protein expression was determined by Western analyses . RESULTS : Antibodies directed toward the C - terminal portion of Q9GZV9 revealed that the native Q9GZV9 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media ; however , the three mutated proteins were detected only as the 32 kD band . An N - terminal FLAG - tagged native Q9GZV9 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody , whereas the R176Q mutant resolved primarily as the 36 kD protein species . Cleavage of Q9GZV9 was not enhanced by extracellular incubation of Q9GZV9 with HEK293 cells . Native and mutant FGF - 23s bound heparin . CONCLUSIONS : Q9GZV9 proteins containing the P30518 mutations are secreted , and produce polypeptides less sensitive to protease cleavage than wild - type Q9GZV9 . Therefore , the P30518 mutations may protect Q9GZV9 from proteolysis , thereby potentially elevating circulating concentrations of Q9GZV9 and leading to phosphate wasting in P30518 patients .", "___MASK100___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK100___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK100___ is a promising pharmacological tool in the treatment of renal edema .", "Risk of infections of biological therapies with accent on inflammatory bowel disease . BACKGROUND : Biological therapies using anti - tumor necrosis factor ( P01375 ) - α agents have an important impact in the treatment of inflammatory bowel disease , rheumatoid arthritis , psoriasis , and other inflammatory conditions . However , a significant number of patients lose their response to these medications over time . Clinical trials have demonstrated that antibodies against anti - P01375 agents may impact treatment response and increase the risk of infusion reactions . Of concern is also the possibility of developing adverse events induced by anti - P01375 agents . The purpose of the present systematic review is to describe the current knowledge on the risk of infections associated with anti - P01375 agents antagonists , as well as integrin antagonists . We also intend to describe case reports of these adverse events in inflammatory bowel disease patients . METHODS : Currently approved anti - P01375 biologicals in Q9UKU7 include the monoclonal antibodies infliximab , adalimumab , certolizumab pegol and DB06674 . Integrin antagonists include natalizumab , etrolizumab and vedolizumab . RESULTS : The most frequently - reported adverse events of these biologicals were infections , and these are described in detail in this study . DISCUSSION : Most adverse events are due to the failure of host immunological control , which involves de novo infection , or reactivation of latent bacterial or viral infection , often with a different expression of disease . CONCLUSION : Risk assessment in individuals undergoing treatment with biologicals represents a step towards achieving treatment personalization to identify those patients that will safely benefit from this therapeutic approach . Patients and physicians must be alert for anti - P01375 agents and anti - integrin medication as potential causes of drug - induced infections and monitor the therapies . Personalizing therapeutic vigilance promises to optimize benefits while minimizing infections .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK79___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "Clinically relevant advances in rheumatoid arthritis therapy . Owing to the success of biologics in the treatment of rheumatoid arthritis ( RA ) , several novel drugs have been introduced in the therapeutic armamentarium , although not all of them have been approved in all countries worldwide . Among the drugs are tumour necrosis factor ( P01375 ) inhibitors such as certolizumab pegol and DB06674 ( the latter of which was the first P01375 blocker shown to be effective in patients who had been unsuccessfully treated with other P01375 blockers and which can be applied only once a month ) , and the interleukin - 6 receptor antagonist tocilizumab , which not only opens up a completely new field of anti - inflammatory modulation of RA pathophysiology , but also highlights the challenge of novel potential side effects . Moreover , aside from clinical studies showing efficacy in the inhibition of osteoclast activation by the anti - O14788 ( receptor activator of nuclear factor - kappa B ligand ) antibody denosumab , an improved form of steroid application known as slow - release ' tempus tablet ' for treatment of RA and several developments in the small - molecule area have been addressed by clinical trials .", "DB08904 in axial spondyloarthritis . The axial spondyloarthritis ( SpA ) classification criteria cover both patients with ankylosing spondylitis and non - radiographic axial SpA . After failure of NSAIDs P01375 - α - inhibitors ( P01375 - blockers ) can be given to patients with active axial SpA . Until recently , the P01375 - blockers infliximab , adalimumab , etanercept and DB06674 are labeled for the treatment of active ankylosing spondylitis while for active nr - axSpA only adalimumab has been approved in Europe . The P01375 - blocker certolizumab pegol has recently been evaluated in the RAPID - axSpA trial which is the first placebo - controlled randomized - controlled trial in the entire group of axial SpA . An elevated P02741 and / or evidence of bone marrow edema on Q9BWK5 of the sacroiliac joints were required for inclusion in RAPID - axSpA , and patients could have been preexposed to P01375 - blockers . The interesting data of this important trial in the context of the emerging therapeutic field of non - radiographic axial SpA therapy is discussed in this review .", "___MASK23___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK23___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .", "Advances in the management of psoriatic arthritis . Psoriatic arthritis ( PsA ) , which affects musculoskeletal structures , skin and nails , is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and variable course . Patients with PsA are more likely than healthy individuals to have metabolic syndrome or cardiovascular disease . To include these comorbidities , ' psoriatic disease ' has been suggested as an umbrella term . The management of PsA has changed tremendously over the past decade owing to early diagnosis and improvement in treatment strategies , including , early referral from dermatologists and primary - care physicians to rheumatologists , early initiation of therapy , treating to the target of remission or low disease activity , and advances in pharmacological therapy . Outcome assessment is also improving , because of validated instruments for clinical disease manifestations . The commercialization of P01375 blockers , including adalimumab , etanercept , DB06674 and infliximab , is representative of a revolution in the treatment of PsA . A new anti - P01375 agent , certolizumab pegol , and a fully human monoclonal antibody against IL - 12 and IL - 23 , ustekinumab , are approved for the treatment of active PsA . The efficacy of ustekinumab suggests that inhibiting the type 17 T helper pathway might be an alternative to blocking P01375 . PsA management must now use improved measures to predict patient outcomes and define remission , and develop better - targeted therapies .", "Engineering the response to vascular injury : divergent effects of deregulated Q01094 expression on vascular smooth muscle cells and endothelial cells result in endothelial recovery and inhibition of neointimal growth . P01375 - alpha ( P01375 ) is expressed locally in the vessel wall after angioplasty and induces growth arrest and apoptosis in endothelial cells ( ECs ) , thereby delaying reendothelialization . Prior studies have shown that direct antagonism of P01375 , using a systemically administered soluble receptor , can enhance endothelial recovery and reduce neointimal thickening . These studies have also shown that downregulation of the transcription factor Q01094 was a key mechanism of P01375 ' s effect on ECs . We now show that Ad - Q01094 overexpression at sites of balloon injury accelerates functional endothelial recovery , consistent with the prior in vitro findings . Moreover these studies also reveal divergent effects of P01375 and overexpression of Q01094 on ECs versus VSMCs . P01375 exposure of VSMCs had no affect on proliferation or apoptosis , in contrast to the effect seen in ECs . In Ad - Q01094 - transduced VSMCs , however , P01375 - induced marked apoptosis in contrast to the survival effect seen in ECs . Finally , these studies suggest that differential activation of NF - kappaB may play a key role in mediating these opposing effects . Nuclear translocation and transcriptional activity of NF - kappaB was markedly attenuated in Ad - Q01094 - transduced VSMCs , whereas it remained active in similarly treated ECs when the cells were exposed to P01375 . These studies reveal that overexpression of Ad - Q01094 primes VSMCs to P01375 - induced apoptosis . Furthermore , Q01094 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF - kappaB activation . The divergent responses of VSMCs and ECs to Q01094 overexpression provide unique therapeutic possibilities : simultaneously targeting the cell cycle of two different cell types , within same tissue microenvironment resulting in opposite and biologically complimentary effects .", "Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .", "Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .", "Miscellaneous adverse events with biologic agents ( excludes infection and malignancy ) . Anti - tumor necrosis factor - α ( anti - P01375 ) agents are frequently used in the treatment of inflammatory bowel disease ( Q9UKU7 ) . Currently , there are 4 anti - P01375 therapies that are Food and Drug Administration - approved for moderate to severe Q9UKU7 : infliximab , adalimumab , DB06674 , and certolizumab pegol . For most noninfectious , nonmalignant adverse events , cessation of anti - P01375 therapy typically leads to improvement or resolution of drug - induced complications . In this article , the current knowledge regarding the noninfectious and nonmalignant toxicities associated with anti - P01375 agents is summarized .", "Golimumab : clinical update on its use for ulcerative colitis . Monoclonal antibodies directed against tumor necrosis factor alpha ( anti - P01375 - α agents ) have dramatically changed the therapeutical approach to inflammatory bowel diseases , such as Crohn ' s disease and ulcerative colitis . A new anti - P01375 drug , DB06674 , has recently been approved for patients with moderate to severe ulcerative colitis . Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti - P01375 agents , such as infliximab and adalimumab . This review gives an overview on DB06674 in the treatment of moderate to severe ulcerative colitis .", "17 ___MASK93___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .", "Immunogenicity of anti - P01375 biologic therapies for rheumatoid arthritis . Currently , five anti - P01375 biologic agents are approved for the treatment of rheumatoid arthritis ( RA ) : adalimumab , infliximab , etanercept , DB06674 and certolizumab pegol . Formation of anti - drug antibodies ( P00813 ) has been associated with all five agents . In the case of adalimumab and infliximab , immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response , but for the other three agents , data on immunogenicity are scarce , suggesting that further research would be valuable . Low P00813 levels might not influence the efficacy of anti - P01375 therapy , whereas high P00813 levels impair treatment efficacy by considerably reducing unbound drug levels . Immunogenicity is not only an issue in patients treated with anti - P01375 biologic agents ; the immunogenicity of other therapeutic proteins , such as factor VIII and interferons , is well known and has been investigated for many years . The results of such studies suggest that investigations to determine the optimal treatment regimen ( drug dosing , treatment schedule and co - medication ) required to minimize the likelihood of P00813 formation might be an effective and practical way to deal with the immunogenicity of anti - P01375 biologic agents for RA .", "New biologic therapeutics for ulcerative colitis and Crohn ' s disease . INTRODUCTION : Some inflammatory bowel disease ( Q9UKU7 ) patients especially those with refractory Crohn ' s disease ( CD ) or relapsing ulcerative colitis ( UC ) do not respond to current therapies . The newly introduced biological drugs have got some interest due to their specificity and selectivity in modulation of inflammatory elements . AREAS COVERED : In 46 included randomized , placebo - controlled clinical trials , the efficacy and safety of different biologic drugs have been evaluated in moderately to severely active CD or UC patients . Current investigated drugs include new anti - P01375 drugs ( adalimumab , certolizumab pegol , etanercept , onercept and DB06674 ) , anti - P11836 ( rituximab ) , T - cell inhibitors ( abatacept ) and anti - α4 integrins ( natalizumab and vedolizumab ) . DB00051 , certolizumab , and DB06674 showed significant efficacy in induction of remission and maintenance in CD and UC patients with a rate of adverse events similar to placebo in the major trials . DB00108 and vedolizumab were effective in the treatment of moderately to severely active CD and UC patients . However , vedolizumab caused less adverse effects than natalizumab . onercept , etanercept , rituximab and abatacept were all well tolerated but were not effective in CD or UC patients . EXPERT OPINION : Anti - P01375 drugs , except for onercept and etanercept , and anti - α4 integrins exhibit beneficial therapeutic effects . Although they were all well tolerated , the incidence of progressive multifocal leukoencephalopathy associated with natalizumab should not be missed .", "P01375 - α antagonists beyond approved indications : stories of success and prospects for the future . Tumour necrosis factor alpha ( P01375 - α ) is a key molecule of the inflammatory response and data derived from studies in experimental animal models and humans suggest that P01375 - α may be implicated in the pathogenesis of various autoimmune and non - infectious inflammatory conditions . Over the past decade pharmaceutical agents directed against P01375 - α ( infliximab , adalimumab and etanercept ) have been widely and successfully employed for the management of rheumatoid arthritis ( RA ) , ankylosing spondylitis ( AS ) , psoriasis , psoriatic arthritis , juvenile idiopathic arthritis and inflammatory bowel disease , whereas two novel anti - P01375 - α agents , DB06674 and certolimumab pegol , recently entered the market for the treatment of RA , AS , Crohn ' s disease and psoriasis . Encouraged by the positive results obtained from the use of P01375 - α antagonists in terms of efficacy and safety and due to the increasingly accumulating evidence regarding the implication of P01375 - α in the pathogenesis of numerous disorders , anti - P01375 - α agents have been considered for the management of diseases other than the ones they were initially approved for . Although in the case of multiple sclerosis and chronic heart failure the outcome from the administration of P01375 - α blockers had been less than favourable , in other cases of non - infectious inflammatory conditions the response to P01375 - α inhibition had been fairly beneficial . More specifically , according to well - documented clinical trials , anti - P01375 - α agents exhibited favourable results in Behçet ' s disease , non - infectious ocular inflammation , pyoderma gangrenosum and hidradenitis suppurativa . In this review we discuss the successful outcomes as well as the prospects for the future from the off - label use of P01375 - α antagonists .", "Update on the treatment of peripheral arthritis in psoriatic arthritis . Psoriatic arthritis is a chronic , disabling disease for which therapies have been borrowed from rheumatoid arthritis and spondylitis . Traditional disease - modifying antirheumatic drugs ( DMARDs ) remain the first choice for the treatment of peripheral arthritis despite scarce evidence of their efficacy or ability to halt radiographic progression . P01375 antagonists have the greatest level of evidence for symptom control and radiographic progression . They are currently used after the failure of DMARDs to effectively treat peripheral arthritis , enthesitis , and dactylitis , and are the first choice when axial disease predominates . Despite the use of these treatments , 30 % to 40 % of patients will still have active disease . Among new drugs , evidence of efficacy has already been published with regard to anti - IL12 / 23 monoclonal antibody ( ustekimumab ) and DB06674 . Results are forthcoming from trials with certolizumab pegol , abatacept , and rituximab . As knowledge of the pathogenesis of psoriatic arthritis evolves and differences among other arthritis conditions become evident , therapies targeting these distinct features are needed .", "P10275 coregulator Q96L73 - alpha interacts with death receptor - 6 revealed by the yeast two - hybrid . Q96L73 - alpha is a newly identified androgen receptor coactivator . In order to further elucidate its precise role in cells , using the Q96L73 - alpha fragment containing four P20941 and one Q01105 conserved domains as bait we revealed an Q96L73 - alpha - P20941 - Q01105 - interacting protein , death receptor - 6 ( O75509 ) , in the yeast two - hybrid screening . O75509 is the member of P01375 receptor family and has a death domain in its intracellular cytoplasmic portion ( DR6cp ) to mediate the cell apoptosis . The interaction between Q96L73 - alpha - P20941 - Q01105 and DR6cp was confirmed in vitro and in vivo . Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between Q96L73 - alpha and O75509 .", "Golimumab and immunogenicity ? 2010 and beyond . Immunogenicity is a frequent adverse event observed with biological agents ' therapy . Challenges of management in patients with rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis treated with DB06674 , an anti - P01375 blocker , include limited generation of antibodies like anti - nuclear , anti - DB06674 , and anti - double stranded DNA antibodies . We conducted here a meta - analysis study in order to evaluate and compare the newly generated antibody levels after DB06674 therapy . The examination of original clinical trials revealed that their levels were neither higher nor significant . Moreover , no evident associations between the induced - antibodies and lupus - like syndromes and / or infusion site reaction were reported . The reduced patients cohort and the absence of systematic newly generated antibodies follow - up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy , and / or predicting for their worse prognosis . Hence , further studies are required to ascertain the real impact of the induced antibodies after DB06674 ' s therapy .", "The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .", "Subacute lupus erythematosus during treatment with DB06674 for seronegative rheumatoid arthritis . We report on a 52 - year - old woman with a history of severe seronegative rheumatoid arthritis . Several conventional therapies and biological therapy with etanercept and infliximab had been unsuccessful . In 2010 she was given DB06674 subcutaneously at a monthly dose of 50 mg . She had a negative Q14201 titre . After 16 months of uninterrupted therapy and sustained response , she developed skin lesions on the upper trunk , back and upper extremities , which worsened on exposure to the sun . The skin biopsy was compatible with subacute lupus erythematosus . Laboratory findings included an Q14201 titre 1 : 640 , negative anti - Ro / SSA and anti - DNA antibodies . Topical corticosteroid therapy proved inadequate . The patient ' s condition improved only after discontinuation of DB06674 . The causal relationship between subacute cutaneous lupus erythematosus and DB06674 is not dose - related and occurs with some delay ( a typical feature of immunological adverse reactions ) . The association is likely , but not confirmed ( because re - challenge was not performed ) . However , a clear improvement was noted after withdrawal . Based on this case , we hypothesized the aetiological role of DB06674 - associated immunogenicity . P01375 - α antagonist - induced lupus - like syndrome ( TAILS ) is a well - known side effect of this class of substances . The British Society of Rheumatology recommends discontinuation of the causal anti - P01375 - α treatment in patients with TAILS .", "[ New biologic and non biologic disease modifying anti - rheumatic drugs for rheumatoid arthritis ] . P01375 inhibitors , infliximab , etanercept and adalimumab , and tocilizumab are available in Japan and have been successful at improving the signs and symptoms of RA and , thereby , have set a new standard for disease control of RA and have the potential to protect joints from structural damage or to improve quality of life and mortality . However , the rate of successful induction of remission was about 30 % and the treatment strategies for the patients who do not respond to these biologics should be established . Randomized clinical trials targeting T or B lymphocytes have been conducted in addition to the new anti - P01375 blockers like DB06674 or certolizumab pegol . Anti - P11836 antibodies such as rituximab ( chimeric ) , ocrelizumab ( humanized ) , ofatuzumab ( full human ) demonstrated effectiveness to the patients who do not respond to P01375 blockers . P16410 Ig , which can transduce negative signal into T lymphocytes in the co - stimulatory pathway , has also showed a good response to refractory RA . Furthermore , low molecular agents such as Jak ( Janus kinase ) 3 or syk ( spleen tyrosine kinase ) inhibitors demonstrated rapid and strong suppression of synovitis and are thought to be new candidates for the drugs to overcome refractory RA .", "Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK89___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK89___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK89___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK89___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK89___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK89___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK89___ .", "Predictive value of circulating interleukin - 6 and heart - type fatty acid binding protein for three months clinical outcome in acute cerebral infarction : multiple blood markers profiling study . INTRODUCTION : There is no single blood marker for predicting the prognosis in ischemic stroke . A combination of multiple blood markers may enhance the ability to predict long - term outcome following ischemic stroke . METHODS : Blood concentrations of neuronal markers ( neuron - specific enolase , visinin - like protein 1 , heart type fatty acid binding protein ( hFABP ) and neuroglobin ) , astroglial markers ( P04271 and glial fibrillary acidic protein ) , inflammatory markers ( P05231 , P01375 - α , and P02741 ) , blood - brain barrier marker ( matrix metalloproteinase 9 ) , and haemostatic markers ( D - dimer and P05121 ) were measured within 24 hours after stroke onset . The discrimination and reclassification for favorable and poor outcome were compared after adding individual or a combination of blood markers to the clinical model of stroke outcome . RESULTS : In multivariate analysis , natural log - transformed ( log ) P05231 ( odds ratio ( OR ) : 1 . 75 , 95 % CI : 1 . 25 to 2 . 25 , P = 0 . 001 ) and loghFABP ( OR : 3 . 23 , 95 % CI : 1 . 44 to 7 . 27 , P = 0 . 005 ) were independently associated with poor outcome . The addition of a single blood marker to the clinical model did not improve the discriminating ability of the clinical model of stroke outcome . However , the addition of the combination of logIL - 6 and loghFABP to the clinical model showed improved discrimination ( area under receiver operating characteristic ( AUROC ) curve : 0 . 939 versus 0 . 910 , P = 0 . 03 ) and reclassification performance ( net reclassification improvement index : 0 . 18 , P = 0 . 005 ) . CONCLUSIONS : A combination of circulating P05231 and hFABP level has an additive clinical value for the prediction of stroke outcome .", "Occurrence of adverse events in patients with JIA receiving biologic agents : long - term follow - up in a real - life setting . OBJECTIVE : The aim of this study was to carry out a safety evaluation of biologic agents in patients with JIA and associated uveitis . METHODS : In three tertiary centres in Finland , all adverse events ( AEs ) in 348 consecutive patients were collected . AEs were classified according to the Common Terminology Criteria for AEs . RESULTS : A total of 1516 patient - years ( py ) were included : 710 on etanercept , 591 on infliximab , 188 on adalimumab , 8 on rituximab , 5 on anakinra , 6 on tocilizumab , 6 on abatacept and 1 on DB06674 . The median follow - up of an individual patient was 51 months ( range 1 - 155 ) . The most common of the 2902 AEs ( 191 / 100 py ) observed were mild infections , infusion or injection site reactions and alanine aminotransferase elevations . At least one AE occurred in 319 ( 92 % ) patients and 121 ( 35 % ) had at least one serious AE ( SAE ) . The rate of SAEs was 11 . 4 / 100 py on etanercept , 11 . 8 on infliximab , 10 . 1 on adalimumab , 15 . 7 on abatacept , 31 . 2 on tocilizumab and 87 . 5 on rituximab , higher than with most anti - P01375 agents ( P = 0 . 005 ) . No cases of malignant neoplasms or tuberculosis were detected . New - onset uveitis occurred in 9 patients , psoriasis or psoriasiform lesions in 13 and Q9UKU7 in 6 . CONCLUSION : Mild and moderate AEs in patients with JIA treated with biologics were more frequent than previously reported . SAEs were observed in one - third of the patients , but SAEs seldom led to drug discontinuation .", "Round window membrane permeability to DB06674 in guinea pigs : a pilot study . OBJECTIVES / HYPOTHESIS : Autoimmune inner ear disorder is one of a few types of sensorineural hearing loss that is treatable and potentially reversible . Treatment involves oral steroids and methotrexate . Other treatment modalities have been tried with variable success . All such treatments are systemic , with inherent side effects limiting their effectiveness . Recently , tumor necrosis factor ( P01375 ) - α blockers have been suggested as a modality of treatment . The objective of this study was to assess the round window membrane permeability to DB06674 , a P01375 - α blocker . This study is the first to look at the feasibility of local DB06674 delivery into the inner ear , which may allow for targeted immune modulation of autoimmune inner ear disorders without the consequences of systemic treatment . STUDY DESIGN : This is a single - blinded , placebo - controlled , pilot study using guinea pigs to assess round window membrane permeability to DB06674 . METHODS : Golimumab was instilled into the guinea pigs ' middle ear . Inner ear fluid was sampled through the round window membrane after approximately 30 minutes of drug exposure . Golimumab presence in the inner ear was assessed by enzyme - linked immunosorbent assay in both drug - treated and control ears . RESULTS : Higher concentrations of DB06674 were detected in the inner ear fluid samples of DB06674 - exposed ears than in the control ears . The difference was statistically significant ( P < . 001 ) . CONCLUSIONS : Golimumab crosses the round window membrane and is detected in measurable concentrations in the inner ear fluid after 30 minutes of exposure to the membrane . Further studies are needed to learn its pharmacokinetics and the time needed to reach optimal concentration in the inner ear . LEVEL OF EVIDENCE : NA . Laryngoscope , 123 : 2840 - 2844 , 2013 ." ]

[ "___MASK100___", "___MASK23___", "___MASK78___", "___MASK79___", "___MASK82___", "___MASK89___", "___MASK8___", "___MASK93___", "___MASK96___" ]

[ "Human gray matter : feasibility of single - slab 3D double inversion - recovery high - spatial - resolution MR imaging . The purpose of this study was to develop and prospectively evaluate the feasibility of a single - slab three - dimensional ( 3D ) double inversion - recovery , or P30518 , sequence for magnetic resonance imaging at 1 . 5 T . The study was approved by the local ethics committee , and informed consent was obtained from six healthy control subjects ( one woman , five men ; age range , 26 - 47 years ) and two patients with multiple sclerosis ( one woman , aged 39 ; one man , aged 56 ) . Gray matter ( GM ) - only images were obtained by selectively suppressing cerebrospinal fluid ( P04141 ) and white matter ( WM ) signals . Whole - brain high - spatial - resolution 3D images ( 1 . 2 x 1 . 2 x 1 . 3 mm ) were acquired within 10 minutes . Cortical and deep GM structures were clearly delineated from WM and P04141 , and there were regional differences in GM signal intensity . No flow artifacts from blood or P04141 were observed . These GM images with high spatial resolution are suitable to identify cortical pathologic conditions and can potentially be used for segmentation purposes to determine cortical thickness or volume .", "Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK26___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .", "Expression of the human concentrative nucleotide transporter 1 ( O00337 ) gene correlates with clinical response in patients affected by Waldenström ' s Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) undergoing a combination treatment with 2 - chloro - 2 '- deoxyadenosine ( DB00242 ) and DB00073 . PURPOSE : Resistance to nucleoside analogues agents is likely to be multifactorial and could involve a number of mechanisms affecting drug penetration , metabolism and targeting . In vitro studies of resistant human cell lines have confirmed that human concentrative nucleoside transporter 1 ( O00337 ) - deficient cells display resistance . EXPERIMENTAL DESIGN : We applied real - time PCR method to assess the mRNA expression of equilibrative and concentrative nucleoside transporter ( hENT1 , O00337 ) , deoxycytidine and deoxyguanosine kinase ( P27707 , Q16854 ) , 5 '- nucleotidase ( 5 '- NT ) , ribonucleotide reductase catalytic and regulatory ( P23921 , P31350 ) subunits in bone marrow cells from 32 patients with Waldenström ' s Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) who received 2CdA - based chemotherapy . Responses to chemotherapy , were then correlated to the expression of these markers . RESULTS : All 32 patients enrolled expressed lower levels of O00337 as compared to healthy donors . In univariate analysis , lower expression level of O00337 ( p = 0 . 0021 ) and P31350 ( p = 0 . 02 ) correlated with response to chemotherapy . In particular , patients with low levels of O00337 achieved inferior clinical response . No significant correlation between these genes expression and age , stage of disease was found . This study suggests that nucleotidase expression levels can be used to identify subgroups of WM and SLL patients who will likely respond differently to a 2CdA - based therapy .", "The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .", "The P04035 inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides . The 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids . Because pravastatin is a water - soluble organic anion , it can not easily penetrate the lipid bilayer of the cell membrane . As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified , we examined the roles of the organic anion transporter family on pravastatin - treated islet and adipocyte functions . Rat oatp1 / slco1a1 , oatp2 / slco1a4 and oatp3 / slco1a5 were expressed in the pancreas , and rat oatp3 / slco1a5 was also detected in rat insulinoma cell line P01308 - 1e . ___MASK83___ was transported not only by oatp1 / slco1a1 and oatp2 / slco1a4 , but also by rat oatp3 / slco1a5 . ___MASK83___ uptake into P01308 - 1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin , both of which are known to inhibit oatp family - mediated uptake . In addition , pravastatin enhanced the glucose - stimulated insulin secretion from P01308 - 1e cells . When fat - loaded db / db mice were treated with pravastatin , glucose intolerance and insulin resistance were prevented . In addition , insulin secretion from isolated islets was enhanced by pravastatin . These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat / glucose conditions .", "Elevated serum levels of soluble P78423 in patients with microscopic polyangiitis . OBJECTIVES : To test the hypothesis that P78423 contributes to the pathogenesis of microscopic polyangiitis . METHODS : Serum samples from 18 patients with microscopic polyangiitis ( ___MASK47___ ) , who fulfilled the revised criteria of the American College of Rheumatology ( P10323 ) , were collected during both the newly diagnosed , untreated active disease states and inactive disease states . Also serum was from patients with large vessel vasculitis ( LVV ) , including giant cell arteritis ( n = 4 ) and Takayasu arteritis ( n = 3 ) , and from 52 healthy individuals . Soluble ( s ) P78423 levels in serum were measured using an enzyme - linked immunosorbent assay . Disease activity was assessed using Birmingham vasculitis activity scores ( BVAS ) . Expression of P49238 was examined by flow cytometry . RESULTS : Serum sCX3CL1 levels were significantly higher in ___MASK47___ patients than in either LVV group or healthy individuals . The elevated sCX3CL1 levels seen in ___MASK47___ patients correlated positively with BVAS , as well as with CRP levels and P03372 , and similarly increased expression of cell - surface P49238 was seen on peripheral blood P01730 and CD8 T cells from patients with ___MASK47___ . Notably , sCX3CL1 levels and P49238 expression were diminished during clinical remission following treatment . CONCLUSION : Our findings suggest that P78423 may be involved in the pathogenesis of ___MASK47___ , and may serve as a useful serologic marker of disease activity in systemic vasculitis .", "___MASK79___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK79___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK79___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .", "P25116 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy . Genetic variations of the protease - activated receptor - 1 ( P25116 ) have been associated with platelet receptor density and linked to thrombin receptor - activating peptide ( TRAP ) - induced phenotypes of platelet aggregation and P16109 expression . We investigated whether the P25116 intervening sequence - 14 A > T dimorphism influences platelet procoagulant activity . We also determined whether the Q9H244 antagonist clopidogrel could offset any observed functional polymorphism of the P25116 receptor by inhibiting Q9H244 - mediated amplification of TRAP - induced responses . We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP - induced platelet aggregation and markers of procoagulant activity . Platelet responses were measured at baseline , 4 h post clopidogrel 300 mg , and 10 and 28 days following clopidogrel 75 mg daily . Each patient was genotyped for the P25116 intervening sequence - 14 A / T dimorphism . Increased platelet aggregation and procoagulant responses were observed with P25116 A allele homozygotes . DB00758 significantly inhibited these platelet responses regardless of P25116 genotype , but did not offset the hyper - reactivity associated with the A / A homozygotes . We conclude that a common sequence variation within the P25116 gene influences TRAP - induced platelet procoagulant activity as well as aggregation . Higher platelet reactivity associated with P25116 IVSn - 14 A allele homozygotes persists despite clopidogrel therapy . These individuals may be at higher risk of thromboembolic events and may require additional anti - platelet medication .", "An association between P23921 haplotype and gemcitabine - induced neutropenia in breast cancer patients . PURPOSE : We examined the pattern of single - nucleotide polymorphisms ( SNPs ) of gemcitabine metabolism - related and target genes in breast cancer patients and evaluated their association with drug response or toxicity . PATIENTS AND METHODS : SNPs in deoxycytidine kinase ( P27707 ) , deoxycytidine monophosphate deaminase ( P32321 ) , and ribonucleotide reductase M1 polypeptide ( P23921 ) were analyzed with genomic DNA of 10 breast cancer cell lines , 74 peripheral blood mononuclear cell ( PBMC ) samples from advanced breast cancer patients treated with gemcitabine , and 56 PBMC samples from healthy volunteers . RESULTS : The incidences of SNPs of breast cancer patients were 1 . 4 % in P27707 ( 626 A > G ) , 10 . 8 % in P32321 ( 315 T > C ) , 40 . 5 % in the first P23921 ( 1082 C > A ) , 44 . 6 % in the second P23921 ( 2455 A > G ) , 44 . 6 % in the third P23921 ( 2464 G > A ) , and 23 % in two P23921 sites ( 2455 A > G and 2464 G > A ) that were similar to those of the normal control group . We found a double SNP of P23921 ( 2455 A > G and 2464 G > A ) to be the novel haplotype that was associated with a lower frequency of chemotherapy - induced toxicity , such as neutropenia ( p < . 01 ) and G - P04141 requirement ( p < . 005 ) . CONCLUSION : P23921 haplotype showed an association with susceptibility to gemcitabine monotherapy in breast cancer patients .", "Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK90___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .", "P25116 14 - amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by P16109 - dependent mechanism . Thrombin cleaves its receptor at arginine - 41 , resulting in the generation of a new receptor NH2 - terminus with the sequence SFLLRNPNDKYEPF . This peptide ( TRP - 14 ) may signal a variety of thrombin ' s responses . We examined the effects of TRP - 14 in inducing endothelial cell hyperadhesivity and neutrophil ( PMN ) adhesion to endothelial cell monolayers . Human umbilical vein endothelial cells ( HUVECs ) challenged with TRP - 14 ( 10 (- 4 ) to 10 (- 5 ) M ) produced concentration - dependent increases in endothelial adhesivity to PMN . In contrast , position 1 to 2 inverted peptide ( FSLLRNPNDKYEPF ) did not induce the response . The adhesion response was transient ; that is , PMN adhesion increased within 15 minutes and decreased by 75 minutes after TRP - 14 challenge of HUVECs . The transient endothelial adhesiveness paralleled the time course of P16109 expression . TRP - 14 - induced release of P16109 from intracellular stores may be a critical determinant of the response since treatment of endothelial cells with anti - P16109 monoclonal antibody ( mAb ) P55008 prevented the increase in PMN adhesion . Control nonneutralizing anti - P16109 mAb P28222 and mAb P23921 / 1 directed against intercellular adhesion molecule - 1 ( P05362 ) on HUVECs were ineffective . The results indicate that the \" tethered ligand \" of the thrombin receptor created by the proteolytic action of thrombin on its receptor ( i . e . , TRP - 14 ) signals increased endothelial adhesiveness by a P16109 - dependent mechanism . Thrombin - induced PMN adhesion may involve formation of a new NH2 - terminus of the endothelial thrombin receptor with the sequence SFLLRNPNDKYEPF followed by activation of endothelial second messenger pathways and the transient expression of P16109 .", "Q8WZ71 and Q8WUP2 as novel marker genes of cisplatin sensitivity in non - small cell lung cancer cells . Even after development of molecular targeting therapies , platinum - based chemotherapy is still a standard care for treatment of locally advanced non - small cell lung cancer ( NSCLC ) . So far , critical molecular markers capable to predict the therapeutic response in NSCLC patients remain undetermined . We here attempted to identify novel biomarker genes for cisplatin ( DB00515 ) for a tailored therapy . Initial screening to explorer association of IC ( 50 ) values of DB00515 obtained by MTT assay and gene expression levels measured with oligonucleotide microarray and real - time RT - PCR provided 6 candidate genes , namely , Q8TB37 , Q96H12 , P17014 , Q8WZ71 , P49841 , and Q8WUP2 using 9 lung cancer cells consisting of 3 small and 6 NSCLC cells . These 6 genes together with 5 reported biomarkers , i . e . , P09211 , P07992 , P38398 , P42345 , and P23921 , were subjected to a linear regression analysis using 12 NSCLC cell lines including 6 additional NSCLC cells : only Q8WUP2 and Q8WZ71 genes showed positive associations with statistical significances ( P = . 016 and . 026 , respectively ) . The biological significance of these genes was explored by in vitro experiments : Knockdown experiments in PC - 9 / DB00515 cells revealed that the reduced expression of Q8WZ71 significantly decreased the chemo - resistance against DB00515 ( P < . 0001 ) , while 2 transformants of PC - 6 cells stably over - expressing Q8WUP2 resulted in an enhanced resistance to DB00515 ( P = . 004 and P = . 001 ) . Furthermore , a stepwise multiple regression analysis demonstrated the best prediction formula could be fixed when we used expression data of Q8WZ71 and Q8WUP2 ( R ( 2 ) = 0 . 755 , P = . 0018 ) . Q8WZ71 and Q8WUP2 may be powerful predictive biomarkers for DB00515 therapy in NSCLC .", "A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK96___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .", "Activation of serotonin receptor - 2B rescues small - for - size liver graft failure in mice . The implantation of grafts below 30 % of the normal liver volume is associated with a high risk of failure known as small - for - size ( SFS ) syndrome . Strategies to rescue small grafts may have a dramatic impact on organ shortage . Serotonin is a potent growth factor for the liver . The goal of this study was to determine whether enhanced serotonin signaling could prevent the deleterious effects of SFS syndrome . We performed 30 % normal liver volume transplantations in wild - type C57 / BL6 and interleukin - 6 ( P05231 ) (-/-) mice . Some animals received α - methyl - 5 - HT ( DOI ) , an agonist of serotonin receptor - 2 ( P41595 ) . Endpoints included long - term survival , serum and hepatic markers of liver injury and regeneration , assessment of hepatic microcirculation by intravital fluorescence microscopy and scanning electron microscopy , and transcript levels of a variety of serotonin receptors , tumor necrosis factor α , and P05231 . All recipients of small grafts ( controls ) died within 2 - 4 days of transplantation , whereas half of those receiving DOI survived permanently . Control animals disclosed major liver injury , including diffuse microvesicular steatosis in hepatocytes , impairment of microcirculation , and a failure of regeneration , whereas these parameters were dramatically improved in animals subjected to DOI . Blockage of P41595 blunted the protective effects of DOI . Whereas P05231 levels were higher in DOI - treated animals , P05231 (-/-) mice were still protected by DOI , suggesting a protective pathway independent of P05231 . CONCLUSION : Serotonin through its action on receptor - 2B protects SFS liver grafts from injury and prevents microcirculation and regeneration . The mechanism of hepato - protection is independent of P05231 .", "An investigation of a workplace cluster of Bell ' s palsy . We undertook a study to confirm the existence of an apparent cluster of Bell ' s palsy in an industrial plant ( \" W4 \" ) , and to test etiologic hypotheses regarding chemical exposures , immune suppression , and infectious etiologies . Cases were enumerated by questionnaire . Employees with a history of Bell ' s palsy ( \" cases \" ) were invited to participate in a study that included medical history , T cell studies , viral and Lyme disease serologies , and blink reflex studies . Thirty - three unaffected volunteers from W4 and 32 from a comparison building were also tested . Extensive environmental studies were carried out in W4 , evaluating infectious , chemical , and radiation exposures . The lifetime incidence of self - reported Bell ' s palsy was 11 . 6 / 10 , 000 person - years ( P - Y ) in W4 and 2 . 4 cases / 10 , 000 P - Y in the comparison building ( RR = 4 . 8 , P < . 05 ) ; the comparison rate was similar to that reported in previous population studies . When restricted to cases occurring after the onset of work , the W4 incidence was 29 . 2 cases / 10 , 000 P - Y , compared to 4 . 8 cases / 10 , 000 P - Y in the comparison building ( RR = 6 . 1 , P < . 05 ) . The cases and noncases did not differ with respect to clinical histories or infectious disease titers . The W4 noncases had small but significant decreases in T lymphocyte ( 1974 +/- 86 vs 2291 +/- 103 ) and P01730 ( 1083 +/- 318 vs 1459 +/- 494 ) counts compared to the remote noncases . The cases had significantly prolonged P23921 , LR1 , and LFC values compared to both groups of noncases . No medical or environmental factors were identified that could explain an excess of disease .", "Predictive molecular markers : has the time come for routine use in lung cancer ? Although some evidence exists to support the use of clinical factors such as performance status and weight loss to predict response and toxicity to therapy in non - small cell lung cancer ( NSCLC ) patients , researchers have shown little prospective data on the use of molecular markers to facilitate selection of specific chemotherapy or new molecularly targeted agents in this patient population . Breast cancer exemplifies the growing role that molecular markers are playing , not only as prognostic factors , but also in predicting response to targeted treatments such as hormonal therapy , and more recently , trastuzumab ( Herceptin ) . Although several studies have examined molecular markers in lung cancer and have shown promising potential value , these studies were retrospective and require prospective validation . To identify molecular markers that reliably predict response and to be able to individualize cytotoxic and targeted therapy for NSCLC patients are the ultimate goals of future trials . This article focuses on a selected number of promising markers under study in lung cancer , including those thought to play roles in response to DNA damaging chemotherapy ( excision repair cross - complementing [ P07992 ] , xeroderma pigmentosum group D [ P18074 ] ) , taxane resistance ( beta - tubulin III ) , antimetabolite therapy ( P23921 ) , irinotecan metabolism ( P22309 ) and epidermal growth factor receptor ( P00533 ) pathway inhibition . To date , none of these markers can be recommended for routine use in clinical practice .", "Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK56___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .", "An ordered NotI fragment map of human chromosome band 11p15 . An ordered NotI fragment map containing over 60 loci and encompassing approximately 17 Mb has been constructed for human chromosome band 11p15 . Forty - two probes , including 11 NotI - linking cosmids , were subregionally mapped to 11p15 using a subset of the J1 - deletion hybrids . These and 23 other probes defining loci previously mapped to 11p15 were hybridized to genomic DNA digested with NotI and 5 other infrequently cleaving restriction enzymes and separated by pulsed - field gel electrophoresis . Thirty - nine distinct NotI fragments were detected encompassing approximately 85 % of the estimated length of 11p15 . The predicted order of the gene loci used is cen - P15172 - PTH - CALCA - P78524 - P25800 - P02790 - P68871 - P23921 - TH / P01308 / P01344 - H19 - P07339 - Q02817 - P21917 - P01112 - P13489 - tel . This map will allow higher resolution mapping of new 11p15 markers , facilitate positional cloning of disease genes , and provide a framework for the physical mapping of 11p15 in clone contigs .", "Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK54___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .", "Cytokine regulation of intercellular adhesion molecule - 1 ( P05362 ) expression on human glioblastoma cells . Intercellular adhesion molecule - 1 ( P05362 ) has recently been identified as one of the ligands for lymphocyte function - associated antigen - 1 ( LFA - 1 ) . Immunohistochemical staining of frozen tissue sections using the P05362 antibody P23921 / 1 demonstrated significant levels of P05362 expression on human glioblastoma cells and on intratumoural vascular endothelial cells . P05362 was weakly expressed or absent from low grade gliomas and absent from normal and fetal brain . P05362 expression was similar to that of MHC class II . HLA - DR antigens . Glioblastoma cell lines constitutively expressed P05362 to a minimal or moderate extent . Surface antigen expression of P05362 and P05362 - specific mRNA could be significantly increased by incubating glioblastoma cells with interleukin - 1 beta ( P01584 ) , tumour necrosis factor - alpha ( P01375 ) , and interferon - gamma ( P01579 ) . P60568 , P05112 , P05231 and transforming growth factor beta 2 ( TGF - beta 2 ) had no significant effect on surface antigen expression . Significant enhancement of P05362 expression was obtained using P01375 and P01584 at 1 - 10 U / ml and at 500 U / ml of P01579 . Induction of P05362 specific mRNA was observed 4 h after cytokine treatment and decreased by 24 h . Surface antigen expression of P05362 increased for up to 48 h after treatment .", "P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV - associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . ___MASK78___ , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV - induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R ." ]

[ "___MASK26___", "___MASK47___", "___MASK54___", "___MASK56___", "___MASK78___", "___MASK79___", "___MASK83___", "___MASK90___", "___MASK96___" ]

[ "Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK41___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .", "Expression of genes associated with bone resorption is increased and bone formation is decreased in mice fed a high - fat diet . A high - fat diet ( HFD ) leads to an increased risk of osteoporosis - related fractures , but the molecular mechanisms for its effects on bone metabolism have rarely been addressed . The present study investigated the possible molecular mechanisms for the dyslipidemic HFD - induced bone loss through comparing femoral gene expression profiles in HFD - fed mice versus the normal diet - fed mice during the growth stage . We used Affymetrix 430A Gene Chips to identify the significant changes in expression of the genes involved in bone metabolism , lipid metabolism , and the related signal transduction pathways . Quantitative RT - PCR was carried out on some significant genes for corroboration of the microarray results . At the conclusion of the 12 - week feeding , the down - regulation of most of the genes related to bone formation and the up - regulation of most of the genes related to bone resorption were observed in the HFD - fed mice , consistent with the changes in plasma bone metabolic biomarkers . Together , the HFD induced a decrease in the majority of the adipogenesis - , lipid biosynthesis - , and fatty acid oxidation - related gene expression , such as PPARg and P02649 . Furthermore , some genes engaged in the related signal transduction pathway were strongly regulated at the transcript level , including P22692 , TGFbR1 , IL - 17a , P05112 , and P04637 . These results indicate that an HFD may induce inhibitory bone formation and enhanced bone resorption , thus causing adverse bone status .", "aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK89___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .", "Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK44___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK44___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .", "Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK96___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK96___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .", "' A variant of uncertain significance ' and the proliferation of human disease gene databases . The rapid accumulation of mutation data has led to the creation of nearly 300 locus - specific mutation databases . These sites may contain a few dozen to almost 20 , 000 mutations for a given gene . Many of the mutations are uncharacterised and have no known effects on the gene product , the ' variant of uncertain significance ' . Here , the statistics of mutation distribution are examined for six different gene databases : P38398 and P51587 , haemoglobin - beta ( P68871 ) , P00492 , P13569 and P04637 . The percentage of all possible point mutations for a protein ( the mutation space ) is calculated for each gene and the question ' How much mutation data is enough ? ' is raised .", "[ Moclobemide ( ___MASK26___ ) , the first P21397 - inhibitor : really something new ? ] .", "Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .", "Signaling pathways in adrenocortical cancer . Adrenocortical carcinoma is a rare tumor that carries a very poor prognosis . Despite efforts to develop new therapeutic regimens to treat this disease , surgery remains the mainstay of treatment . Laboratory studies of adrenocortical cancers have revealed a wide variety of signaling pathways that can be altered in these neoplasms . Although ___MASK72___ signaling through adenylyl cyclase and protein kinase A is important for normal adrenal cellular physiology , there is evidence to suggest that this pathway may inhibit the growth of adrenocortical tumors , and that inactivation of the Q01718 may promote tumor formation . Although multiple signal transduction pathways are essential for normal adrenal growth and hormone secretion , efforts to identify events required for neoplastic transformation have met with limited success . Alterations that have frequently been observed in adrenocortical carcinoma include up - regulation of the P01344 system , as well as mutations in P04637 and DB01367 . Current studies aim to elucidate the mechanisms of tumor growth by studying proproliferative signaling pathways , such as those involving Akt / P31749 and the mitogen - activated protein kinases ( MAPKs ) . Although studies of single pathways have been helpful in guiding investigations , new tools to study the integration and multiplicity of signaling pathways hold the hope of improved understanding of the signaling pathway alterations in adrenocortical cancer .", "Changes in tissue transglutaminase activity and expression during retinoic acid - induced growth arrest and apoptosis in primary cultures of human epithelial prostate cells . We treated primary epithelial cells from human normal prostate ( NEPC ) and prostate cancer ( CEPC ) with all - trans - retinoic acid ( RA ) to study whether it regulates the activity of tissue transglutaminase ( tTGase ) , an enzyme that accumulates in cells undergoing apoptosis . tTGase activity was assessed by [ 14C ] spermidine incorporation ; tTGase , P04637 , Bcl - 2 , and P38936 protein levels were evaluated by Western blotting ; and RA receptors ( RAR alpha , - beta , and - gamma ) , tTGase , retinol - binding protein ( P02753 ) , and cellular P02753 type I transcripts were determined by semiquantitative RT - PCR . After 72 - 96 h of 10 (- 6 ) mol / L RA treatment , cell growth inhibition and apoptosis were associated with increased tTGase activity in both NEPC and CEPC , and with increased tTGase protein and messenger ribonucleic acid levels only in NEPC . Moreover , RA down - regulated RAR alpha and - beta and increased P02753 messenger ribonucleic acid levels in NEPC , whereas it increased RAR beta gene expression and decreased Bcl - 2 protein levels in CEPC . Our results suggest that RA induces tTGase gene expression and enzyme activity in normal prostate cells , and that RA - regulated pathways are impaired in cancer cells . Moreover , down - regulation of Bcl - 2 protein and up - regulation of RAR beta suggest that retinoid may act on the genetic defect responsible for prostate cancer progression .", "Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK74___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK74___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK74___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK74___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK74___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK74___ increased the protein expression of hepatic P05181 and ___MASK74___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK74___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK74___ and RFP - induced hepatotoxicity .", "Defining the molecular basis of amyloid inhibitors : human islet amyloid polypeptide - insulin interactions . Human islet amyloid polypeptide ( hIAPP or P10997 ) is a 37 residue hormone that is cosecreted with insulin from the pancreatic islets . The aggregation of hIAPP plays a role in the progression of type 2 diabetes and contributes to the failure of islet cell grafts . Despite considerable effort , little is known about the mode of action of P10997 amyloid inhibitors , and this has limited rational drug design . P01308 is one of the most potent inhibitors of hIAPP fibril formation , but its inhibition mechanism is not understood . In this study , the aggregation of mixtures of hIAPP with insulin , as well as with the separate A and B chains of insulin , were characterized using ion mobility spectrometry - based mass spectrometry and atomic force microscopy . P01308 and the insulin B chain target the hIAPP monomer in its compact isoform and shift the equilibrium away from its extended isoform , an aggregation - prone conformation , and thus inhibit hIAPP from forming β - sheets and subsequently amyloid fibrils . All - atom molecular modeling supports these conclusions .", "Clinical correlates of promoter hypermethylation of four target genes in head and neck cancer : a cooperative group correlative study . PURPOSE : Promoter hypermethylation is a well - documented mechanism for tumor - specific alteration of suppressor gene activity in human malignancy including head and neck cancer ( HNC ) . The abrogation of specific suppressor gene activity may influence tumor behavior and clinical outcome . In this study we examined methylation of P43146 , Q12756 , P24530 , and p16 ( INK4a ) in a large cohort of HNC patients from Eastern Cooperative Group ( ECOG ) 4393 / Radiation Therapy Oncology Group ( RTOG ) 9614 to identify clinical correlates of methylation of these genes . EXPERIMENTAL DESIGN : Methylation was assessed by quantitative methylation - specific PCR in DNA from tumor specimens and was considered as a continuous and a binary variable . Clinical data including demographics , stage , risk factor exposure , treatment , and outcome were collected by ECOG and RTOG . Methylation status was also correlated with mutation of P04637 ( previously reported ) and human papilloma virus status . RESULTS : Methylation results were available for 368 cases , 353 of which also have p53 mutation status . At least one methylation event was present in all tumors . In multivariate analysis of the entire cohort , methylation of p16 was associated with decreased survival ( HR = 1 . 008 ; P = 0 . 045 ) . However , in tumors with disruptive P04637 mutation ( poor prognostic group ) , the additional presence of methylation of p16 was protective ( P = 0 . 019 considering p16 methylation as a continuous variable ) . CONCLUSION : Methylation of tumor - related genes contributes to the biological behavior of HNC and influences overall survival in conjunction with other known prognostic molecular events .", "P10997 - driven metabolic reprogramming induces regression of p53 - deficient tumours in vivo . P04637 is commonly altered in human cancer , and Tp53 reactivation suppresses tumours in vivo in mice ( P04637 and Tp53 are also known as p53 ) . This strategy has proven difficult to implement therapeutically , and here we examine an alternative strategy by manipulating the p53 family members , Tp63 and Tp73 ( also known as p63 and p73 , respectively ) . The acidic transactivation - domain - bearing ( TA ) isoforms of p63 and p73 structurally and functionally resemble p53 , whereas the ΔN isoforms ( lacking the acidic transactivation domain ) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant - negative fashion against p53 , TAp63 and TAp73 to inhibit their tumour - suppressive functions . The p53 family interacts extensively in cellular processes that promote tumour suppression , such as apoptosis and autophagy , thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway . Here we show that deletion of the ΔN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53 - deficient tumours through upregulation of P10997 , the gene that encodes amylin , a 37 - amino - acid peptide co - secreted with insulin by the β cells of the pancreas . We found that P10997 is causally involved in this tumour regression and that amylin functions through the calcitonin receptor ( CalcR ) and receptor activity modifying protein 3 ( O60896 ) to inhibit glycolysis and induce reactive oxygen species and apoptosis . DB01278 , a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes , caused rapid tumour regression in p53 - deficient thymic lymphomas , representing a novel strategy to target p53 - deficient cancers .", "Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK40___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .", "Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK29___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .", "E3 ubiquitin ligase Q13049 negatively regulates tumor suppressor p53 to promote tumorigenesis . P04637 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses , including apoptosis , cell cycle arrest and senescence . To ensure its proper levels and functions in cells , p53 is tightly regulated mainly through post - translational modifications , such as ubiquitination . Here , we identified E3 ubiquitin ligase Q13049 as a novel p53 target gene and negative regulator to regulate p53 - mediated stress responses . In response to stress , such as DNA damage , p53 binds to the p53 responsive element in the promoter of the Q13049 gene and transcriptionally induces the expression of Q13049 in cells . In turn , Q13049 interacts with p53 and promotes p53 degradation through ubiquitination . Thus , Q13049 negatively regulates p53 - mediated apoptosis , cell cycle arrest and senescence in response to stress . Q13049 is frequently overexpressed in different types of human tumors . Q13049 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53 - dependent manner . Taken together , our results demonstrated that as a novel p53 target and a novel negative regulator for p53 , Q13049 has an important role in regulation of p53 and p53 - mediated cellular stress responses . Furthermore , our results also revealed that impairing p53 function is a novel mechanism for Q13049 in tumorigenesis ." ]

[ "___MASK26___", "___MASK29___", "___MASK40___", "___MASK41___", "___MASK44___", "___MASK72___", "___MASK74___", "___MASK89___", "___MASK96___" ]

[ "Expression of cyclooxygenase - 2 in urinary bladder in rats with cyclophosphamide - induced cystitis . These studies examined the expression of cyclooxygenase - 2 ( P35354 ) expression in the urothelium and suburothelial space and detrusor from rats treated with cyclophosphamide ( CYP ) to induce acute ( 4 h ) , intermediate ( 48 h ) , or chronic ( 10 - day ) cystitis . Western blot analysis and immunohistochemistry were used to demonstrate P35354 expression . In whole mount preparations of urinary bladder , nerve fibers in the suburothelial plexus , and inflammatory cell infiltrates were characterized for P35354 expression after CYP - induced cystitis . P35354 expression significantly ( P < or = 0 . 01 ) increased in the urothelium + suburothelium and detrusor smooth muscle with acute , intermediate , and chronic ( 10 - day ) CYP - induced cystitis , but expression in urothelium + suburothelium was significantly greater . CYP - induced upregulation of P35354 showed by immunostaining in the urothelium + suburothelium was similar to that observed with Western blot analysis and also demonstrated P35354 inflammatory cell infiltrates ( P42081 + ) and nerve fibers ( A6NDG6 + ) in the suburothelial plexus . Although P35354 expression was significantly ( P < or = 0 . 01 ) increased in detrusor smooth muscle , immunohistochemistry failed to demonstrate an obvious change in P35354 - immunoreactivity ( IR ) in detrusor muscle , but P35354 inflammatory infiltrates were present throughout the detrusor . P35354 - IR nerve fibers exhibited increased density in the suburothelial plexus with acute or chronic CYP - induced cystitis . P35354 - IR macrophages ( P42081 + ) were present throughout the urinary bladder with acute and chronic CYP - induced cystitis . These studies demonstrate cellular targets in the urinary bladder where P35354 inhibitors may act .", "Rational development of DB06681 ( belatacept ) , a high - affinity variant of P16410 - Ig with potent immunosuppressive properties . Current success in organ transplantation is dependent upon the use of calcineurin - inhibitor - based immunosuppressive regimens . Unfortunately , current immunotherapy targets molecules with ubiquitous expression resulting in devastating non - immune side effects . T - cell costimulation has been identified as a new potential immunosuppressive target . The best characterized pathway includes P10747 , its homologue P16410 and their ligands P33681 and P42081 . While an immunoglobulin fusion protein construct of P16410 suppressed rejection in rodents , it lacked efficacy in primate transplant models . In an attempt to increase the biologic potency of the parent molecule a novel , modified version of P16410 - Ig , DB06681 ( belatacept ) , was constructed . Two amino acid substitutions ( L104E and A29Y ) gave rise to slower dissociation rates for both P42081 and P33681 . The increased avidity resulted in a 10 - fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre - clinical primate model . The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants .", "Viral - induced P10747 loss evokes costimulation independent alloimmunity . BACKGROUND : DB06681 , a P33681 - specific fusion protein , blocks P10747 - P33681 costimulation and prevents kidney allograft rejection . However , it is ineffective in a sizable minority of patients . Although T - cell receptor and P10747 engagement are known to initiate T - cell activation , many human antigen - experienced T - cells lose P10747 , and can be activated independent of P10747 signals . We posit that these cells are central drivers of costimulation blockade resistant rejection ( CoBRR ) and propose that CoBRR might relate to an accumulation of P10747 (-) T - cells resulting from viral antigen exposure . MATERIALS AND METHODS : We infected C57BL / 6 mice with polyomavirus ( a BK virus analog ) , murine cytomegalovirus ( a human cytomegalovirus analog ) , and gammaherpesvirus ( HV68 ; an Epstein - Barr virus analog ) and assessed for P10747 expression relative to mock infection controls . We then used mixed lymphocyte reaction ( P08235 ) assays to assess the alloreactive response of these mice against major histocompatibility complex - mismatched cells . RESULTS : We demonstrated that infection with polyomavirus , murine CMV , and HV68 can induce P10747 downregulation in mice . We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic , costimulation blockade resistant , alloreactive response against major histocompatibility complex - mismatched cells without prior alloantigen exposure . Further analysis revealed that gammherpesvirus - induced oligoclonal T - cell expansion is required for the increased alloreactivity . CONCLUSIONS : Virus exposure results in reduced T - cell expression of P10747 , the target of costimulation blockade therapy . These viruses also contribute to increased alloreactivity . Thus , P10747 downregulation after viral infection may play a seminal role in driving CoBRR .", "What ' s in the pipeline ? New immunosuppressive drugs in transplantation . In the pipeline , there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials . The major target of new agents are cell - surface molecules important in immune cell interactions ( especially the costimulatory pathway ) , signaling pathways that activate T cells , T - cell proliferation and trafficking and recruitment of immune cells responsible for rejection . The most promising biologic agents include a humanized anti - CD11a ( anti - LFA1 ) , humanized anti - P33681 . 1 / P33681 . 2 , a second - generation DB01281 ( DB06681 ) and a humanized antibody to anti - P08575 RB . Inhibitors of T - cell activation and signaling are still in preclinical development . The most interesting inhibitors of T - cell proliferation include inhibitors of the Janus protein tyrosine kinase , P52333 , and FK778 , a leflunomide analog . Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes . Early trials of FTY720 , a synthetic small molecule with functional homology to sphingosine - 1 phosphate leading to lymphocyte sequestration , appear very promising ; however , enthusiasm for this drug is mitigated by its potential cardiac side - effects . Antagonists to several chemokine receptors , including P32246 , P49682 and P51681 , have been shown to be effective in experimental transplantation and are likely to be considered for clinical development .", "Pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept in adult kidney transplant recipients . BACKGROUND AND OBJECTIVES : DB06681 is a first - in - class , selective co - stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients . The objective of this study was to report the pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept . METHODS : The pharmacokinetics , pharmacodynamics ( P42081 receptor occupancy ) , and immunogenicity of belatacept were studied in de novo adult kidney transplant recipients in phase II and III clinical studies . RESULTS : Following multiple doses of 5 or 10 mg / kg , the geometric mean ( percentage coefficient of variation ) maximum serum concentration and area under the serum concentration - time curve over one dosing interval of belatacept were 136 ( 20 % ) and 238 ( 27 % ) μg / mL , and 13 , 587 ( 27 % ) and 21 , 241 ( 35 % ) μg · h / mL , respectively . The median belatacept elimination half - life was 8 - 9 days . DB06681 exhibited concentration - dependent binding to P42081 receptors . The pre - dose P42081 receptor occupancy by belatacept decreased from 94 to 65 % between day 5 and 1 year post - transplant , with corresponding pre - dose trough serum concentrations of belatacept decreasing from ~ 35 to 4 μg / mL during this period . The cumulative incidence of developing anti - belatacept antibodies was 5 . 3 % up to 3 years post - transplant and had no impact on belatacept exposure . CONCLUSIONS : DB06681 in adult kidney transplant demonstrated linear pharmacokinetics with low variability , concentration - dependent pharmacodynamics , and a low incidence of anti - drug antibodies .", "DB06681 : from rational design to clinical application . Gradually improved immunosuppression has contributed significantly to the progress achieved in transplantation medicine so far . Nevertheless , current drug regimens are associated with late graft loss -- in particular as a result of immunologic damage or drug toxicity -- and substantial morbidity . Recently , the costimulation blocker belatacept ( marketed under the name Nulojix ® ) has been approved for immunosuppression in renal transplantation . DB06681 ( a mutated version of DB01281 ) is a fusion protein rationally designed to block P10747 , a critical activating receptor on T cells , by binding and saturating its ligands P33681 - 1 and P33681 - 2 . In phase II and III trials , belatacept was compared with cyclosporine ( in combination with basiliximab , DB00688 , and steroids ) . Advantages observed with belatacept include superior graft function , preservation of renal structure and improved cardiovascular risk profile . Concerns associated with belatacept are a higher frequency of cellular rejection episodes and more post - transplant lymphoproliferative disorder ( PTLD ) cases especially in EBV seronegative patients , who should be excluded from belatacept - based regimens . Thus , after almost three decades of calcineurin inhibitors as mainstay of immunosuppression , belatacept offers a potential alternative . In this article , we will provide an overview of belatacept ' s preclinical development and will discuss the available evidence from clinical trials .", "DB09201 inhibits oxidized - low density lipoprotein induced immune maturation of dendritic cells . BACKGROUND : The peroxisome proliferator - activated receptor ( Q07869 ) activation has generally been shown to have anti - inflammatory effects and dendritic cells ( DCs ) are the most efficient antigen presenting cells that play an active role in the development of atherosclerosis . The effects of PPARgamma on DCs maturation and immune function remain unknown now and we , therefore , studied the influence of PPARgamma agonist ciglitazone on the maturation and immune function of DCs . METHODS : Human monocytes were purified and immature DCs derived ; ciglitazone ( 25 micromol / L ) was added to the medium for 24 hours ; ox - LDL ( 50 microg / ml ) was then added to the medium for another 24 hours . The immunophenotypic expressions ( CD1a , P25942 , P42081 , and HLA - DR ) were analyzed by FACS and endocytosis function by FITC - dextran and the cytokines secretions of culture supernatants ( IL - 12 , P22301 , TNFalpha , and P60568 ) were measured with ELISA . RESULTS : DB09201 reduced ox - LDL induced immunophenotypic expressions of DCs ( P25942 , CD1a , and HLA - DR ) . Ox - LDL inhibited the endocytosis of DCs , which was prevented by ciglitazone ; ciglitazone attenuated ox - LDL induced cytokine secretions of DCs ( IL - 12 , 116 +/- 29 versus 34 +/- 3 pg / ml * ; P22301 , 49 +/- 1 versus 28 +/- 9 pg / ml * ; TNFalpha , 46 +/- 16 versus 24 +/- 8 pg / ml * , * P < 0 . 05 compared with ox - LDL , respectively ) . CONCLUSION : Our study suggested that one of the anti - inflammatory mechanisms of P37231 agonist ciglitazone was mediated by inhibiting the ox - LDL induced maturation and immune function of DCs .", "DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .", "Technology evaluation : DB06681 , Bristol - Myers Squibb . Bristol - Myers Squibb is developing belatacept , a soluble fusion protein of the P33681 - binding domain of P16410 with amino acid changes A29Y and L104E and an Ig tail , which inhibits lymphocyte co - stimulation through P10747 , for the potential treatment of solid organ transplant rejection . DB06681 is currently undergoing phase III clinical trials .", "The impact of biological agents interfering with receptor / ligand binding in the immune system . We herein discuss the impact of biological agents based on the ability of monoclonal antibodies to target specific molecules . This approach has given to clinical immunologists a spectrum of drugs able to manipulate the immune system . In the first session , we discuss drugs targeting T - cell function by : ( 1 ) targeting P10747 mediated costimulation ( DB01281 and DB06681 ) ; ( 2 ) interfering with interleukin - 2 receptor ( DB00074 and DB00111 ) ; ( 3 ) blocking cell adhesion and homing ( DB00092 , DB00095 , DB00108 ) . The second session is dedicated to drugs targeting cytokines or their receptors . The best known and largely experimented case is represented by drugs targeting tumor necrosis factor ( P01375 ) ( DB00065 , Adalilumab , Certolizumab ) or its p75 receptor ( DB00005 ) . However , newer products are now available to target other inflammatory cytokines including P05231 , P10145 , IL - 12 , P40933 , Q14116 , IL - 23 . These agents have the potential to become powerful tools in the control of several immune - mediated diseases , especially auto - immune and inflammatory ones . They traslate into reality the prediction that antibodies will eventually become \" magic bullets which seek their own target \" ( P . Ehrich , 1906 ) .", "T cell costimulation : a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation . T cells are central mediators of adaptive immunity . As such , they are involved in both normal immune responses ( e . g . , rejection of a transplanted organ ) and abnormal ones ( e . g . , rheumatoid arthritis ) . T cells require both antigen - specific and costimulatory signals for their full activation . Advances in protein engineering and an increased understanding of the immune response have culminated in the evolution and creation of protein therapeutics that target specific costimulatory molecules . The selective costimulation modulator abatacept ( CTLA - 4Ig ) binds to P33681 and P42081 , blocking interaction with P10747 , and is approved for the treatment of moderate to severe rheumatoid arthritis . DB06681 , currently enrolling phase III trials in renal transplantation , was rationally designed from abatacept to bind with more avidity to P42081 , providing the more potent immunosuppressive properties required for immunosuppression in transplantation . This review describes the relevant immunology and summarizes recent clinical findings on these two molecules . Although both inhibit the P10747 costimulatory pathway , they are tailored for specific disease states -- abatacept for autoimmune diseases and belatacept for transplantation .", "Differential expression and function of phosphodiesterase 4 ( DB05876 ) subtypes in human primary P01730 + T cells : predominant role of Q08499 . Type 4 phosphodiesterases ( DB05876 ) are critical regulators in TCR signaling by attenuating the negative constraint of DB02527 . In this study , we show that anti - CD3 / P10747 stimulation of human primary P01730 (+) T cells increases the expression of the DB05876 subtypes P27815 , Q07343 , and Q08499 in a specific and time - dependent manner . P27815 and Q08499 mRNAs as well as enzyme activities were up - regulated within 5 days , Q07343 showed a transient up - regulation with highest levels after 24 h . The induction was shown to be independent of different stimulation conditions and was similar in naive and memory T cell subpopulations . To elucidate the functional impact of individual DB05876 subtypes on T cell function , we used DB05876 subtype - specific short - interfering RNAs ( siRNAs ) . Knockdown of either Q07343 or Q08499 inhibited P60568 release 24 h after stimulation ( time point of maximal P60568 concentrations ) to an extent similar to that observed with the panPDE4 inhibitor RP73401 ( piclamilast ) . Substantial amounts of P01579 or P05113 were measured only at later time points . siRNA targeting Q08499 showed a predominant inhibitory effect on these cytokines measured after 72 h . However , the inhibition of all cytokines was most effective when DB05876 siRNAs were applied in combination . Although the effect of DB05876 inhibition on T cell proliferation is small , the Q08499 - targeting siRNA alone was as effective as the panPDE4 inhibitor , whereas P27815 or Q07343 siRNAs had hardly an effect . In summary , individual DB05876 subtypes have overall nonredundant , but complementary , time - dependent roles in propagating various T cell functions and Q08499 is the form likely playing a predominant role .", "Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .", "P28906 + hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM - P04141 + P01375 alpha . Human dendritic cells ( DC ) can now be generated in vitro in large numbers by culturing P28906 + hematopoietic progenitors in presence of GM - P04141 + P01375 alpha for 12 d . The present study demonstrates that cord blood P28906 + HPC indeed differentiate along two independent DC pathways . At early time points ( day 5 - 7 ) during the culture , two subsets of DC precursors identified by the exclusive expression of CD1a and P08571 emerge independently . Both precursor subsets mature at day 12 - 14 into DC with typical morphology and phenotype ( P33681 , Q01151 , P42081 , P19256 , high HLA class II ) . CD1a + precursors give rise to cells characterized by the expression of Birbeck granules , the Lag antigen and P12830 , three markers specifically expressed on Langerhans cells in the epidermis . In contrast , the P08571 + progenitors mature into CD1a + DC lacking Birbeck granules , P12830 , and Lag antigen but expressing P06729 , P21926 , P34810 , and the coagulation factor XIIIa described in dermal dendritic cells . The two mature DC were equally potent in stimulating allogeneic CD45RA + naive T cells . Interestingly , the P08571 + precursors , but not the CD1a + precursors , represent bipotent cells that can be induced to differentiate , in response to P09603 , into macrophage - like cells , lacking accessory function for T cells . Altogether , these results demonstrate that different pathways of DC development exist : the Langerhans cells and the P08571 (+)- derived DC related to dermal DC or circulating blood DC . The physiological relevance of these two pathways of DC development is discussed with regard to their potential in vivo counterparts .", "DB06681 : a new era of immunosuppression ? Q8N1N2 T - cell activation in alloimmunity requires the engagement of several costimulatory molecules . P16410 - Ig and its commercially available fusion proteins , belatacept and abatacept , are used to block P33681 / 86 and promote T - cell tolerance . DB06681 , a higher binding affinity molecule , is currently approved for clinical use in renal transplantation . The results of two Phase III clinical trials showed a similar patient / graft survival , with better renal function at a 3 - year follow - up compared with conventional immunosuppression . There was a higher risk of early rejection and post - transplant lymphoproliferative disorder , especially with EBV - negative patients receiving kidneys from EBV - positive donors . DB06681 - treated groups had a better cardiovascular and metabolic profile . The authors review both preclinical and human studies of P16410 - Igs .", "Assessment of belatacept - mediated costimulation blockade through evaluation of P33681 / 86 - receptor saturation . BACKGROUND : The selective inhibitor of T - cell costimulation , belatacept , blocks P10747 - mediated T - cell activation by binding P33681 and P42081 on antigen - presenting cells . Understanding the extent to which belatacept binds to its targets in patients may enable correlation of belatacept exposure to receptor saturation as a pharmacodynamic measure of costimulation blockade . METHODS : Flow cytometry - based receptor competition assays were developed to monitor concentration - dependent occupancy of P33681 and P42081 receptors in whole blood and dendritic cell cultures in vitro . Receptor occupancy was correlated with inhibition of mixed leukocyte reactions and clinical validation was obtained by comparing receptor saturation in whole blood from healthy volunteers and in de novo renal transplant recipients participating in studies comparing cyclosporine and belatacept - based immunosuppression . RESULTS : DB06681 saturated P33681 and P42081 receptors in whole blood and dendritic cell cultures , although the belatacept concentrations required for P42081 - receptor saturation were approximately 10 - fold higher than those required for P33681 saturation ( IC50 = 0 . 102 microg / mL vs . 0 . 009 microg / mL ) . Primary alloresponses were inhibited at the belatacept concentration required for P42081 - receptor saturation , but not at the lower concentration needed to saturate P33681 . Whole blood from belatacept - treated patients had significantly lower levels of free P42081 receptors versus pretransplant levels , healthy volunteers , or cyclosporine - treated patients . P42081 - receptor saturation correlated with belatacept dose / dose frequency and remained consistently more than 80 % . CONCLUSIONS : These results suggest that belatacept - mediated inhibition of alloresponses involved in transplant rejection correlates with P42081 saturation , indicating that P42081 - receptor occupancy may be a valid pharmacodynamic measure of costimulation blockade and provide the first direct clinical evidence that belatacept binds to one of its targets .", "The insulin - like growth factor - binding protein 1 gene is a primary target of peroxisome proliferator - activated receptors . P08833 ( P08833 ) is a biomarker for metabolic and hyperproliferative diseases . At the same time , the nuclear receptors peroxisome proliferator - activated receptors ( PPARs ) are known for their critical role in the development of both the metabolic syndrome and various cancers . Here we demonstrate , in human hepatocellular carcinoma cells and in normal mouse liver , that P08833 mRNA expression is under the primary control of Q07869 ligands . We applied an improved in silico screening approach for Q07869 response elements ( PPREs ) and identified five candidate PPREs located within 10 kb of the transcription start site ( TSS ) of the P08833 gene . Chromatin immunoprecipitation assays showed that , in living cells , the genomic region containing the most proximal PPRE , at position - 1200 ( relative to the TSS ) , preferentially associates with multiple Q07869 subtypes and various other components of the transcriptional apparatus , which include their heterodimerizing partner , retinoid X receptor , as well as phosphorylated RNA polymerase II , co - repressor , co - activator , and mediator proteins . Moreover , further chromatin immunoprecipitation assays demonstrated that the TSS regions of the P08833 gene and those of the related P18065 , - 5 , and - 6 , but not of P17936 and - 4 genes , bind PPARs as well . We also show that these additional Q07869 binding genes contain a number of candidate PPREs and that their mRNA levels respond quickly to the presence of Q07869 ligands , indicating that they are also primary Q07869 target genes .", "Advances in immunosuppression for kidney transplantation : new strategies for preserving kidney function and reducing cardiovascular risk . The development of new immunosuppressants for renal transplantation is aimed not only at improving & nbsp ; short - term outcomes , but also at achieving better safety , cardiovascular , and metabolic profiles and at decreasing & nbsp ; nephrotoxicity . DB06681 is a fusion protein that inhibits T cell activation by binding to P33681 and P42081 antigens . Clinical trials , particularly the BENEFIT and BENEFIT - EXT studies , have shown that belatacept preserves function and structure in renal grafts . The effects of belatacept provide long - term , sustained results , and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors . Compared to calcineurin inhibitors , belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile .", "P49771 promotes myeloid dendritic cell differentiation of human hematopoietic progenitor cells : possible application for cancer immunotherapy . Current in vitro culture systems allow the generation of human dendritic progenitor cells ( CFU - DCs ) . The aim of this study was to assess the effect of P49771 ( FL ) on the proliferation of human peripheral blood - derived myeloid CFU - DCs and their differentiation into more committed precursor cells ( pDCs ) using in vitro culture systems . Immunomagnetically separated P28906 + cells were cultured in serum - free , as well as in serum - containing , liquid suspension cultures to investigate the expansion and / or proliferation / differentiation of CFU - DCs , pDCs , and more mature dendritic cells ( DCs ) . FACS - sorted P28906 + Flt3 +/- cells were cultured in methylcellulose to assay hematopoietic progenitors , including CFU - DCs . In the clonal cell culture supplemented with granulocyte / macrophage ( GM ) colony - stimulating factor ( P04141 ) , interleukin - 4 , and tumor necrosis factor alpha , the frequency of CFU - DCs was significantly higher in the P28906 + Flt3 + fraction than in the P28906 + Flt3 - population , thus suggesting functional Flt3 expression on CFU - DCs . Serum - free suspension culture of P28906 + cells revealed the potent effect of FL on the expansion of CFU - DCs in synergy with GM - P04141 and thrombopoietin ( P07202 ) . In addition , FL strongly induced the maturation of CFU - DCs into functional CD1a + pDCs in serum - containing liquid suspension culture . Moreover , these FL - generated pDCs showed remarkable potential to differentiate into mature DCs with surface Q01151 / P42081 expression , which induced a distinct allogeneic T - cell response . These results clearly demonstrate that FL supports not only the proliferation of early hematopoietic progenitor cells , but also the maturation process of committed precursor cells along with the DC - lineage differentiation . Therefore , it is possible to develop a more efficient DC - based cancer immunotherapy using this specific cytokine combination , GM - P04141 + P07202 + FL in vitro in the near future .", "Genetic determinants of diabetes are similarly associated with other immune - mediated diseases . PURPOSE OF REVIEW : I discuss the increasing number of genes discovered to exert pleiotropic action on susceptibility to diabetes and simultaneously to other immune - mediated diseases . While a genetic correlation between type 1 diabetes and autoimmunity is not surprising , the mechanism of a relationship to other conditions such as atopy is less obvious . The recent wave of genome - wide association studies offers confirmation of previously recognized risk loci , but also novel loci that also are likely to act via multiple pathogenetic pathways . I will review this material more in a genetical than an immunological way . RECENT FINDINGS : Identification of Q9BYX4 , an RNA helicase involved in the innate immune response to viral infection as a risk factor for type 1 diabetes and rheumatoid arthritis . Confirmation of the roles of P16410 and Q9Y2R2 as general immune function modulators with a nonlinear dose - response effect on autoimmunity , and confirmation of the role of P01589 , which may act via a regulatory T cell subset on immune disease risk . Expansion of the role of P37231 in immunity . SUMMARY : The wave of genome - wide association studies already experienced in the last 2 years has solidified what we thought we knew and added a list of genes in new pathways . The association of Q9BYX4 with type 1 diabetes may offer a real window into early events in the development of that disease .", "Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK33___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK33___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .", "Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK27___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .", "Production and characterization of DB06681 , a variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin , in Pichia pastoris . Blocking the P10747 / P33681 costimulatory pathway is a promising strategy in the treatment of graft rejection , graft - versus - host disease and autoimmune diseases . DB06681 , a high - affinity variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin ( DB01281 ) , is a more potent inhibitor of the interaction between P10747 and P33681 than is DB01281 . In a previous study , DB06681 was produced in a mammalian cell system , which is time - consuming and expensive . To obtain DB06681 more efficiently and cost effectively , we attempted to produce DB06681 using a Pichia pastoris expression system . The gene encoding DB06681 , with an additional 6 - DB00117 tag at the N - terminus , was cloned into the yeast vector pPIC9K and expressed in the P . pastoris strain GS115 . Under the optimized induction conditions for protein expression ( inoculum density , OD ( 600 ) = 80 ; methanol concentration added daily , 1 . 0 - 3 . 0 % ; induction time point , 72 - 96 h ; culture medium pH = 6 . 0 ) , the yield of purified DB06681 was approximately 30 mg l (- 1 ) by one - step Ni - agarose affinity chromatography . Q96IV0 F treatment showed the purified DB06681 to be post - translational modified by N - linked glycosylation . In biological function assays , DB06681 expressed in P . pastoris demonstrated specific binding to P33681 - 1 / P33681 - 2 - positive Raji cells and also suppressed lymphocyte proliferation in a dose - dependent manner . These results suggest that DB06681 produced in P . pastoris is biologically active and will be useful for experimental therapy on immunotherapy for transplant rejection and autoimmune diseases .", "Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK10___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK10___ who were treated with a single dose of mifepristone .", "Rosiglitazone promotes the differentiation of Langerhans cells and inhibits that of other dendritic cell types from CD133 positive hematopoietic precursors . Dendritic cells and their precursors express P37231 , whose stimulation has inhibitory effects on the maturation and function of dendritic cells in vivo . Dendritic cells can differentiate in vitro from CD133 + progenitors ; the influence of P37231 stimulation on this process is unknown . We have addressed the effect of P37231 agonist rosiglitazone , at a concentration as used in clinics , on the differentiation of dendritic cells from human CD133 + progenitors . Cells were harvested from cord blood by density gradient and immunomagnetic separation , and cultured for 18 days with fetal calf serum , cytokines and 1 μmol / L rosiglitazone . Analyses included flow cytometry , electron microscopy and mixed lymphocyte reaction . As expected , control cells generated without rosiglitazone were dendritic , expressed MHC - II , P33681 , Q01151 and P42081 and stimulated mixed reaction potently . A minority of cells expressed the Langerhans cell marker Q9UJ71 / langerin , but none contained Birbeck granules . With rosiglitazone much fewer cells were generated ; they were all dendritic , expressed differentiation and maturation - related antigens in higher percentage and were better stimulators of lymphocytes than those generated without the drug . The vast majority of cells expressed Q9UJ71 / langerin and many contained Birbeck granules , i . e . were full - fledged Langerhans cells . We conclude that stimulation of P37231 , while negatively affecting the number of generated cells , promotes the maturation of human cord blood CD133 positive precursors into efficient , immunostimulating dendritic cells with a Langerhans cell phenotype .", "P52333 activity is necessary for phosphorylation of cytosolic phospholipase A2 and prostaglandin E2 synthesis by macrophages infected with Francisella tularensis live vaccine strain . Francisella tularensis , the causative agent of tularemia , modulates the host immune response to gain a survival advantage within the host . One mechanism of immune evasion is the ability of F . tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 ( DB00917 ) , which alters the host T cell response making the host more susceptible to Francisella growth . DB00917 is synthesized by a tightly regulated biosynthetic pathway following stimulation . The synthesis of DB00917 begins with the liberation of arachidonic acid ( AA ) from membrane phospholipids by cytosolic phospholipase A2 ( P47712 ) . AA is subsequently converted to the unstable intermediate PGH2 by cyclooxygenase - 2 ( P35354 ) , and PGH2 undergoes an isomerization reaction to generate DB00917 . Our objective was to identify F . tularensis - activated host signaling pathways that regulate the activity of the enzymes in the DB00917 - biosynthetic pathway . In this study , we show that P47712 , p38 mitogen - activated protein kinase ( MAPK ) , and P52333 ( P52333 ) signaling are necessary for F . tularensis - induced DB00917 production . Inhibition of P52333 activity reduced the phosphorylation of P47712 and P35354 protein levels . In addition , P52333 regulates P47712 phosphorylation independent of transcription . Moreover , p38 MAPK activity is required for F . tularensis - induced P35354 protein synthesis , but not for the phosphorylation of P47712 . This research highlights a unique signaling axis in which P52333 and p38 MAPK regulate the activity of multiple enzymes of the DB00917 - biosynthetic pathway in macrophages infected with F . tularensis .", "Development of a chimeric anti - P25942 monoclonal antibody that synergizes with DB06681 to prolong islet allograft survival . In recent years , reagents have been developed that specifically target signals critical for effective T cell activation and function . Manipulation of the P10747 / P33681 / 86 and P25942 / CD154 pathways has exhibited extraordinary efficacy , particularly when the pathways are blocked simultaneously . Despite the reported efficacy of anti - CD154 in rodents and higher models , its future clinical use is uncertain due to reported thromboembolic events in clinical trials . To circumvent this potential complication , we developed and evaluated a chimeric Ab targeting P25942 ( Chi220 , BMS - 224819 ) as an alternative to CD154 . Although Chi220 blocks CD154 binding , it also possesses partial agonist properties and weak stimulatory potential . The anti - P25942 was tested alone and in combination with a rationally designed , high affinity variant of P16410 - Ig , DB06681 ( belatacept ) , in a nonhuman primate model of islet transplantation . Although either agent alone only modestly prolonged islet survival ( Chi220 alone : 14 , 16 , and 84 days ; DB06681 alone : 58 and 60 days ) , their combination ( DB06681 and Chi220 ) dramatically facilitated long term survival ( 237 , 237 , 220 , > 185 , and 172 days ) . We found that the effects of Chi220 treatment were not mediated solely through deletion of P11836 - bearing cells and that the combined therapy did not significantly impair established antiviral immunity .", "DB06681 and sirolimus prolong nonhuman primate islet allograft survival : adverse consequences of concomitant alefacept therapy . Calcineurin inhibitors ( CNI ) and steroids are known to promote insulin resistance , and their avoidance after islet transplantation is preferred from a metabolic standpoint . DB06681 , a P33681 - specific mediator of costimulation blockade ( CoB ) , is clinically indicated as a CNI alternative in renal transplantation , and we have endeavored to develop a clinically translatable , belatacept - based regimen that could obviate the need for both CNIs and steroids . Based on the known synergy between CoB and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched islet allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on CoB - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation . All received belatacept and sirolimus ; six also received alefacept . DB06681 and sirolimus significantly prolonged rejection - free graft survival ( median 225 days compared to 8 days in controls receiving basiliximab and sirolimus ; p = 0 . 022 ) . The addition of alefacept provided no additional survival benefit , but was associated with Cytomegalovirus reactivation in four of six animals . No recipients produced donor - specific alloantibodies . The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys , but induction with alefacept provides no survival benefit and increases the risk of viral reactivation .", "Gateways to clinical trials . Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity , the drug discovery and development portal , http :// integrity . prous . com . This issue focuses on the following selection of drugs : 2F5 , 2G12 , abetimus sodium , ABI - 007 , adalimumab , adefovir dipivoxil , DB05387 , alefacept , altropane , aminolevulinic acid hydrochloride , aminolevulinic acid methyl ester , aminopterin , anakinra , aprinocarsen sodium , atazanavir , atlizumab , atomoxetine hydrochloride ; P33681 - 1 vaccine , bevacizumab , DB04851 dicitrate , BMS - 188667 , brasofensine sulfate , bryostatin 1 ; cantuzumab mertansine , Q99698 - 828 , cinacalcet hydrochloride , cipamfylline , creatine , CVT - 3146 ; darbepoetin alfa , DITPA , drotrecogin alfa ( activated ) , duloxetine hydrochloride ; edatrexate , efalizumab , ENMD - 0997 , epoetin , erlosamide , esomeprazole magnesium , etiprednol dicloacetate , etoricoxib , everolimus , ezetimibe ; fampridine , fenretinide , FTY - 720 ; P05019 / P17936 , IL - 1 cytokine trap , ilodecakin , interferon beta , ISIS - 104838 , ISIS - 2503 , ISIS - 5132 , ivabradine hydrochloride ; lafutidine , lanthanum carbonate , l - DB00125 hydrochloride , DB06681 , lerdelimumab , levetiracetam , levobupivacaine hydrochloride , levosimendan , lopinavir ; melagatran , mibefradil hydrochloride , miglustat , morphine - 6 - glucuronide ; nesiritide ; omalizumab , omapatrilat ; p24 - VLP , parecoxib sodium , peginterferon alfa - 2a , peginterferon alfa - 2b , pegsunercept , pitavastatin calcium , plevitrexed , prasterone , pregabalin , PRO - 2000 , prucalopride ; rapacuronium bromide , rebimastat , RGA - 0853 , rubitecan , ruboxistaurin mesilate hydrate , RWJ - 67657 ; S - 16020 - 2 , sarizotan , SLV - 306 , stiripentol ; DB05809 , tenecteplase , teriparatide , tezacitabine , tipifarnib , trabectedin , troglitazone ; valdecoxib , vardenafil ; Z - 338 , ziconotide .", "Maturation of dendritic cells by recombinant human P29965 - trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production . Dendritic cells ( DC ) have been shown to be potent inducers of specific cytotoxic T - cell responses both in vivo and in vitro . Furthermore , exposure to cytokines such as tumour necrosis factor ( P01375 ) - alpha or P25942 triggering changes DC phenotype and cytokine production and may enhance the T - cell activating capacity of the DC . We studied DC phenotype and cytokine production as well as the T - cell proliferation and cytotoxic T lympocyte ( CTL ) activation induced by DC generated in vitro . In addition , the effect of exposure to recombinant human P29965 - trimer ( huCD40LT ) on these parameters was investigated . Effective differentiation of monocytes derived from freshly isolated peripheral blood mononuclear cells ( PBMC ) was obtained with granulocyte macrophage - colony stimulating factor ( GM - P04141 ) and interleukin ( IL ) - 4 . The DC expression of human leucocyte antigen ( HLA ) molecules , P33681 , Q01151 , and P42081 was markedly enhanced by exposure to huCD40LT even compared to P01375 exposure . Only a moderate cytokine production was observed initially , while P01375 addition or P25942 triggering , especially , induced enhanced production of P05231 and IL - 12 p40 . Surprisingly , comparable induction of T - cell proliferation by a DC allostimulus or through the presentation of PPD , and influenza M1 - peptide specific CTL activity was obtained with nonmaturated ( Q01151 - ) and maturated ( Q01151 + ) DC . In conclusion , a final maturation of monocyte - derived DC through huCD40LT resulted in a highly homogeneous cell population with enhanced surface marker expression and high production of pro - inflammatory cytokines . In addition , the induction of responses to allo or recall antigens presented by huCD40LT maturated DC was comparable to the responses obtained with the DC maturated through P01375 exposure .", "Quantitative analysis predicts the relative therapeutic efficacy of different forms of DB01281 . Modulating the activities of costimulatory molecules controlling immune responses holds considerable promise for immunotherapy . DB01281 ( abatacept ) , a soluble version of the T cell - expressed membrane receptor P16410 , is approved for the treatment of rheumatoid arthritis . Like natural P16410 molecules , DB01281 ligates P33681 - 1 and P33681 - 2 on antigen presenting cells , preventing P10747 - mediated costimulation of T cells . However , DB01281 can also prevent ligation of P16410 , potentially blocking vital inhibitory signals , thereby augmenting immunity . There have been no quantitative analyses of the likely effects of DB01281 on costimulatory interactions at the immunological synapse . We present a mathematical model , based on rigorous biophysical and expression data , for simulating the effects of abatacept and a mutated derivative , DB06681 , on the synaptic interactions of P10747 and P16410 . The simulations reveal an unexpectedly large window within which P10747 , but not P16410 , ligation is blocked by DB01281 , perhaps explaining the efficacy of abatacept at the recommended therapeutic dose ( 10mg / kg ) and its relative safety . However , the simulations suggest that the present dosing regimen is close to the maximum theoretically safe dose . The simulations also show that , within the therapeutic window , DB06681 enhances the interaction of P16410 with the more potent of its two native ligands , P33681 - 1 . They also suggest that P16410 ligation by P33681 - 1 could , in principle , be enhanced by further decreasing the off - rate of DB01281 for binding to P33681 - 2 . Our findings therefore offer molecular explanations for why DB06681 might prove to be more effective than abatacept in a clinical setting , and suggest ways in which its therapeutic efficacy could be further optimised .", "Costimulation blockade in autoimmunity and transplantation . Signaling through the costimulation receptors is a critical pathway in the regulation of T - cell activation . The selective costimulation inhibitor abatacept ( cytotoxic T lymphocyte - associated antigen 4 - Ig ) binds to P33681 and P42081 on antigen - presenting cells , blocking interaction with P10747 on T cells , and is approved for the treatment of moderate to severe rheumatoid arthritis . DB06681 ( DB06681 ) , currently enrolling phase III trials in renal transplantation , was rationally designed from abatacept to bind with more avidity to P42081 , providing the more potent immunosuppressive properties required for immunosuppression in transplantation . This review describes the relevant preclinical studies and summarizes recent clinical findings on these 2 molecules in autoimmune diseases and organ transplantation . Although both inhibit the P10747 costimulatory pathway , they are tailored for specific disease states -- abatacept for autoimmune diseases and belatacept for transplantation .", "Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK11___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .", "Role of genetic susceptibility to latent adenoviral infection and decreased lung function . BACKGROUND : Latent adenoviral infection may amplify cigarette smoke - induced lung inflammation and therefore play an important role in the development of chronic obstructive pulmonary disease ( P48444 ) . Adenoviruses can evade the human immune response via their 19 - kDa protein ( 19K ) which delays the expression of class I human leukocyte antigen ( HLA ) proteins . The 19K protein shows higher affinity to HLA - P33681 and A2 compared with HLA - A1 and A3 . The receptor for adenovirus ( P78310 ) and integrin beta ( 5 ) ( P18084 ) are host factors which might affect adenovirus infection . Therefore , we investigated the contribution of HLA , P78310 , and P18084 genetic variants to the presence of the E1A gene and to level of lung function . METHODS : Study subjects were assayed for HLA - P33681 , A1 , A2 and A3 by PCR - based assays using allele - specific primers . Polymorphisms of the P78310 and P18084 genes were genotyped by PCR - based restriction fragment length polymorphism assays . Detection of adenoviral E1A gene was performed by a real - time PCR TaqMan assay . RESULTS : E1A positive individuals had a lower Q99581 ( 1 ) compared with E1A negative individuals . However , there was no significant difference in E1A positivity rate between the high ( HLA - P33681 and A2 ) and low ( HLA - A1 and A3 ) 19K affinity groups . There was also no significant difference in Q99581 ( 1 ) level between each affinity group . There was no significant difference in E1A positivity rate or lung function among the P78310 and P18084 genotypes . CONCLUSIONS : Genetic variants in HLA , P78310 and P18084 do not influence latent adenoviral infections and are not associated with P48444 .", "Prolonged , low - dose anti - thymocyte globulin , combined with P16410 - Ig , promotes engraftment in a stringent transplant model . BACKGROUND : Despite significant nephrotoxicity , calcineurin inhibitors ( CNIs ) remain the cornerstone of immunosuppression in solid organ transplantation . We , along with others , have reported tolerogenic properties of anti - thymocyte globulin ( ATG , Thymoglobulin ® ) , evinced by its ability both to spare Tregs from depletion in vivo and , when administered at low , non - depleting doses , to expand Tregs ex vivo . Clinical trials investigating P33681 / P10747 blockade ( DB06681 , DB06681 ) in kidney transplant recipients have proven that the replacement of toxic CNI use is feasible in selected populations . METHODS : Rabbit polyclonal anti - murine thymocyte globulin ( mATG ) was administered as induction and / or prolonged , low - dose therapy , in combination with P16410 - Ig , in a stringent , fully MHC - mismatched murine skin transplant model to assess graft survival and mechanisms of action . RESULTS : Prolonged , low - dose mATG , combined with P16410 - Ig , effectively promotes engraftment in a stringent transplant model . Our data demonstrate that mATG achieves graft acceptance primarily by promoting Tregs , while P16410 - Ig enhances mATG function by limiting activation of the effector T cell pool in the early stages of treatment , and by inhibiting production of anti - rabbit antibodies in the maintenance phase , thereby promoting regulation of alloreactivity . CONCLUSION : These data provide the rationale for development of novel , CNI - free clinical protocols in human transplant recipients .", "Co - signals in organ transplantation . PURPOSE OF REVIEW : The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death . As an immune - specific alternative to conventional immunosuppressants , new biotechnology tools can be used to block the costimulation signal of T - cell activation . RECENT FINDINGS : Many experimental studies , particularly preclinical studies in nonhuman primates , have focused on blocking ' classical ' P33681 / P10747 and P25942 / P29965 pathways , which are critical in primary T - cell activation , but also on new P33681 / P10747 and P01375 / P01375 - R pathways families of costimulatory molecules that can deliver positive or negative costimulation signals to regulate the alloimmune response . SUMMARY : DB06681 is a new fusion protein derived from P16410 - Ig that can be used to prevent acute rejection in renal transplantation instead of calcineurin inhibitors . DB06681 can also prevent acute rejection efficiently in humans and , more interestingly , can improve renal function and cardiovascular risk factors in this population .", "Five - year safety and efficacy of belatacept in renal transplantation . DB06681 is a first - in - class co - stimulation blocker in development for primary maintenance immunosuppression . A Phase II study comparing belatacept with cyclosporine ( DB00091 ) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured Q92565 at 1 year for belatacept , but the incidence of posttransplantation lymphoproliferative disorder was higher . Here , we present the results for the extension of this trial , which aimed to assess long - term safety and efficacy of belatacept . Seventy - eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving DB00091 completed the long - term extension period . Q92565 remained stable in patients who were receiving belatacept for 5 years , and the incidences of death / graft loss or acute rejection were low . The frequencies of serious infections were 16 % for belatacept and 27 % for DB00091 , and neoplasms occurred in 12 % of each group . No patients who were treated with belatacept and one patient who was treated with DB00091 developed posttransplantation lymphoproliferative disorder during the follow - up period . Serious gastrointestinal disorders occurred more frequently with belatacept ( 12 % belatacept versus 8 % DB00091 ) , and serious cardiac disorders occurred more frequently with DB00091 ( 2 % belatacept versus 12 % DB00091 ) . Pharmacokinetic analyses showed consistent exposure to belatacept over time . P42081 receptor saturation was higher in patients who were receiving belatacept every 4 weeks ( 74 % ) compared with every 8 weeks ( 56 % ) . In conclusion , this study demonstrated high patient persistence with intravenous belatacept , stable renal function , predictable pharmacokinetics , and good safety with belatacept over 5 years .", "Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .", "Mesenchymal stem cells control alloreactive CD8 (+) P10747 (-) T cells . P10747 / P33681 co - stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients . However , cells lacking P10747 are not susceptible to belatacept treatment . As CD8 (+) P10747 (-) T - cells have cytotoxic and pathogenic properties , we investigated whether DB05914 ( O60682 ) are effective in controlling these cells . In mixed lymphocyte reactions ( P08235 ) , O60682 and belatacept inhibited peripheral blood mononuclear cell ( PBMC ) proliferation in a dose - dependent manner . O60682 at O60682 / effector cell ratios of 1 : 160 and 1 : 2 · 5 reduced proliferation by 38 · 8 and 92 · 2 % , respectively . DB06681 concentrations of 0 · 1 μg / ml and 10 μg / ml suppressed proliferation by 20 · 7 and 80 · 6 % , respectively . Both treatments in combination did not inhibit each other ' s function . Allostimulated CD8 (+) P10747 (-) T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B , interferon ( IFN ) - γ and tumour necrosis factor ( P01375 ) - α . While belatacept did not affect the proliferation of CD8 (+) P10747 (-) T cells , O60682 reduced the percentage of P10747 (-) T cells in the proliferating CD8 (+) T cell fraction by 45 · 9 % ( P = 0 · 009 ) . CD8 (+) P10747 (-) T cells as effector cells in P08235 in the presence of P01730 (+) T cell help gained P10747 expression , an effect independent of O60682 . In contrast , allostimulated P10747 (+) T cells did not lose P10747 expression in P08235 - O60682 co - culture , suggesting that O60682 control pre - existing P10747 (-) T cells and not newly induced P10747 (-) T cells . In conclusion , alloreactive CD8 (+) P10747 (-) T cells that remain unaffected by belatacept treatment are inhibited by O60682 . This study indicates the potential of an O60682 - belatacept combination therapy to control alloreactivity .", "___MASK63___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK63___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .", "Differential inhibition of autoreactive memory - and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 ( sCTLA4 ) , DB01281 and DB06681 . Cytotoxic T lymphocyte antigen 4 ( P16410 ) is a potent inhibitory co - stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases . An association has been reported of both mRNA expression and serum levels of the soluble splice variant of P16410 ( sCTLA4 ) with type 1 diabetes . Furthermore , recombinant fusion proteins DB01281 and DB06681 have been proposed as therapies for type 1 diabetes . We studied the role of ( s ) P16410 in islet autoimmunity . Binding capacity of the proteins to antigen - presenting cells was determined by flow cytometry in competition and binding assays . Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins DB01281 and DB06681 was measured in a dose - response lymphocyte stimulation test , using a panel of diabetes - associated T cell clones reactive to islet autoantigens . As controls , mixed lymphocyte reactions ( P08235 ) were performed to assess functionality of these proteins in a primary alloreactive setting . All three P16410 molecules were able to bind to antigen - presenting cells and inhibit the expression of P33681 / P42081 . sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose - dependent manner , whereas DB01281 and DB06681 were not . Conversely , DB01281 and DB06681 , rather than sCTLA4 , were able to suppress naive alloreactive proliferation in a P08235 . Our results indicate a differential role for sCTLA4 , DB01281 and DB06681 proteins in memory versus primary immune responses with implications for efficacy in intervention therapy .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "[ Molecular mechanism of age - related osteoporosis ] . Bone loss by ageing has been investigated from standpoints of systemic abnormality and some deficiency in osteoblastic bone formation . This seminar summarizes the involvements of a key molecule of adipocytic differentiation P37231 , essential P05019 signaling molecules P35568 and Q9Y4H2 , and an anti - aging gene klotho in the pathophysiology of age - related osteoporosis .", "Monocytes from type 2 diabetic patients have a pro - inflammatory profile . 1 , 25 - Dihydroxyvitamin D ( 3 ) works as anti - inflammatory . The exact factors contributing to the pathogenesis of type 2 diabetes remain elusive . Lately , it was suggested that inflammation and activation of the innate immune system could be linked to type 2 diabetes pathogenesis and also to the development of common diabetic complications , mainly atherosclerosis . The aim of this study was to investigate the role of monocytes in this sub - clinical inflammatory state and test 1 , 25 - dihydroxyvitamin D ( 3 ) , the active form of Vitamin D , as an anti - inflammatory agent . For this purpose , monocytes from type 2 diabetic patients were compared to monocytes from healthy controls and type 1 diabetic patients . The expression profile of inflammatory markers in freshly isolated and immune - stimulated monocytes was measured by quantitative real - time RT - PCR . Type 2 diabetic patients showed significantly higher expression levels of P01375 , P05231 , IL - 1 , P10145 , P35354 , P05362 and P33681 - 1 compared to controls and type 1 diabetic patients . 1 , 25 - Dihydroxyvitamin D ( 3 ) was able to down - regulate the expression of P01375 , P05231 , IL - 1 , and P10145 , confirming its immunomodulatory properties . From these data we concluded that monocytes from type 2 diabetic patients have a pro - inflammatory profile . In addition , 1 , 25 - dihydroxyvitamin D ( 3 ) was able to modulate inflammation in these monocytes .", "Costimulatory blockade with belatacept in clinical and experimental transplantation - a review . BACKGROUND : Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade . However , long - term follow - up has revealed that these agents are associated with troublesome side effects and chronic toxicity , contributing to graft loss and death . OBJECTIVES : Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation . DB06681 , a high - affinity chimeric fusion protein that binds to P33681 / P42081 on antigen - presenting cells , has shown great promise in renal transplantation and is now in Phase III trials . METHODS : This review explores the development and efficacy of belatacept , compared with currently approved immunosuppressive agents used in transplantation . RESULTS : DB06681 seems to be an effective alternative to current maintenance immunosuppressive therapies , with no apparent end organ toxicity and a minimal side - effect profile . This agent works best when used in combination with therapies that target different pathways of T - cell activation , but the optimal regimen has not yet been identified . Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept - based combinatorial strategies .", "T - cell phenotype in protocol renal biopsy from transplant recipients treated with belatacept - mediated co - stimulatory blockade . BACKGROUND : DB06681 is thought to disrupt the interaction between P33681 / 86 and P10747 , thus preventing T - cell activation by blocking the co - stimulatory second signal . However , the consequences on the T - cell profile in human renal transplant cases have not been determined . METHODS : In this study , we analysed intra - graft levels of the mRNAs for Treg ( Q9BZS1 ) , cytotoxic CD8 T cells ( P10144 ) , Th1 ( INFγ , Tbet ) , Th2 ( P23771 ) and Th17 ( RORγt and Q16552 ) in protocol biopsies obtained 12 months after renal transplantation in recipients treated with DB06681 or calcineurin inhibitor ( CNI ) . RESULTS : Only the intra - graft abundance of Q9BZS1 mRNA was significantly lower ( P < 0 . 001 ) in the DB06681 group than the CNI group . Conclusions . These results are in agreement with in vitro data suggesting that P10747 is a major co - stimulatory signal of both Tregs development and peripheral homeostasis but contrast with clinical trials showing a better 1 - year graft function and a lower incidence of chronic allograft nephropathy in patients receiving DB06681 than patients treated with CNI . They suggest that immune benefits induced by DB06681 are not mediated by Treg expansion and that Q9BZS1 is not by itself a prognostic marker of long - term graft function in a non - inflammatory context . These results have to be , however , considered as preliminary since the size of our study population is limited .", "Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation . Signaling through the costimulatory pathway is critical in the regulation of T cell activation . DB01281 , a selective costimulatory antagonist FDA approved for the treatment of moderate to severe rheumatoid arthritis , binds to P33681 and P42081 on antigen presenting cells , blocking the interaction with P10747 on T cells . DB06681 , a second generation P16410 - Ig with 2 amino acid substitutions , has shown considerable promise in clinical transplantation as part of a maintenance immunosuppression regimen . This review will summarize the role of costimulation in T cell activation , detail the development of costimulation antagonists and highlight the pertinent clinical trials completed and ongoing utilizing belatacept as part of an immunosuppressive regimen in organ transplantation .", "Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK43___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .", "A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK79___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .", "Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .", "Chronic induction . What ' s new in the pipeline . Induction therapy with biological agents was introduced the in the 1970s and the rationale , concepts and approach have remained almost unchanged for 30 years . However , the novel biological agents being developed for induction therapy are being designed for chronic rather than short - term therapy with several objectives : reduce dependence on toxic and nephrotoxic agents , improve outcome and ultimately facilitate the emergence of tolerance . The biological agents include efalizumab , a humanized anti - CD11a ( anti - LFA1 ) , anti - CD154 , anti - P25942 , a number of agents targeting P40933 and its receptor , and costimulation blockade with humanized antibodies to P33681 / P42081 and the fusion receptor protein DB06681 , a second generation DB01281 . The past decade has witnessed an unprecedented number of small molecules / oral drugs that have been developed and approved for renal transplantation ; the next decade , however , may witness the emergence of a new class of biological induction agents that may displace some of the currently used drugs .", "The antipsoriatic activity of P22301 is rather caused by effects on peripheral blood cells than by a direct effect on human keratinocytes . P22301 is a promising candidate for the treatment of cutaneous disorders . Antipsoriatic efficacy of systemic P22301 treatment has been already demonstrated . This includes histomorphological changes in the epidermis , suggesting effects on keratinocytes . However , less is known about direct effects of P22301 on this cell population , although effects are likely since P22301 receptor expression on keratinocytes has been demonstrated recently . Therefore we analysed the effects of P22301 on keratinocytes in vitro , using concentrations of human recombinant P22301 corresponding to those detectable in plasma during therapy . Proliferation , cytokine formation ( P05231 , P10145 , IL - 1ra ) , and expression of surface molecules ( MHC class I and II , costimulatory molecules P33681 and P42081 , CD29 , CD54 , CD95 ) were measured in stimulated and unstimulated cells . Although stimulation influenced the expression levels of certain surface markers , no or only slight effects of P22301 were found . In contrast considerable inhibitory effects of P22301 on surface molecule expression and cytokine secretion by peripheral blood human monocytes were observed . Our results suggest that the antipsoriatic activity of P22301 is rather caused by modulatory effects on circulating immune cells , which subsequently might infiltrate the skin , than by direct effects on human keratinocytes . Considering the remarkable antipsoriatic activity of P22301 and the observation that P22301 seem to act on peripheral blood mononuclear cells but not on keratinocytes provide further evidence that circulating immune cells play a key role in the pathology of psoriasis . Finally , our results argue against the value of P22301 therapy in dermatoses strictly limited to keratinocyte involvement .", "Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK29___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .", "Novel immunosuppression : small molecules and biologics . Kidney transplantation today has excellent short - term outcomes that have paralleled the use of new immunosuppressive agents introduced in the 1990s . In addition to reducing acute rejection , the goals for developing new agents is to improve long - term outcome , minimize nephrotoxicity , and reduce infectious , cardiovascular , and malignancy - related complications . Novel small molecules and biological agents currently in clinical development may help to minimize the use of calcineurin inhibitors and steroids . These small molecules include FTY720 , a sphingosine phosphate - receptor modulator , FK778 , an inhibitor of pyrimidine synthesis , CP - 690550 , a P52333 inhibitor , and AEB - 071 , a protein kinase C inhibitor . The biological agents include drugs targeting interleukin - 15 , anti - P25942 , belatacept ( DB06681 ) , a second - generation CTLY4Ig that blocks the interaction between P33681 / 86 and P10747 costimulatory pathways , and efalizumab , a humanized anti - LFA1 monoclonal antibody . These new agents currently in preclinical and clinical trials appear promising and may represent the emergence of novel immunosuppressive agents that can deliver immunosuppression without long - term toxicity .", "DB06681 in clinical and experimental transplantation - progress and promise . DB06681 is a fusion protein composed of the Fc fragment of a human IgG ( 1 ) immunoglobulin linked to the extracellular domain of cytotoxic T - lymphocyte - associated antigen 4 ( P16410 ) . P16410 is a molecule crucial for T - cell costimulation , selectively blocking the process of T - cell activation . DB06681 binds surface costimulatory ligands ( P33681 and P42081 ) of antigen - presenting cells . Studies on nonhuman primates , as well as phase II and III clinical trials are here reviewed . DB06681 is a promising therapy in organ transplantation and in the future can be used to induce tolerance .", "The P04035 inhibitor , atorvastatin , promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease . Statins , 3 - hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors , which are approved for cholesterol reduction , may also be beneficial in the treatment of inflammatory diseases . ___MASK80___ ( Lipitor ) was tested in chronic and relapsing experimental autoimmune encephalomyelitis , a P01730 (+) Th1 - mediated central nervous system ( CNS ) demyelinating disease model of multiple sclerosis . Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis . ___MASK80___ induced P42226 phosphorylation and secretion of Th2 cytokines ( interleukin ( IL ) - 4 , P05113 and P22301 ) and transforming growth factor ( TGF ) - beta . Conversely , Q14765 phosphorylation was inhibited and secretion of Th1 cytokines ( P60568 , IL - 12 , interferon ( IFN ) - gamma and tumour necrosis factor ( P01375 ) - alpha ) was suppressed . ___MASK80___ promoted differentiation of Th0 cells into Th2 cells . In adoptive transfer , these Th2 cells protected recipient mice from EAE induction . ___MASK80___ reduced CNS infiltration and major histocompatibility complex ( MHC ) class II expression . Treatment of microglia inhibited P01579 - inducible transcription at multiple P33076 ( P33076 ) promoters and suppressed class II upregulation . ___MASK80___ suppressed P01579 - inducible expression of P25942 , P33681 and P42081 co - stimulatory molecules . l - Mevalonate , the product of P04035 , reversed atorvastatin ' s effects on antigen - presenting cells ( P25054 ) and T cells . ___MASK80___ treatment of either P25054 or T cells suppressed antigen - specific T - cell activation . Thus , atorvastatin has pleiotropic immunomodulatory effects involving both P25054 and T - cell compartments . Statins may be beneficial for multiple sclerosis and other Th1 - mediated autoimmune diseases .", "The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .", "DB06681 and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion . DB06681 is an inhibitor of P10747 / P33681 costimulation that is clinically indicated as a calcineurin inhibitor ( CNI ) alternative in combination with mycophenolate mofetil and steroids after renal transplantation . We sought to develop a clinically translatable , nonlymphocyte depleting , belatacept - based regimen that could obviate the need for both CNIs and steroids . Thus , based on murine data showing synergy between costimulation blockade and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched renal allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on costimulation blockade - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . DB06681 and sirolimus therapy successfully prevented rejection in all animals . Tolerance was not induced , as animals rejected after withdrawal of therapy . The regimen did not deplete T cells . Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen , despite causing an intended depletion of memory T cells , and caused a marked reduction in regulatory T cells . Furthermore , alefacept - treated animals had a significantly increased incidence of CMV reactivation , suggesting that this combination overly compromised protective immunity . These data support belatacept and sirolimus as a clinically translatable , nondepleting , CNI - free , steroid - sparing immunomodulatory regimen that promotes sustained rejection - free allograft survival after renal transplantation .", "P26718 receptor regulates human effector T - cell cytokine production . Although innate immune signals shape the activation of naive T cells , it is unclear how innate signals influence effector T - cell function . This study determined the effects of stimulating the P26718 receptor in conjunction with the TCR on human effector CD8 (+) T cells . Stimulation of CD8 (+) T cells through CD3 and P26718 simultaneously or through a chimeric P26718 receptor , which consists of P26718 fused to the intracellular region of CD3ζ , activated β - catenin and increased expression of β - catenin - induced genes , whereas T cells stimulated through the TCR or a combination of the TCR and P10747 did not . Activation by TCR and P26718 prevented expression and production of anti - inflammatory cytokines P22301 , P15248 , P35225 , and P15692 - α in a β - catenin - and Q07869 γ - dependent manner . P26718 stimulation also modulated the cytokine secretion of T cells activated simultaneously through CD3 and P10747 . These data indicate that activating CD8 (+) T cells through the P26718 receptor along with the TCR modulates signal transduction and the production of anti - inflammatory cytokines . Thus , human effector T cells alter their function depending on which innate receptors are engaged in conjunction with the TCR complex .", "P04035 inhibitors deplete circulating classical and non - classical monocytes following human heart transplantation . BACKGROUND : Monocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage / dendritic cell lineages . To date , the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated . This study was designed to assess the effects of statin administration on the monocyte repertoire . METHODS : 108 patients were recruited into the study . Clinical data were collected from patients ' notes . Peripheral blood immunophenotype was determined via flow cytometry ( using CD11c , P08571 , CD16 , CD49d , CD64 , P33681 and CD195 ) . RESULTS : There were fewer circulating classical ( p = 0 . 0001 ) and non - classical ( p = 0 . 0013 ) monocytes in patients treated with a statin . CD64 expression was down - regulated ( p = 0 . 011 and p = 0 . 049 ) whereas CD49d expression was up - regulated ( p = 0 . 004 and p = 0 . 022 ) on classical and non - classical monocytes in this group . Patients receiving ___MASK80___ had fewer circulating classical monocytes ( p = 0 . 001 ) compared to patients administered DB00175 . Patients receiving DB00175 had fewer circulating non - classical monocytes ( p = 0 . 029 ) compared to patients administered ___MASK80___ . DISCUSSION : Statin administration alters the circulating monocyte repertoire following heart transplantation , including population size , FcgammaRI and VLA - 4 adhesion molecule expression . Furthermore , different statin treatments are associated with a selective depletion of macrophage or DC ( re ) generating monocytes .", "[ Use of new non - nephrotoxic immunosuppressive drugs in kidney transplantation , especially after ischemia - reperfusion injury ] . Medium - and long - term renal graft survival depends on 4 main factors : the quality of the harvested graft , ischemia - reperfusion injury during harvesting and re - implantation , rejection , and the nephrotoxicity of certain drugs ( especially immunosuppressants ) used in this setting . The most nephrotoxic immunosuppressive drugs are the anticalcineurins ( cyclosporine A and tacrolimus ) , a class discovered in the late 1970s and currently representing a basic component of all immunosuppressive protocols for solid organ graft recipients . The renal tubular and vascular toxicity of anticalcineurins is due to their immunosuppressive mechanism : they block the calcineurin pathway and thereby prevent transmission of the first signal from the T cell receptor to the nucleus , which normally triggers cytokine synthesis , New non - nephrotoxic immunosuppressants are therefore needed , especially for grafts of poor quality or subject to severe ischemia - reperfusion injury . Attention is turning to \" old \" molecules such as anti - thymocyte globulins , but exciting new immunosuppressants are now appearing . DB00092 is a fusion protein that binds to the immunological synapse - associated molecule P06729 , which normally interacts with LFA - 3 . DB06681 , another fusion protein , blocks the T cell second signal CD 28 - P33681 . 1 / P33681 . 2 . Finally , new chemical agents are being developed , such as sautrasporine , a tyrosine kinase inhibitor , and tofacitinib , a Jak inhibitor .", "Introduction to the use of belatacept : a fusion protein for the prevention of posttransplant kidney rejection . The development of new immunosuppressive drugs for kidney transplantation resulted both in better short - term outcomes and in decreased metabolic , cardiovascular , and nephrotoxicity risk . DB06681 belongs to a new class of immunosuppressive drugs that selectively inhibits T - cell activation by preventing P10747 activation and by binding its ligands P33681 - 1 and P33681 - 2 . The result is an inactivation of costimulatory pathways . A comparative analysis of the BENEFIT and BENEFIT - EXT datasets showed belatacept regimens resulted in better cardiovascular and metabolic risk profiles than did cyclosporin A ( DB00091 ) regimens : belatacept likewise outperformed DB00091 in terms of lower blood pressure and serum lipids and less new onset diabetes after transplantation . About 20 % of belatacept - treated patients developed adverse effects which included anemia , pyrexia , neutropenia , diarrhea , urinary tract infection , headache , and peripheral edema . At present , belatacept does not seem to predispose patients to a higher rate of infection than DB00091 maintenance immunosuppression . The risk of posttransplant lymphoproliferative diseases was higher in Epstein - Barr virus ( EBV ) - seronegative patients than in EBV - seropositive patients , but the risk may be reduced by use of a less intensive regimen and avoidance of EBV - negative patients and of patients whose pretransplant EBV serology is unknown . DB06681 provides a new option for immunosuppressive therapy in kidney transplantation , but needs further evaluation in terms of the late effects that may derive from prolonged blockage of the costimulatory system and the induction of tolerance status .", "Omega - 3 fatty acids attenuate dendritic cell function via NF - κB independent of PPARγ . Long - chain n - 3 polyunsaturated fatty acids ( n - 3 PUFA ) have been shown to modulate the immune response and have therapeutic effects in inflammatory disorders . PUFA are also peroxisome proliferators - activator receptor - gamma ( PPARγ ) ligands ; a family of ligand - activated transcription factors , which when activated antagonise the pro - inflammatory capability of nuclear factor κB ( NF - κB ) . PPARγ plays a role in dendritic cell ( DC ) maturation and n - 3 PUFA have been shown to affect DC maturation by decreasing activation of NF - κB . While n - 3 PUFA can function as Q07869 ligands , it is not known whether the NF - κB - mediated immunomodulatory properties of n - 3 PUFA are PPARγ - dependent . In this study we examined whether the immunomodulatory effects of n - 3 PUFA on DC activation were mediated through activation of PPARγ . Treatment of murine bone marrow derived DCs with docosahexaenoic acid ( DB01708 ; 25 μM ) and eicosapentaenoic acid ( EPA ; 25 μM ) attenuated LPS - induced DC maturation . This was characterised by suppression of IL - 12 production and expression of P25942 , P33681 , P42081 and MHC II and enhanced production of P22301 and expression of IL - 10R . This was coincident with enhanced PPARγ expression , suppressed NF - κB activity and increased the physical interaction and cellular colocalization between NF - κB with PPARγ . To understand the functional implication of the physical association of PPARγ with NF - κB , we determined whether the specific PPARγ inhibitor , GW9662 could abolish the anti - inflammatory effect of n - 3 PUFA Inhibiting PPARγ did not impede the NF - κB - mediated anti - inflammatory cytokine profile induced by EPA and DB01708 alone . Thus n - 3 PUFA activate PPARγ and interact with NF - κB in DC . However , the anti - inflammatory effects of EPA and DB01708 on DCs are independent of PPARγ ." ]

[ "___MASK10___", "___MASK11___", "___MASK27___", "___MASK29___", "___MASK33___", "___MASK43___", "___MASK63___", "___MASK79___", "___MASK80___" ]

[ "[ The role of matrix metalloproteinases and their inhibitors in pathogenesis of pancreatic pseudocysts ] . The investigation was conducted in 47 patients , operated on for pancreatic pseudocysts ( PP ) . Activity of matrix metalloproteinases ( P14780 ) and content of their tissue inhibitor ( P16035 ) were determined in the blood serum for estimation of inflammatory factors , hypoxia severity and state of the pancreatic tissue reconstruction . High activity of P14780 and P16035 in presence of PP types I and II was noted in patients , what , probably , is caused by compensation reaction , directed towards inhibition of the collagen system destruction ( predominantly of collagen type IV ) and prevention of further reconstruction of pancreatic connective tissue . While progressing of pancreatic fibrosis the P14780 activity and the P16035 level have lowered in comparison with these indices while its absence . In PP type III the P14780 activity was by 83 . 6 % higher , than in a control group , but , by 51 . 4 and 35 . 1 % lower , than in PP types I and IV . In all the patients endothelial dysfunction with endothelial injury was observed , witnessed by significant rising of the P15692 content in the blood serum . It have created favorable conditions for pancreatic tissue remodeling while parenchymal defect have been constituted by tissue , owing lower level of organization , including a cicatricial one . In cases of cellular repeated affection more activation of pancreatic stellate cells and enhancement of production of extracellular matrix component were noted .", "[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK13___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .", "DB09280 - ___MASK44___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .", "Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours . The emergence of fibroblast growth factor receptor ( FGFR ) family fusions across diverse cancers has brought attention to FGFR - derived cancer therapies . The discovery of the first recurrent FGFR fusion in glioblastoma was followed by discoveries of FGFR fusions in bladder , lung , breast , thyroid , oral , and prostate cancers . Drug targeting of FGFR fusions has shown promising results and should soon be translating into clinical trials . FGFR fusions form as a result of various mechanisms – predominantly deletion for P11362 , translocation for P21802 , and tandem duplication for P22607 . The ability to exploit the unique targetability of FGFR fusions proves that FGFR - derived therapies could have a promising future in cancer therapeutics . Drug targeting of fusion genes has proven to be an extremely effective therapeutic approach for cancers such as the recurrent BCR – P00519 fusion in chronic myeloid leukaemia . The recent discovery of recurrent FGFR family fusions in several cancer types has brought to attention the unique therapeutic potential for FGFR - positive patients . Understanding the diverse mechanisms of FGFR fusion formation and their oncogenic potential will shed light on the impact of FGFR - derived therapy in the future .", "[ ___MASK74___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK74___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .", "Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .", "___MASK97___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK19___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )", "___MASK94___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK94___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .", "Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case - control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme - linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0 . 88 ( 95 % CI 0 . 84 - 0 . 93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays .", "Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .", "Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .", "DB09079 , a triple angiokinase inhibitor , enhances cytotoxic therapy response in pancreatic cancer . Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma ( PDAC ) therapy . P15692 , PDGF , FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC . DB09079 is a triple angiokinase inhibitor that targets P17948 / 2 / 3 , P11362 / 2 / 3 and PDGFRα / β signaling . We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC . DB09079 inhibited proliferation of cells from multiple lineages found in PDAC , with gemcitabine enhancing inhibitory effects . DB09079 blocked PI3K / MAPK activity and induced apoptosis in vitro and in vivo . In a heterotopic model , net local tumor growth compared to controls ( 100 % ) was 60 . 8 ± 10 . 5 % in the gemcitabine group , - 2 . 1 ± 9 . 9 % after nintedanib therapy and - 12 . 4 ± 16 % after gemcitabine plus nintedanib therapy . Effects of therapy on intratumoral proliferation , microvessel density and apoptosis corresponded with tumor growth inhibition data . In a PDAC survival model , median animal survival after gemcitabine , nintedanib and gemcitabine plus nintedanib was 25 , 31 and 38 days , respectively , compared to 16 days in controls . The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib - controlled mechanisms as targets for improved clinical PDAC therapy .", "Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 .", "[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK73___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK73___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .", "Inhibition of the liver expression of arylalkylamine N - acetyltransferase increases the expression of angiogenic factors in cholangiocytes . BACKGROUND AND AIMS : Reduction of biliary serotonin N - acetyltransferase ( Q16613 ) expression and melatonin administration / secretion in cholangiocytes increases biliary proliferation and the expression of SR , P13569 and Cl (-)/ HCO3 ( - ) P04920 . The balance between biliary proliferation / damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor - A / C ( P15692 / C ) . VEGFs are secreted by several epithelia , where they modulate cell growth by autocrine and paracrine mechanisms . No data exists regarding the effect of Q16613 modulation on the expressions of VEGFs by cholangiocytes . METHODS : In this study , we evaluated the effect of local modulation of biliary Q16613 expression on the cholangiocytes synthesis of P15692 / C . RESULTS : The decrease in Q16613 expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of P15692 / C . Overexpression of Q16613 in cholangiocyte lines decreased the expression of P15692 / C . CONCLUSIONS : Modulation of melatonin synthesis may affect the expression of P15692 / C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of P15692 / C expression regulating biliary functions .", "Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .", "Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK32___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .", "P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK33___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome ." ]

[ "___MASK13___", "___MASK19___", "___MASK32___", "___MASK33___", "___MASK44___", "___MASK73___", "___MASK74___", "___MASK94___", "___MASK97___" ]

[ "Glucagon - like peptide - 1 stimulates luteinizing hormone - releasing hormone secretion in a rodent hypothalamic neuronal cell line . To examine the influence of the putative satiety factor ( P0C6A0 ) on the hypothalamo - pituitary - gonadal axis , we used GT1 - 7 cells as a model of neuronal luteinizing hormone - releasing hormone ( P01148 ) release . P0C6A0 caused a concentration - dependent increase in P01148 release from GT1 - 7 cells . Specific , saturable P0C6A0 binding sites were demonstrated on these cells . The binding of [ 125I ] P0C6A0 was time - dependent and consistent with a single binding site ( Kd = 0 . 07 +/- 0 . 016 nM ; binding capacity = 160 +/- 11 fmol / mg protein ) . The specific P43220 agonists , exendin - 3 and exendin - 4 , also showed high affinity ( Ki = 0 . 3 +/- 0 . 05 and 0 . 32 +/- 0 . 06 nM , respectively ) as did the antagonist exendin -( 9 - 39 ) ( Ki = 0 . 98 +/- 0 . 24 nM ) . At concentrations that increased P01148 release , P0C6A0 ( 0 . 5 - 10 nM ) also caused an increase in intracellular DB02527 in GT1 - 7 cells ( 10 nM P0C6A0 : 7 . 66 +/- 0 . 4 vs . control : 0 . 23 +/- 0 . 02 nmol / mg protein ; P < 0 . 001 ) . Intracerebroventricular injection of P0C6A0 at a single concentration ( 10 microg ) produced a prompt increase in the plasma luteinizing hormone concentration in male rats ( P0C6A0 : 1 . 09 +/- 0 . 11 vs . saline : 0 . 69 +/- 0 . 06 ng / ml ; P < 0 . 005 ) . P0C6A0 levels in the hypothalami of 48 - h - fasted male rats showed a decrease , indicating a possible association of the satiety factor with the low luteinizing hormone levels in animals with a negative energy balance .", "Tumor suppressor function of P09936 is associated with epigenetic regulation in prostate cancer -- novel predictor of biochemical recurrence after radical surgery . BACKGROUND : The expression level of protein G product 9 . 5 ( P09936 ) is downregulated because of promoter CpG hypermethylation in several tumors . We speculated that impaired regulation of P09936 through epigenetic pathways is associated with the pathogenesis of prostate cancer . METHODS : CpG methylation of the P09936 gene was analyzed in cultured prostate cancer cell lines , 226 localized prostate cancer samples from radical prostatectomy cases , and 80 benign prostate hyperplasia ( BPH ) tissues . RESULTS : Following 5 - aza - 2 '- deoxycytidune treatment , increased P09936 mRNA transcript expression was found in the LNCaP and PC3 cell lines . With bisulfite DNA sequencing , partial methylation of the P09936 promoter was shown in LNCaP whereas complete methylation was found in PC3 cells . After transfection of P09936 siRNA , cell viability was significantly accelerated in LNCaP but not in PC3 cells as compared with control siRNA transfection . Promoter methylation of P09936 was extremely low in only one of 80 BPH tissues , whereas it was found in 37 of 226 prostate cancer tissues . Expression of the mRNA transcript of P09936 was significantly lower in methylation ( + ) than methylation ( - ) prostate cancer tissues . Multivariate analysis of biochemical recurrence ( P11274 ) after an radical prostatectomy revealed pT category and P09936 methylation as prognostically relevant . Further stratification with the pT category in addition to methylation status identified a stepwise reduction of P11274 - free probability . CONCLUSION : This is the first clinical and comprehensive study of inactivation of the P09936 gene via epigenetic pathways in primary prostate cancer . Q9P2X3 : CpG methylation of P09936 in primary prostate cancer might become useful as a molecular marker for early clinical prediction of P11274 after radical prostatectomy .", "Sebaceous carcinoma of the breast : case report and review of the literature . Sebaceous differentiation has been described in only limited examples of benign and malignant epithelial lesions of the breast . We report a rare case of mammary sebaceous carcinoma to further delineate its morphologic features . Microscopically , the tumor , arising in the right mammary gland of a 63 - year - old woman , was composed of well - defined solid sheets or lobules of atypical epithelial cells including many large pale or clear cells with often scalloped nuclei and coarsely vacuolated cytoplasm , in which abundant lipid droplets were identified with oil - red - O staining . Immunohistochemical expressions of cytokeratin , epithelial membrane antigen , and receptors of estrogen and progesterone were detected , whereas P12273 , S - 100 protein , vimentin , alpha - smooth muscle actin , p63 , androgen receptor , and the P04626 / neu protein were not expressed . Besides , a subset of the tumor cells co - expressed synaptophysin , neurofilament , and P09936 , suggesting neuroendocrine differentiation that is a hitherto undescribed phenomenon in the mammary tumors with sebaceous features . This case would expand the morphologic diversity of carcinoma of the breast .", "P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration - response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed .", "P06401 membrane component 1 is a functional part of the glucagon - like peptide - 1 ( P0C6A0 ) receptor complex in pancreatic β cells . Glucagon - like peptide - 1 ( P0C6A0 ) is an incretin hormone that regulates glucose homeostasis . Because of their direct stimulation of insulin secretion from pancreatic β cells , P43220 ( P43220 ) agonists are now important therapeutic options for the treatment of type 2 diabetes . To better understand the mechanisms that control the insulinotropic actions of P0C6A0 , affinity purification and mass spectrometry ( AP - MS ) were employed to uncover potential proteins that functionally interact with the P43220 . AP - MS performed on Chinese hamster ovary cells or MIN6 β cells , both expressing the human P43220 , revealed 99 proteins potentially associated with the P43220 . Three novel P43220 interactors ( O00264 , Rab5b , and Rab5c ) were further validated through co - immunoprecipitation / immunoblotting , fluorescence resonance energy transfer , and immunofluorescence . Functional studies revealed that overexpression of O00264 , a novel cell surface receptor that associated with liganded P43220 , enhanced P0C6A0 - induced insulin secretion ( GIIS ) with the most robust effect . Knockdown of O00264 in β cells decreased GIIS , indicative of positive interaction with P43220 . To gain insight mechanistically , we demonstrated that the cell surface O00264 ligand P4 - BSA increased GIIS , whereas its antagonist AG - 205 decreased GIIS . It was then found that O00264 increased P0C6A0 - induced DB02527 accumulation . O00264 activation and GIIS induced by P4 - BSA could be blocked by inhibition of adenylyl cyclase / O95398 signaling or the P01133 receptor - PI3K signal transduction pathway . These data reveal a dual mechanism for O00264 - increased GIIS mediated through DB02527 and P01133 receptor signaling . In conclusion , we identified several novel P43220 interacting proteins . O00264 expressed on the cell surface of β cells was shown to interact with the activated P43220 to enhance the insulinotropic actions of P0C6A0 .", "___MASK86___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .", "Neuroprotective effect of the glucagon - like peptide - 1 receptor agonist , synthetic exendin - 4 , in streptozotocin - induced diabetic rats . BACKGROUND AND PURPOSE : Glucagon - like peptide - 1 ( P0C6A0 ) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation . The aim of this study was to investigate the effect of the P0C6A0 pathway on peripheral nerves in streptozotocin - induced diabetic rats . EXPERIMENTAL APPROACH : Diabetic and nondiabetic rats were treated with the P43220 agonist , synthetic exendin - 4 ( i . p . , 1 nmol · kg (- 1 )· day (- 1 ) ) or placebo for 24 weeks , and current perception threshold values , DB02527 levels and nerve fibre size in the sciatic nerve were measured . We also investigated P43220 expression , quantitative changes in P09936 - positive intraepidermal nerve fibres and cleaved caspase 3 - stained Schwann cells by immunohistochemistry . KEY RESULTS : P43220 expression was detected in the sciatic nerve and skin . After exendin - 4 treatment , the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced . Also , the decrease in myelinated fibre size or axon / fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated . These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the DB02527 level in exendin - 4 - treated diabetic rats , compared with placebo - treated animals . CONCLUSION AND IMPLICATIONS : DB01276 may prevent peripheral nerve degeneration induced by diabetes in an animal model , supporting the hypothesis that P0C6A0 may be useful in peripheral neuropathy . The neuroprotection is probably attributable to P43220 activation , antiapoptotic effects and restoration of DB02527 content .", "Exenatide twice daily : a review of its use in the management of patients with type 2 diabetes mellitus . Exenatide , administered subcutaneously twice daily ( DB01276 (®) ) , is a synthetic version of the natural peptide exendin - 4 , which is a glucagon - like peptide - 1 ( P0C6A0 ) receptor agonist ( incretin mimetic ) . Exenatide binds to the P43220 with the same affinity as P0C6A0 , but has a much longer half - life , since it is not degraded by the enzyme dipeptidyl peptidase - 4 . Exenatide twice daily enhances glucose - dependent insulin secretion , suppresses inappropriately elevated glucagon secretion , slows gastric emptying and reduces caloric intake . In well - designed clinical trials , adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16 - 52 weeks significantly and dose - dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs ( OADs ) and / or basal insulin . The improvements in glycaemic control and reductions in body weight were stably maintained during long - term therapy ( up to 3 . 5 years ) . The efficacy of adjunctive exenatide twice daily was generally similar to that of basal , prandial or biphasic insulin , sulfonylureas , rosiglitazone and lixisenatide , and less than that of liraglutide , taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin . Exenatide twice daily was generally well tolerated ; mild to moderate nausea and vomiting , which decreased with time on therapy , were the most common adverse events . In patients not receiving concomitant sulfonylureas or insulin , the incidence of hypoglycaemia was low ; when it did occur , it was generally mild in severity . Thus , adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and / or basal insulin .", "New insights into the role of DB02527 in the production and function of the incretin hormone glucagon - like peptide - 1 ( P0C6A0 ) . The proglucagon gene ( gcg ) encodes both glucagon and glucagon - like peptide - 1 ( P0C6A0 ) , produced in pancreatic alpha cells and intestinal endocrine L cells , respectively . The incretin hormone P0C6A0 stimulates insulin secretion and pro - insulin gene transcription . P0C6A0 also enhances pancreatic beta - cell proliferation , inhibits cell apoptosis , and has been utilized in the trans - differentiation of insulin producing cells . A long - term effective P43220 agonist , DB01276 , has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders . The expression of gcg and the production of P0C6A0 can be activated by the elevation of the second messenger cyclic AMP ( DB02527 ) . Recent studies suggest that in addition to protein kinase A ( PKA ) , exchange protein activated by DB02527 ( Epac ) , another effector of DB02527 , and the crosstalk between PKA and the Wnt signaling pathway , are involved in DB02527 - stimulated gcg transcription and P0C6A0 production as well . Finally , functions of P0C6A0 in pancreatic beta cells are also mediated by PKA , Epac , as well as the effector of the Wnt signaling pathway . Together , these novel findings bring us a new insight into the role of DB02527 in the production and function of the incretin hormone P0C6A0 .", "Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK39___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .", "Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK15___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .", "HRAS1 and P01308 genes are relocated but not structurally altered as a result of the t ( 7 ; 11 )( p15 ; p15 ) in a clone from a patient with acute myeloid leukaemia ( M4 ) . A patient whose leukaemic cells carried the rare t ( 7 ; 11 )( p15 ; p15 ) was diagnosed as having acute myelomonocytic leukaemia ( AML - M4 ) , and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation . Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the P00519 and P11274 genes . Chromosome in situ hybridization studies showed that both the HRAS1 and P01308 genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p . Neither HRAS1 nor P01308 were structurally rearranged . Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA . Because the P01308 gene , which was also translocated , is probably located proximal to HRAS1 on chromosome 11p , it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia .", "P01308 - like growth factor - 1 receptor signaling increases the invasive potential of human epidermal growth factor receptor 2 - overexpressing breast cancer cells via Src - focal adhesion kinase and forkhead box protein M1 . Resistance to the human epidermal growth factor receptor ( P04626 ) - targeted antibody trastuzumab is a major clinical concern in the treatment of P04626 - positive metastatic breast cancer . Increased expression or signaling from the insulin - like growth factor - 1 receptor ( IGF - 1R ) has been reported to be associated with trastuzumab resistance . However , the specific molecular and biologic mechanisms through which IGF - 1R promotes resistance or disease progression remain poorly defined . In this study , we found that the major biologic effect promoted by IGF - 1R was invasion , which was mediated by both Src - focal adhesion kinase ( Q05397 ) signaling and Q08050 ( FoxM1 ) . Cotargeting IGF - 1R and P04626 using either IGF - 1R antibodies or IGF - 1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition . Reduced invasion was the most significant biologic effect achieved by cotargeting IGF - 1R and P04626 in trastuzumab - resistant cells . Constitutively active Src blocked the anti - invasive effect of IGF - 1R / P04626 cotargeted therapy . Furthermore , knockdown of FoxM1 blocked DB01277 - mediated invasion , and dual targeting of IGF - 1R and P04626 reduced expression of FoxM1 . Re - expression of FoxM1 restored the invasive potential of IGF - 1R knockdown cells treated with trastuzumab . Overall , our results strongly indicate that therapeutic combinations that cotarget IGF - 1R and P04626 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1 .", "Identification of biomarkers for endometriosis in eutopic endometrial cells from patients with endometriosis using a proteomics approach . Endometriosis is a gynecological disease defined as the presence of endometrial tissue outside the uterine cavity , which is caused by various factors . Proteomic analysis of two sets of eutopic endometrial cells collected from the menstrual blood of females with ( n = 6 ; n = 3 ) or without ( n = 6 ; n = 3 ) endometriosis was performed to identify novel potential biomarkers for endometriosis . The data revealed that samples from endometriosis patients had stem cell characteristics , as they had higher mRNA expression levels of octamer - binding transcription factor 4 ( Q01860 ) , P61073 ( P61073 ) , Q05066 - box containing gene 2 ( P48431 ) and mesenchymal - epithelial transition factor ( MET ) compared with that of the normal controls . Three proteins , collapsin response mediator protein 2 ( Q16555 ) , ubiquitin carboxyl - terminal hydrolase isozyme Q9NUQ9 ( P09936 ) and myosin regulatory light polypeptide 9 ( P24844 ) , were simultaneously identified from the two sets of samples from females with or without endometriosis by two - dimensional electrophoresis ( 2 - DE ) . A difference in Q16555 expression was confirmed with western blotting . Taken together , the results suggest that Q16555 plays a role in the pathogenesis of endometriosis .", "Comparison of two polymer - based immunohistochemical detection systems : ENVISION + and ImmPRESS . The non - specific background reaction produced in avidin - biotin - based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non - avidin - biotin systems , yet there are few reports comparing the performance of non - avidin - biotin , polymer - based methods . In this study we compare two of these methods , ENVISION + trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin - fixed , paraffin - embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut - 1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION + or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION + trade mark in 16 / 18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION + trade mark . Based on these results , ImmPRESS is a good polymer - based detection system for routine immunohistochemistry .", "Suppressive effects of glucagon - like peptide - 1 on interferon - gamma - induced nitric oxide production in insulin - producing cells is mediated by inhibition of tumor necrosis factor - alpha production . During the development of Type 1 diabetes , inflammatory cytokines are known to induce the expression of inducible nitric oxide synthase ( P35228 ) in pancreatic islets , and subsequent production of nitric oxide ( NO ) contributes to beta cell destruction . Glucagon - like peptide - 1 ( P0C6A0 ) has been shown to reduce cytokine - induced apoptosis of beta cells . In this study , we investigated whether P0C6A0 affects cytokine - induced NO production , resulting in the inhibition of beta - cell apoptosis . We treated MIN6N8a mouse beta cells with interferon ( IFN ) - gamma in the presence or absence of P0C6A0 and found that P01579 treatment induced P35228 mRNA expression and NO production , which was significantly inhibited by treatment with P0C6A0 . Blocking of P43220 signaling via the cyclic AMP and phosphatidylinositol 3 - kinase pathway did not directly affect the suppressive effect of P0C6A0 on IFN - gamma - induced P35228 mRNA expression . Further studies revealed that P01579 induced the expression of P01375 mRNA and protein , which synergistically induced NO production , and P0C6A0 treatment inhibited this induction of P01375 . To examine whether the reduction of P01375 by P0C6A0 treatment plays a role in suppressing NO production , we treated MIN6N8a cells with P01579 in the presence of anti - P01375 neutralizing antibody and found that NO production was reduced . In addition , treatment of mouse islets with P0C6A0 inhibited the expression of P35228 and TNFmRNA . These results suggest that P0C6A0 inhibits P01579 - induced NO production by suppression of P01375 production .", "P01308 signaling inhibits the P28335 receptor in choroid plexus via Q96HU1 kinase . BACKGROUND : G protein - coupled receptors ( GPCRs ) interact with heterotrimeric GTP - binding proteins ( G proteins ) to modulate acute changes in intracellular messenger levels and ion channel activity . In contrast , long - term changes in cellular growth , proliferation and differentiation are often mediated by tyrosine kinase receptors and certain GPCRs by activation of mitogen - activated protein ( Q96HU1 ) kinases . Complex interactions occur between these signaling pathways , but the specific mechanisms of such regulatory events are not well - understood . In particular it is not clear whether GPCRs are modulated by tyrosine kinase receptor - Q96HU1 kinase pathways . RESULTS : Here we describe tyrosine kinase receptor regulation of a GPCR via Q96HU1 kinase . P01308 reduced the activity of the P28335 receptor in choroid plexus cells which was blocked by the Q96HU1 kinase kinase ( MEK ) inhibitor , PD 098059 . We demonstrate that the inhibitory effect of insulin and insulin - like growth factor type 1 ( DB01277 ) on the P28335 receptor is dependent on tyrosine kinase , DB01367 and Q96HU1 kinase . The effect may be receptor - specific : insulin had no effect on another GPCR that shares the same G protein signaling pathway as the P28335 receptor . This effect is also direct : activated Q96HU1 kinase mimicked the effect of insulin , and removing a putative Q96HU1 kinase site from the P28335 receptor abolished the effect of insulin . CONCLUSION : These results show that insulin signaling can inhibit P28335 receptor activity and suggest that Q96HU1 kinase may play a direct role in regulating the function of a specific GPCR .", "P01308 - like growth factor binding proteins in the bovine anterior pituitary . P01308 - like growth factor binding proteins ( IGFBPs ) were characterized in bovine anterior pituitary tissue , pituitary conditioned media , and serum collected during the preovulatory and early luteal phases of the estrous cycle . Effects of in vitro treatments of pituitaries with luteinizing hormone - releasing hormone ( P01148 ) , estradiol , and progesterone on IGFBP secretion were also evaluated . Predominant IGFBPs detected in anterior pituitary tissue by immunoprecipitation , ligand blotting , and Northern blotting were P24593 ( 29 kDa ) , P18065 ( 32 kDa ) , and P17936 ( 36 and 39 kDa doublet ) . Conditioned culture media contained P24593 , a slightly larger form of P18065 ( 33 kDa ) , the 36 - and 39 - kDa forms of P17936 , and a more extensively glycosylated form of P17936 ( 44 kDa ) . In serum , P24593 was not readily detected , and P17936 ( 40 - and 44 - kDa doublet ) and P18065 ( 34 kDa ) were larger than in pituitary tissue . Levels of P18065 , - 3 , and - 5 in pituitary tissue decreased during the preovulatory period and were lowest in the early luteal phase . Treatment with P01148 increased P18065 levels in media twofold . Estradiol or progesterone did not alter IGFBP secretion in vitro . Predominant IGFBPs produced and released by anterior pituitary tissue were P18065 , - 3 and - 5 . The activity of IGFBPs fluctuates in the pituitary in association with changes in stage of estrous cycle , implicating IGFBPs as potential regulators of gonadotrope function .", "PEGylated exendin - 4 , a modified P0C6A0 analog exhibits more potent cardioprotection than its unmodified parent molecule on a dose to dose basis in a murine model of myocardial infarction . A Site - specifically PEGylated exendin - 4 ( denoted as PEG - Ex4 ) is an exendin - 4 ( denoted as Ex4 ) analog we developed by site - specific PEGylation of exendin - 4 with a high molecular weight trimeric poly ( ethylene glycol ) ( tPEG ) . It has been shown to possess prolonged half - life in vivo with similar receptor binding affinity compared to unmodified exendin - 4 by our previous work . This study is sought to test whether PEG - Ex4 is suitable for treating myocardial infarction ( MI ) . In the MI model , PEG - Ex4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily . Animal survival rate , heart function , remodeling and neoangiogenesis were evaluated and compared . Tube formation was examined in endothelial cells . In addition , Western blotting and histology were performed to determine the markers of cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved . PEG - Ex4 and Ex4 showed comparable binding affinity to P43220 . In MI mice , PEG - Ex4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily , while Ex4 given at 3 days interval failed to produce protection . PEG - Ex4 elevated endothelial tube formation in vitro and capillary density in the border area of MI . PEG - Ex4 increased Akt activity and P15692 production in a P43220 dependent manner in endothelial cells and antagonism of P43220 , Akt or P15692 abolished the protection of PEG - Ex4 in the MI model . PEG - Ex4 is a potent long - acting P43220 agonist for the treatment of chronic heart disease . Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and P15692 .", "G protein - coupled receptor kinase 2 mediates endothelin - 1 - induced insulin resistance via the inhibition of both Galphaq / 11 and insulin receptor substrate - 1 pathways in 3T3 - Q9NUQ9 adipocytes . G protein - coupled receptor kinases ( GRKs ) regulate seven - transmembrane receptors ( 7TMRs ) by phosphorylating agonist - activated 7TMRs . Recently , we have reported that P25098 can function as a negative regulator of insulin action by interfering with G protein - q / 11 alpha - subunit ( Galphaq / 11 ) signaling , causing decreased glucose transporter 4 ( P14672 ) translocation . We have also reported that chronic endothelin - 1 ( ET - 1 ) treatment leads to heterologous desensitization of insulin signaling with decreased tyrosine phosphorylation of insulin receptor substrate ( P41252 ) - 1 and Galphaq / 11 , and decreased insulin - stimulated glucose transport in 3T3 - Q9NUQ9 adipocytes . In the current study , we have investigated the role of P25098 in chronic ET - 1 - induced insulin resistance . P01308 - induced P14672 translocation was inhibited by pretreatment with ET - 1 for 24 h , and we found that this inhibitory effect was rescued by microinjection of anti - P25098 antibody or P25098 short interfering RNA . We further found that P25098 mediates the inhibitory effects of ET - 1 by two distinct mechanisms . Firstly , adenovirus - mediated overexpression of either wild - type ( WT ) - or kinase - deficient ( KD ) - P25098 inhibited Galphaq / 11 signaling , including tyrosine phosphorylation of Galphaq / 11 and cdc42 - associated phosphatidylinositol 3 - kinase activity . Secondly , ET - 1 treatment caused DB00133 / DB00156 phosphorylation of P35568 and P35568 protein degradation . Overexpression of KD - P25098 , but not WT - P25098 , inhibited ET - 1 - induced serine 612 phosphorylation of P35568 and restored activation of this pathway . Taken together , these results suggest that P25098 mediates ET - 1 - induced insulin resistance by 1 ) inhibition of Galphaq / 11 activation , and this effect is independent of P25098 kinase activity , and 2 ) P25098 kinase activity - mediated P35568 serine phosphorylation and degradation .", "[ Changes in chemokine receptor 4 , interleukin - 6 , and collagen X expression in the ATDC5 cell line stimulated by cyclic tensile strain and stromal cell - derived factor - 1 ] . OBJECTIVE : This study further explores the stromal cell - derived factor - 1 ( P48061 ) / chemokine receptor 4 ( P61073 ) signaling axis mechanism in temporomandibular joint osteoarthritis ( OA ) by detecting the changes in P61073 , interleukin ( IL ) - 6 , and collagen X expression in the ATDC5 cell line stimulated by the cyclic tensile strain and P48061 . METHODS : P01308 - transferrin - selenium ( ITS ) was used to induce ATDC5 cells to differentiate into chondrocyte - like cells . After three weeks , the cells were divided into two groups : those with and without cyclic tensile strain . These groups were further divided into the negative control and P48061 groups . Strain force of 20 % was applied . After 12 h , the total proteins were extracted from cells of the four groups , and Western blot analysis was used to detect the changes in P61073 , P05231 , and collagen X expression . RESULTS : P48061 could enhance P61073 , P05231 , and collagen X expressions in the chondrocytes , and 20 % tensile strain force could further upregulate the three factors . CONCLUSION : Under abnormal tensile force , P48061 can upregulate its specific receptor P61073 , thus increasing its - binding efficiency and resulting in the activation of the P48061 / P61073 axis . This condition enhances the expressions of P05231 and other inflammatory factors and directly damages to cartilage tissue . Such damage directly promotes chondrocyte hypertrophy , which enhances collagen X expression .", "Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK17___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK17___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .", "Population pharmacokinetic study of memantine : effects of clinical and genetic factors . BACKGROUND AND OBJECTIVE : Memantine , a frequently prescribed anti - dementia drug , is mainly eliminated unchanged by the kidneys , partly via tubular secretion . Considerable inter - individual variability in plasma concentrations has been reported . We aimed to investigate clinical and genetic factors influencing memantine disposition . METHODS : A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting . Patients were genotyped for common polymorphisms in renal cation transporters ( O15245 / 2 / 5 , Q96FL8 , P08183 ) and nuclear receptors ( O75469 , Q14994 , RXR , Q07869 ) involved in transporter expression . RESULTS : The average clearance was 5 . 2 L / h with a 27 % inter - individual variability ( percentage coefficient of variation ) . Glomerular filtration rate ( p = 0 . 007 ) and sex ( p = 0 . 001 ) markedly influenced memantine clearance . O75469 rs1523130 was identified as the unique significant genetic covariate for memantine clearance ( p = 0 . 006 ) , with carriers of the O75469 rs1523130 CT / TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype . CONCLUSION : The better understanding of inter - individual variability of memantine disposition might be beneficial in the context of individual dose optimization .", "Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK82___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .", "___MASK39___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK39___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .", "Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .", "The development of DB01276 ( exenatide ) from the venom of the Gila monster as an anti - diabetic agent . The development of DB01276 ( synthetic exendin - 4 ; exenatide ) as a treatment of diabetes arose from two , parallel lines of investigation . The development of the ' incretin concept ' which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals , led to the identification of glucagon - like peptide 1 ( P0C6A0 ) as an important ' incretin ' hormone . P0C6A0 not only increases insulin secretion but increases β - cell proliferation and survival , suppresses glucagon secretion , delays gastric emptying and suppresses appetite , all of these actions contributing to a potential anti - diabetic effect . However , P0C6A0 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases . A systematic investigation of the composition and activity of venom from the Gila monster , Heloderma suspectum , led to the isolation of a 39 - amino acid peptide , designated exendin - 4 , showing 53 % structural homology with P0C6A0 ( 7 - 36 ) . Exendin - 4 mimicked P0C6A0 through stimulating the P43220 . The much greater stability of exendin - 4 led to its experimental and clinical evaluation as an anti - diabetic agent and its introduction to the market in 2005 .", "Oxyntomodulin differentially affects glucagon - like peptide - 1 receptor beta - arrestin recruitment and signaling through Galpha ( s ) . The glucagon - like peptide ( GLP ) - 1 receptor is a promising target for the treatment of type 2 diabetes and obesity , and there is great interest in characterizing the pharmacology of the P43220 and its ligands . In the present report , we have applied bioluminescence resonance energy transfer assays to measure agonist - induced recruitment of betaarrestins and G - protein - coupled receptor kinase ( GRK ) 2 to the P43220 in addition to traditional measurements of second messenger generation . The peptide hormone oxyntomodulin is described in the literature as a full agonist on the glucagon and P0C6A0 receptors . Surprisingly , despite being full agonists in P43220 - mediated DB02527 accumulation , oxyntomodulin and glucagon were observed to be partial agonists in recruiting betaarrestins and P25098 to the P43220 . We suggest that oxyntomodulin and glucagon are biased ligands on the P43220 .", "___MASK34___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK34___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK34___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .", "Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .", "Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high - fat - diet - fed mice . Twenty - four hours before perfusion , animals were injected with 5 '- bromo - 2 '- deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin - positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100 - 150 % ( P < 0 . 001 ) . We also found an increase in young neurons in the DG of high - fat - diet - fed mice after drug treatment ( P < 0 . 001 ) . The P43220 antagonist exendin ( 9 - 36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood - brain barrier and increase neuroneogenesis .", "Dual factor delivery of P48061 and Exendin - 4 for improved survival and function of encapsulated beta cells under hypoxic conditions . A bioartifical pancreas ( BAP ) remains a promising approach for treating insulin - dependent diabetes . Several obstacles to the clinical implementation of a BAP remain , including hypoxia following implantation . Within native pancreatic islets , P48061 and glucagon - like peptide - 1 ( P0C6A0 ) act in a paracrine fashion to promote the survival , function , and proliferation of β - cells . This work sought to investigate if the presentation of P48061 and delivery of a P43220 analog , Exendin - 4 ( Ex - 4 ) , alone and in combination , conferred pro - survival and insulinotropic effects on an encapsulated β - cell line , βTC - tet , cultured under hypoxic conditions of 7 . 6 mmHg O2 . Our findings indicate that presentation of P48061 in the encapsulation matrix completely abrogated apoptosis under hypoxic conditions . Delivery of Ex - 4 increased insulin secretion rate under both normoxic and hypoxic conditions , and additionally reduced apoptosis under hypoxic conditions . Furthermore , presentation of P48061 combined with Ex - 4 delivery significantly increased insulin secretion rate under hypoxic conditions compared to delivery of Ex - 4 alone . These findings demonstrate that the presentation of P48061 combined with the delivery of Ex - 4 may constitute a promising strategy for supporting β - cell function and survival following transplantation .", "P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .", "The relationship between albuminuria and hormone therapy in postmenopausal women . BACKGROUND : Elevated urinary albumin excretion and hormone therapy ( HT ) are associated with increased risk for cardiovascular events . We assessed the relationship between albuminuria and the use of hormonal preparations in postmenopausal women . METHODS : Data from the P01308 Resistance Atherosclerosis Study were obtained at baseline and 5 - year follow - up for analysis . The generalized estimating equation procedure accounting for repeated measures was used for this analysis . HT was the main predictor variable , and log ( e ) urine albumin - creatinine ratio ( P10323 ) was the main outcome variable . RESULTS : Four hundred ninety - one menopausal women were included in the analysis , 36 % ( n = 179 ) of whom received HT ( either oral estrogen , progesterone , or combination therapy ) . At baseline , abnormal albuminuria ( P10323 > or = 25 mg / g ) was present in 11 % of women on HT and 17 % not on HT ( P = 0 . 02 ) . After adjusting for demographics , the presence of diabetes and hypertension , and kidney function , HT was associated with a 19 % reduction in P10323 ( P = 0 . 008 ) and an odds ratio of 0 . 67 ( 95 % confidence interval , 0 . 43 to 1 . 01 ; P = 0 . 06 ) for the presence of abnormal albuminuria . Other predictors of abnormal albuminuria included diabetes , blood pressure , and triglyceride level . CONCLUSION : Results of this study suggest that HT is associated with a reduction in urinary albumin excretion in postmenopausal women .", "[ DB01276 : first once weekly P43220 agonist ( exenatide P10586 ) ] . DB01276 is a new galenic formulation ( long - acting release ) of exenatide , the first agonist of Glucagon - Like Peptide - 1 ( P0C6A0 ) receptors having been commercialized for the management of type 2 diabetes . The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot , which allows one injection per week instead of two injections per day with the initial formulation of exenatide ( DB01276 ) . The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin ( HbA ( 1c ) ) , with a similar weight loss but a better digestive tolerance profile ( less nausea and vomiting after treatment initiation ) , compared with the twice daily 10 microg exenatide . When compared to other glucose - lowering agents , once weekly exenatide is more efficacious than sitagliptin , pioglitazone or basal insulin ( glargine or detemir ) , with the advantage of producing weight loss and lowering arterial blood pressure . It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring , two advantages compared with insulin therapy . DB01276 is currently only reimbursed in Belgium after failure of and in addition to metformin - sulfonylurea combination .", "Molecular physiology of glucagon - like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon - like peptide - 1 ( P0C6A0 ) , a blood glucose - lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase - IV ( DPP - IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post - prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage - dependent K ⁺ channels , O94759 cation channels , intracellular Ca ⁺ release channels , and Ca ⁺- dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .", "The contribution of serotonin P28335 and melanocortin - 4 receptors to the satiety signaling of glucagon - like peptide 1 and liraglutide , a glucagon - like peptide 1 receptor agonist , in mice . Glucagon - like peptide 1 ( P0C6A0 ) , an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L - cells , and liraglutide , a P43220 ( P43220 ) agonist , induce satiety . The serotonin P28335 receptor ( 5 - HT2CR ) and melanoroctin - 4 receptor ( P32245 ) are involved in the regulation of food intake . Here we show that systemic administration of P0C6A0 ( 50 and 200μg / kg ) - induced anorexia was blunted in mice with a 5HT2CR null mutation , and was attenuated in mice with a heterozygous P32245 mutation . On the other hand , systemic administration of liraglutide ( 50 and 100μg / kg ) suppressed food intake in mice lacking 5 - HT2CR , mice with a heterozygous mutation of P32245 and wild - type mice matched for age . Moreover , once - daily consecutive intraperitoneal administration of liraglutide ( 100μg / kg ) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of P32245 as well as wild - type mice . These findings suggest that P0C6A0 and liraglutide induce anorexia via different central pathways .", "Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK93___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .", "Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune - mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 agonist ( exenatide ) . OBSERVATION : A 61 - year - old male patient ( BMI : 25 . 5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid - based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( DB01276 (®) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow - up ( PASI : estimated at 3 - 4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3 . 1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 agonists .", "___MASK24___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK24___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "Exendin - 4 attenuates lipopolysaccharides induced inflammatory response but does not protects H9c2 cells from apoptosis . BACKGROUND : Glucagon - like peptide - 1 ( P0C6A0 ) and its analogues are reported to exert wide - ranging cardiovascular actions in preclinical and clinical studies . We thus investigated whether the P43220 agonist , exendin - 4 , has inhibitory effects on LPS - stimulated inflammatory response in cardiomyoblasts . METHODS : H9c2 cardiomyoblasts were exposed to LPS and treated with exendin - 4 . Expressions of proinflammatory mediators were assessed using quantitative real - time PCR . Nuclear localization of NF - κB was examined using immunoblotting . mRNA expression of inducible nitric oxide synthase ( P35228 ) and nitric oxide ( NO ) production were evaluated by q PCR and NO assay . Furthermore , anti - apoptotic effect of exendin - 4 in LPS - stimulated H9c2 cells was determined using qPCR and immunoblot . RESULTS : Exposure to LPS increased mRNA expressions of P01375 - α , P35354 and P14780 in H9c2 cells . It also caused increases in P35228 mRNA expression and NF - κB nuclear translocation . Exendin - 4 dose - dependently downregulated mRNA levels of P01375 - α , P35354 and P14780 in LPS - stimulated H9c2 cells . It also reduced NF - κB nuclear translocation . Treatment with exendin - 4 showed no effect on LPS - induced apoptosis in H9c2 cells . CONCLUSIONS : Exendin - 4 exerts an effect on cardiomyoblast exposed to LPS by inhibiting mRNA expression of inflammatory mediators and suppressing NF - κB activation . These effects are consistent with some of the observed anti - inflammatory properties of exendin - 4 , as well as its beneficial actions on the cardiovascular system .", "___MASK95___ : kinetic and dynamic profile in the treatment of pain . ___MASK95___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK95___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK95___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK95___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .", "Effect of the combination of metformin and fenofibrate on glucose homeostasis in diabetic Goto - Kakizaki rats . Metformin has been reported to increase the expression of the glucagon - like peptide - 1 ( P0C6A0 ) receptor in pancreatic beta cells in a peroxisome proliferator - activated receptor ( Q07869 ) - α - dependent manner . We investigated whether a PPARα agonist , fenofibrate , exhibits an additive or synergistic effect on glucose metabolism , independent of its lipid - lowering effect , when added to metformin . Non - obese diabetic Goto - Kakizaki ( GK ) rats were divided into four groups and treated for 28 days with metformin , fenofibrate , metformin plus fenofibrate or vehicle . The random blood glucose levels , body weights , food intake and serum lipid profiles were not significantly different among the groups . After 4 weeks , metformin , but not fenofibrate , markedly reduced the blood glucose levels during oral glucose tolerance tests , and this effect was attenuated by adding fenofibrate . Metformin increased the expression of the P43220 in pancreatic islets , whereas fenofibrate did not . During the intraperitoneal glucose tolerance tests with the injection of a P0C6A0 analog , metformin and / or fenofibrate did not alter the insulin secretory responses . In conclusion , fenofibrate did not confer any beneficial effect on glucose homeostasis but reduced metformin ' s glucose - lowering activity in GK rats , thus discouraging the addition of fenofibrate to metformin to improve glycemic control ." ]

[ "___MASK15___", "___MASK17___", "___MASK24___", "___MASK34___", "___MASK39___", "___MASK82___", "___MASK86___", "___MASK93___", "___MASK95___" ]

[ "Involvement of PPARs in Cell Proliferation and Apoptosis in Human Colon Cancer Specimens and in Normal and Cancer Cell Lines . Q07869 involvement in cell growth was investigated \" in vivo \" and \" in vitro \" and was correlated with cell proliferation and apoptotic death . \" In vivo \" PPARgamma and alpha were evaluated in colon cancer specimens and adjacent nonneoplastic colonic mucosa . PPARgamma increased in most cancer specimens versus mucosa , with a decrease in c - Myc and in P12004 proteins , suggesting that colon cancer growth is due to increased cell survival rather than increased proliferation . The prevalence of survival over proliferation was confirmed by Bcl - 2 or Bcl - X ( L ) increase in cancer versus mucosa , and by decreased PPARalpha . \" In vitro \" PPARgamma and PPARalpha were evaluated in human tumor and normal cell lines , treated with natural or synthetic ligands . PPARgamma was involved in inhibiting cell proliferation with a decrease in c - Myc protein , whereas PPARalpha was involved in inducing apoptosis with modulation of Bcl - 2 and Bad proteins . This involvement was confirmed using specific antagonists of two PPARs . Moreover , the results obtained on treating cell lines with Q07869 ligands confirm observations in colon cancer : there is an inverse correlation between PPARalpha and Bcl - 2 and between PPARgamma and c - Myc .", "Arachidonate cascade , apoptosis , and vitamin E in peripheral blood mononuclear cells from hemodialysis patients . BACKGROUND : Lipid peroxidation and oxidative stress are enhanced in peripheral blood mononuclear cells ( PBMCs ) from hemodialysis ( HD ) patients because of upregulation of the P09917 pathway of the arachidonate cascade . 5 - Lipoxygenase activity is specifically inhibited by vitamin E both in vitro and in vivo regardless of its administration route . METHODS : The effect of arachidonate cascade enzymes and vitamin E on oxidative stress and apoptosis was investigated in PBMCs from 16 maintenance HD patients treated for at least 6 months with cuprammonium rayon membranes in a two - step crossover study : after a 4 - week treatment with vitamin E - coated cuprammonium rayon membranes and again after a 4 - week treatment with oral vitamin E . Control PBMCs were obtained from 16 healthy volunteers . RESULTS : Membrane lipoperoxidation , cellular luminescence , membrane fluidity , and leukotriene B ( 4 ) content were significantly greater in PBMCs from HD patients ; lipoxygenase was upregulated , but prostaglandin H synthase ( P61457 ) was not affected . Regardless of administration route , vitamin E partially controlled lipid peroxidation and oxidative stress through direct inhibition of P09917 . Cultured PBMCs from HD patients showed a significant increase in apoptotic cells compared with controls . DB00163 markedly reduced cell luminescence , membrane fluidity , and apoptosis , whereas the P61457 inhibitor indomethacin was ineffective . Similar results were obtained with control PBMCs induced to apoptosis by hydrogen peroxide . CONCLUSION : Reported data suggest that the P09917 branch of the arachidonate cascade is only responsible for membrane peroxidation , oxidative stress , and apoptosis of PBMCs of HD patients , and administration of vitamin E may be helpful in the control of oxidative stress - related disease in these subjects .", "Specific cellular responses to DB00163 . In the last 10 years precise cellular functions of DB00163 , some of which are independent of its antioxidant / radical - scavenging ability , have been revealed . Absorption of DB00163 from the gut is a selective process . Other tocopherols are not absorbed or are absorbed to a lesser extent . At the post - translational level , DB00163 inhibits protein kinase C and P09917 and activates protein phosphatase 2A and diacylglycerol kinase . Some genes [ platelet glycoprotein IV / thrombospondin receptor / class B scavenger receptor ( P16671 ) , DB00163 transfer protein ( alpha - TTP ) , alpha - tropomyosin , connective tissue growth factor and collagenase ] are affected by DB00163 at the transcriptional level . alpha - Tocopherol also inhibits cell proliferation , platelet aggregation , monocyte adhesion and the oxygen burst in neutrophils . Other antioxidants , such as beta - tocopherol and probucol , do not mimic these effects , suggesting a nonantioxidant , DB00163 - specific molecular mechanism .", "Red blood cell surface adhesion molecules : their possible roles in normal human physiology and disease . Human erythrocytes express a relatively large number of known adhesion receptors , despite the fact that red blood cells ( RBCs ) are generally considered to be nonadhesive for endothelial cell surfaces . Some of these adhesion receptors are expressed by many other tissues , while others have more limited tissue distribution . Some adhesion receptors , including P16671 and VLA - 4 , are only expressed by immature erythroid cells , while others are present on mature erythrocytes . The structure and function of these proteins is reviewed here . LW , P16671 , P19256 , and CD147 have been shown in other tissues to mediate cell - cell interaction . Other receptors , such as P16070 , VLA - 4 , and B - P62158 / LU , can mediate adhesion to components of extracellular matrix . In addition , their roles in normal erythropolesis , as well as in the pathophysiology of human disease , are summarized . The most convincing evidence for a pathophysiologic role for any of these receptors on erythrocytes comes from studies of cells from patients homozygous for hemoglobin S , as RBC adhesion is thought to contribute to vaso - occlusion . Thus , receptors such as B - P62158 / LU may become targets for future therapy aimed at preventing or ameliorating this thrombotic process .", "Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK10___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK10___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK10___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .", "Group IB secretory phospholipase A2 stimulates leukotriene B4 production by a unique mechanism in human neutrophils . We found that group IB secretory phospholipase A ( 2 ) ( sPLA ( 2 )- IB ) stimulates leukotriene B4 ( LTB4 ) production in the absence of cytochalasin B in human neutrophils . Although LTB4 production has been reported to be associated with arachidonic acid release , the exogenous addition of sPLA ( 2 )- IB did not induce this release from human neutrophils , suggesting that sPLA ( 2 )- IB stimulates LTB4 production without affecting arachidonic acid . Moreover , the intracellular signaling events induced by sPLA ( 2 )- IB included an increase in intracellular Ca ( 2 +) , which is required for LTB4 production . sPLA ( 2 )- IB also stimulated mitogen - activated protein kinase P29323 , but its activity was not required for LTB4 production . In terms of functional aspects , the supernatant of sPLA ( 2 )- IB - stimulated human neutrophils caused chemotactic migration , which was almost completely inhibited by preincubating these cells with three different P09917 inhibitors ( MK - 886 , AA - 861 , or NDGA ) . Taken together , we suggest that sPLA ( 2 )- IB plays a role in the modulation of inflammatory and immune responses by inducing LTB4 production in human neutrophils .", "Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK98___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .", "Cytoprotective properties of DB00163 are related to gene regulation in cultured D - galactosamine - treated human hepatocytes . DB00163 ( DB00163 ) has demonstrated antioxidant activity and gene - regulatory properties . d - Galactosamine ( D - GalN ) - induced cell death is mediated by nitric oxide in hepatocytes , and it is associated with hepatic steatosis . The beneficial properties of DB00163 and their relation to oxidative stress and gene regulation were assessed in D - GalN - induced cell death . Hepatocytes were isolated from human liver resections by a collagenase perfusion technique . alpha - Tocopherol ( 50 microM ) was administered at the advanced stages ( 10 h ) of D - GalN - induced cell death in cultured hepatocytes . Cell death , oxidative stress , DB00163 metabolism , and NF - kappaB - , pregnane X receptor ( O75469 ) - , and peroxisome proliferator - activated receptor ( Q07869 ) - associated gene regulation were estimated in the hepatocytes . D - GalN increased cell death and DB00163 metabolism . alpha - Tocopherol exerted a moderate beneficial effect against apoptosis and necrosis induced by D - GalN . Induction ( rifampicin ) or inhibition ( ketoconazole ) of DB00163 metabolism and overexpression of O75469 showed that the increase in O75469 - related P08684 expression caused by DB00163 enhanced cell death in hepatocytes . Nevertheless , the reduction in NF - kappaB activation and inducible nitric oxide synthase expression and the enhancement of Q07869 and carnitine palmitoyl transferase gene expression by DB00163 may be relevant for cell survival . In conclusion , the cytoprotective properties of DB00163 are mostly related to gene regulation rather than to antioxidant activity in toxin - induced cell death in hepatocytes .", "DB00163 - related inhibition of monocyte P09917 and cardiovascular outcome in maintenance hemodialysis patients . A daily supplement of vitamin E is recommended for the secondary prevention of cardiovascular events in end - stage renal disease patients on maintenance hemodialysis . DB00163 has been entrusted with therapeutic properties against cardiovascular disease for more than 60 years . Several epidemiological studies and intervention trials have been performed with vitamin E , and some of them showed that it prevents atherosclerosis . For a long time , vitamin E was assumed to act by decreasing the oxidation of low - density lipoproteins , a key step in atherosclerosis initiation . However , at the cellular level vitamin E interferes with smooth muscle cell proliferation , platelet aggregation , monocyte adhesion , and oxidized low - density lipoproteins uptake and cytokine production , all reactions implied in the progression of atherosclerosis . Recent research points out that these effects may be not only the result of the antioxidant activity of vitamin E but also of its distinct molecular actions . These biological properties of vitamin E may allow to design better strategies for primary and secondary prevention of cardiovascular disease , with a potential exploitation of vitamin E supplements in primary and secondary prevention of major adverse cardiovascular events in all uremic patients . In this review , we also outline relevant patents on vitamin E and lipoxygenase inhibitors .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .", "DB00163 80th anniversary : a double life , not only fighting radicals . Recent research on DB00163 has revealed specific cellular functions of this compound belonging to the vitamin E family . Alpha - tocopherol can act as a radical scavenger , as a pro - oxidant , as an anti - alkylation agent and , most important , by mechanisms that are independent of the above properties . To the last group belong protein kinase C and P09917 inhibition at post - translational level , as well as DB00163 activation of protein phosphatase 2A and diacylglycerol kinase . Furthermore , at transcriptional level , several genes ( P16671 , alpha - TTP , alpha - tropomyosin , and collagenase ) are modulated by DB00163 . These effects result in inhibition of smooth muscle cell proliferation , platelet aggregation , and monocyte adhesion and may be related to the alleged protection of atherosclerosis by vitamin E . On the other side , epidemiological and intervention studies have shown some inconsistent results . Rather than disregarding vitamin E as a means to protect against atherosclerosis progression , it would be wiser to better design clinical trials based on current knowledge of the biological properties of the molecule .", "P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK20___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .", "Trichostatin A induces P09917 promoter activity and mRNA expression via inhibition of histone deacetylase 2 and 3 . The P09917 ( P09917 ) is the key enzyme in the formation of leukotrienes . We have previously shown that the histone deacetylase ( HDAC ) inhibitor trichostatin A ( P32119 ) activates P09917 transcription via recruitment of Sp1 , Sp3 and RNA polymerase II to the proximal promoter . To identify the HDACs involved in the regulation of P09917 promoter activity isoform - specific HDAC inhibitors were applied . P09917 promoter activity and mRNA expression were up - regulated by the class I HDAC inhibitors apicidin and MS - 275 but not by class II inhibitors . Knockdown of HDAC 1 , 2 and 3 revealed that Q92769 and O15379 but not Q13547 is involved in the up - regulation of P09917 mRNA expression . To analyse the chromatin modifications at the P09917 promoter associated with HDAC inhibition , the time course of P09917 mRNA induction by trichostatin A was investigated and the concomitant changes in histone modifications at the P09917 promoter in HL - 60 , U937 and Mono Mac6 cells were determined . Chromatin immunoprecipitation analysis revealed that trichostatin A increases acetylation of histones H3 and H4 at the P09917 core promoter in HL - 60 and U937 cells whereas no significant changes were observed in Mono Mac6 cells . The appearance of H3 and H4 acetylation preceded the P09917 mRNA induction whereas in all three cell lines , induction of P09917 mRNA expression correlated with histone H3 lysine 4 trimethylation ( H3K4me3 ) , a marker for transcriptional activity of gene promoters .", "High glucose augments the angiotensin II - induced activation of O60674 in vascular smooth muscle cells via the polyol pathway . Angiotensin II ( Ang II ) , protein kinase C ( PKC ) , reactive oxygen species ( ROS ) generated by NADPH oxidase , the activation of O60674 ( O60674 ) , and the polyol pathway play important parts in the hyperproliferation of vascular smooth muscle cells ( VSMC ) , a characteristic feature of diabetic macroangiopathy . The precise mechanism , however , remains unclear . This study investigated the relation between the polyol pathway , P05771 , ROS , O60674 , and Ang II in the development of diabetic macroangiopathy . VSMC cultured in high glucose ( HG ; 25 mm ) showed significant increases in the tyrosine phosphorylation of O60674 , production of ROS , and proliferation activities when compared with VSMC cultured in normal glucose ( 5 . 5 mm ( NG ) ) . Both the aldose reductase specific inhibitor ( zopolrestat ) or transfection with aldose reductase antisense oligonucleotide blocked the phosphorylation of O60674 , the production of ROS , and proliferation of VSMC induced by HG , but it had no effect on the Ang II - induced activation of these parameters in both NG and HG . However , transfection with P05771 antisense oligonucleotide , preincubation with a P05771 - specific inhibitor ( LY379196 ) or apocynin ( NADPH oxidase - specific inhibitor ) , or electroporation of NADPH oxidase antibodies blocked the Ang II - induced O60674 phosphorylation , production of ROS , and proliferation of VSMC in both NG and HG . These observations suggest that the polyol pathway hyperactivity induced by HG contributes to the development of diabetic macroangiopathy through a P05771 - ROS activation of O60674 .", "Effects of dietary vitamin E on the biosynthesis of P09917 products by rat polymorphonuclear leukocytes ( PMNL ) . Activation of polymorphonuclear neutrophils ( PMNL ) leads to the release of arachidonate from cellular phospholipids via a phospholipase A2 , and conversion of products of the P09917 pathway . Evidence to date indicates the dietary vitamin E ( ( R , R , R ) - DB00163 ) can influence both cyclooxygenase and phospholipase A2 activities and that the effect of this vitamin is cell / tissue specific . The present study was undertaken in order to examine the effects of varying dietary tocopherol on PMNL tocopherol content and P09917 product profile using the ionophore A23187 as stimulant in the presence and absence of exogenous arachidonate . Feeding semi - purified diets containing 0 , 30 or 3000 ppm of ( R , R , R ) - DB00163 acetate to weanling rats for 17 weeks resulted in a dose - related enrichment of PMNL tocopherol . Stimulation of PMNL elicited a significant and rapid loss of tocopherol . When PMNL were stimulated with A23187 alone , the synthesis of 5 - HETE , LTB4 and 19 - hydroxy - LTB4 was decreased in proportion to increasing dietary tocopherol concentrations . However , when exogenous arachidonate was provided with A23187 , intermediate amounts of dietary tocopherol ( 30 ppm ) still suppressed the formation of P09917 products , but high doses ( 3000 ppm ) did not have any additional inhibitory effect . This differential response to high concentrations of vitamin E in the presence and absence of exogenous arachidonate highly suggest that at these concentrations , tocopherol may act principally at the level of substrate release whereas at lower concentrations , P09917 is inhibited . Data from this study demonstrated that attenuation of the formation of P09917 products in PMNL can be achieved by dietary vitamin E enrichment .", "Inhibition of P09917 by vitamin E . Purified P09917 from potato tubers was inhibited strongly by vitamin E and its analogs . The inhibition by d - DB00163 was found to be irreversible and non - competitive with respect to arachidonic acid . An IC50 of 5 microM was calculated for d - DB00163 . The inhibition appears to be unrelated to its antioxidant function . Binding studies with 14C - labelled d - DB00163 revealed that there is a strong interaction between vitamin E and P09917 . Tryptic digestion and peptide mapping of P09917 - vitamin E complex indicate that vitamin E binds strongly to a single peptide . These studies suggest that cellular vitamin E levels may have profound influence on the formation of leukotrienes .", "Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK65___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .", "New isoflavonoids as inhibitors of porcine P09917 . The inhibitory activity of new isoflavonoids on P09917 of porcine leukocytes was investigated . Isoflavans ( I ) proved to be stronger inhibitors than isoflavones ( II ) . The isoflavans containing ortho - hydroxy groups in ring A showed the lowest Ki values ( 0 . 8 - 50 microM ) . In comparison , isoflavans with meta - dihydroxy groups exhibited Ki values higher than 150 microM . The effect of commercial antioxidants was tested also on porcine P09917 . Butylated hydroxyanisole ( Ki : 25 microM ) and butylated hydroxytoluene ( Ki : 55 microM ) revealed moderate inhibitory activity , whereas L - ascorbic acid , L - ascorbyl palmitate , dl - DB00163 and n - propyl gallate showed weak inhibitory activities ( Ki : 100 - 260 microM ) .", "Identification of regions of leukotriene C4 synthase which direct the enzyme to its nuclear envelope localization . Leukotrienes ( LTs ) are fatty acid derivatives formed by oxygenation of arachidonic acid via the P09917 ( P09917 ) pathway . Upon activation of inflammatory cells P09917 is translocated to the nuclear envelope ( NE ) where it converts arachidonic acid to the unstable epoxide P09960 . P09960 is further converted to LTC4 by conjugation with glutathione , a reaction catalyzed by the integral membrane protein Q16873 ( Q16873 ) , which is localized on the NE and endoplasmic reticulum ( ER ) . We now report the mapping of regions of Q16873 that are important for its subcellular localization . Multiple constructs encoding fusion proteins of green fluorescent protein ( GFP ) as the N - terminal part and various truncated variants of human Q16873 as C - terminal part were prepared and transfected into P29320 293 / T or COS - 7 cells . Constructs encoding hydrophobic region 1 of Q16873 ( amino acids 6 - 27 ) did not give distinct membrane localized fluorescence . In contrast hydrophobic region 2 ( amino acids 60 - 89 ) gave a localization pattern similar to that of full length Q16873 . Hydrophobic region 3 ( amino acids 114 - 135 ) directed GFP to a localization indistinguishable from that of full length Q16873 . A minimal directing sequence , amino acids 117 - 132 , was identified by further truncation . The involvement of the hydrophobic regions in the homo - oligomerization of Q16873 was investigated using bioluminescence resonance energy transfer ( BRET ) analysis in living cells . BRET data showed that hydrophobic regions 1 and 3 each allowed oligomerization to occur . These regions most likely form transmembrane helices , suggesting that homo - oligomerization of Q16873 is due to helix - helix interactions in the membrane .", "Inhibitory effects of a phosphate diester of DB00163 and ascorbic acid ( EPC - P04264 ) on myocardial infarction in rats . The inhibitory effect of a phosphate diester of DB00163 and ascorbic acid ( EPC - P04264 ) was examined in myocardial infarction induced in rats , in comparison with a selective P09917 inhibitor , AA - 861 . EPC - P04264 significantly reduced the infarct size at 24 and 48 h after ligation , whereas AA - 861 reduced it only at 48 h after ligation . In in - vitro experiments , EPC - P04264 inhibited not only superoxide anion generation ( IC50 = 4 . 2 x 10 (- 5 ) M ) , but also acid phosphatase activity ( IC50 = 2 . 4 x 10 (- 5 ) M ) in rat polymorphonuclear leukocytes in a concentration - dependent manner , while AA - 861 showed marginal effects on both actions . These results indicated that EPC - P04264 induced cardioprotective effects by affecting neutrophil functions by inhibition of generation of superoxide - anion generation and acid - phosphatase activity . The mechanism of the reduction of the infarct size by EPC - P04264 differed from that of AA - 861 , which latter inhibited P09917 and the formation of leukotriene B4 .", "Alpha - tocopherol prevents cyclosporin A - mediated activation of phospholipase A2 and inhibition of Na + , K (+)- adenosine triphosphatase activity in cultured hamster renal tubular cells . At concentrations of 0 . 5 microM and upward , cyclosporin A ( DB00091 ) caused dose - related inhibition of the growth of a hamster renal tubular cell line ( Q86TB3 ATCC ; Q16663 ) in vitro . Inhibition of cell growth was due to the cytotoxic properties of DB00091 which were associated with enhancement of activity of phospholipase A2 ( P04054 ) according to the increased generation of arachidonic acid and lysophosphatidylcholine ( Q16549 ) . Arachidonate per se , at concentrations of up to 20 microM , did not affect the growth of Q86TB3 cells , while cyclooxygenase and P09917 inhibitors failed to protect the cells against the antiproliferative effects of DB00091 . However , Q16549 caused dose - related inhibition of the growth of Q86TB3 cells . Moreover , coincubation with lysophospholipase or DB00163 ( AT , vitamin E ) , a P04054 inhibitory and lysophospholipid - complexing agent , protected the Q86TB3 cells against both DB00091 and Q16549 . The Na + , K (+)- ATPase activity of Q86TB3 cells was also inhibited by DB00091 , with the enzyme being protected by inclusion of AT or lysophospholipase . Increased activity of P04054 and inhibition of Na + , K (+)- ATPase preceded cytotoxicity and cytolysis . Excessive production of lysophospholipids and consequent inhibition of Na + , K (+)- ATPase in renal tubular cells is a possible mechanism of DB00091 - induced nephrotoxicity . The protective effects of AT suggest that this agent may be clinically useful in preventing the renal side effects of DB00091 .", "Chemical modifications of band 3 protein affect the adhesion of Plasmodium falciparum - infected erythrocytes to P16671 . The role of the erythrocyte anion exchanger , band 3 protein ( P02730 ) , in the adhesion of Plasmodium falciparum - infected erythrocytes to P16671 and thrombospondin ( P07996 ) was studied . Two specific anion exchange inhibitors that bind covalently to different regions of the band 3 molecule affected cytoadherence in dissimilar ways . Modification of lysine 539 by diisothiocyanostilbene sulfonic acid ( DIDS ) resulted in a significant reduction in the adhesive properties of parasitized erythrocytes for P16671 , but not P07996 , whereas treatment with fluorescein - 5 - maleimide , which modifies lysine 430 , was without effect on both P07996 and P16671 binding . The adhesive properties of the DIDS binding region ( DBR ) was demonstrated by competition experiments using synthetic peptides and by direct interaction of such peptides with P16671 transfected CHO cells . The results suggest that host membrane proteins such as P02730 contribute to the adhesion of malaria - infected erythrocytes to P16671 .", "Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK33___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .", "Chemopreventive efficacy and mechanism of licofelone in a mouse lung tumor model via aspiration . Our previous study comparing inhalation and aspiration to administer agents directly to lung indicated that aspiration route is as effective as inhalation while reducing costs for equipment and chemopreventive agent . This study evaluated the chemopreventive efficacy and mechanism of licofelone , a dual inhibitor of P35354 and P09917 ( 5 - Lox ) , via oropharyngeal aspiration against mouse lung adenoma . Eight - week - old female A / J mice were given three doses of benzo [ a ] pyrene ( B [ a ] P ; 2 mg / dose , gavage ) to induce lung adenomas . After dysplasia developed , the mice were given licofelone ( 0 , 0 . 03 , 0 . 1 , or 0 . 3 mg / kg ) for 16 weeks , and tumor incidence and multiplicity in lung were measured . In addition , the expression of a series of biomarkers in lung cancer progression was evaluated at 2 and 16 weeks . DB04725 showed dose - related inhibition of B [ a ] P - induced tumor incidence and multiplicity at 0 . 03 and 0 . 1 mg / kg following 16 - week treatment . DB04725 also showed dose - dependent inhibition of P35354 ( 25 % - 41 % ) and 5 - Lox ( 35 % - 61 % ) at 2 and 16 weeks and proliferating cell nuclear antigen ( P12004 ; 41 % - 61 % ) at 16 weeks . A dose - dependent increase in apoptosis ( 1 . 5 - to 2 . 4 - fold ) was also observed in licofelone groups . A marginal inhibition of survivin was observed at one dose . In conclusion , this study showed that licofelone via aspiration showed chemopreventive efficacy against mouse lung adenoma with good correlation to early and late biomarkers of lung cancer progression . This is the first study to show that the aspiration route can be an excellent inexpensive alternative to inhalation for direct delivery of drugs to rodent lungs for efficacy testing of potential chemopreventive agents .", "Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK78___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .", "Gamma - tocopherol , but not DB00163 , decreases proinflammatory eicosanoids and inflammation damage in rats . Gamma - tocopherol ( gammaT ) , the major form of vitamin E in U . S . diets , and its physiological metabolite 2 , 7 , 8 - trimethyl - 2 -( beta - carboxyethyl )- 6 - hydroxychroman ( gamma - CEHC ) , in contrast to DB00163 ( alphaT ) , the primary vitamin E in supplements , inhibit cyclooxygenase - catalyzed synthesis of prostaglandin E2 ( DB00917 ) in activated macrophages and epithelial cells . Here we report that in carrageenan - induced inflammation in male Wistar rats , administration of gammaT ( 33 or 100 mg / kg ) and gamma - CEHC ( 2 mg / pouch ) , but not alphaT ( 33 mg / kg ) , significantly reduced DB00917 synthesis at the site of inflammation . gammaT , but not alphaT , significantly inhibited the formation of leukotriene B4 , a potent chemotactic agent synthesized by the P09917 of neutrophils . Although gammaT had no effect on neutrophil infiltration , it significantly attenuated the partial loss of food consumption caused by inflammation - associated discomfort . Administration of gammaT led consistently to a significant reduction of inflammation - mediated increase in 8 - isoprostane , a biomarker of lipid peroxidation . gammaT at 100 mg / kg reduced P01375 ( 65 % ; P = 0 . 069 ) , total nitrate / nitrite ( 40 % ; P = 0 . 1 ) , and lactate dehydrogenase activity ( 30 % ; P = 0 . 067 ) . Collectively , gammaT inhibits proinflammatory DB00917 and LTB4 , decreases P01375 , and attenuates inflammation - mediated damage . These findings provide strong evidence that gammaT shows anti - inflammatory activities in vivo that may be important for human disease prevention and therapy .", "Alpha - tocopherol as a modulator of smooth muscle cell proliferation . The effects of DB00163 and beta - tocopherol have been studied in rat and human aortic smooth muscle cells . Alpha - tocopherol , but not beta - tocopherol , inhibited smooth muscle cell proliferation and protein kinase C in a dose - dependent manner , at concentrations ranging from 10 to 50 microM . Beta - tocopherol added simultaneously with DB00163 prevented both proliferation and protein kinase C inhibition . Protein kinase C inhibition was cell cycle - dependent and it was prevented by okadaic acid , a protein phosphatase inhibitor . Protein kinase C activity measured from aortas of cholesterol - fed rabbits was also inhibited by DB00163 . By using protein kinase C ( PKC ) isoform - specific inhibitors and immunoprecipitation reactions it was found that P17252 was selectively inhibited by DB00163 . Further , an activation of protein phosphatase 2A by DB00163 was found , which caused P17252 dephosphorylation and inhibition . Ultimately , this cascade of events at the level of cell signal transduction leads to the inhibition of smooth muscle cell proliferation .", "DB00163 prevents diabetes - induced abnormal retinal blood flow via the diacylglycerol - protein kinase C pathway . We have characterized effects of d - DB00163 ( vitamin E ) on activation of protein kinase C ( PKC ) and diacylglycerol ( DAG ) levels in retinal tissues of diabetic rats and correlated its effects to diabetes - induced changes in retinal hemodynamics . Membrane PKC specific activities were increased by 71 % in streptozocin - induced diabetic rats compared with controls ( P < 0 . 05 ) . Western blot analysis showed that membrane P05771 II was increased by 133 +/- 5 % ( P < 0 . 05 ) . Injection of d - DB00163 ( 40 mg / kg ip ) every other day prevented the increases in membrane PKC specific activity and P05771 II protein by immunoblots . Diabetes - induced increases in DAG levels were also normalized by d - DB00163 treatment of 2 wk duration . Physiologically , angiographic abnormalities of retinal hemodynamics based on computerized video - based fluorescein angiography and associated with increases of DAG and membranous PKC levels were also prevented by d - DB00163 treatment in diabetic rats . The effect of d - DB00163 on retinal vascular cells was also studied . Exposure of retinal endothelial cells to 22 mM glucose for 3 days increased total DAG and [ 3H ] palmitate - labeled DAG levels by 35 +/- 8 and 50 +/- 8 % ( P < 0 . 05 ) , respectively , compared with exposure to 5 . 5 mM glucose . The presence of d - DB00163 ( 50 micrograms / ml ) prevented the increases in total DAG and [ 3H ] palmitate - labeled DAG levels in cells exposed to 22 mM glucose . These findings suggested that treatment with d - DB00163 can prevent diabetes - induced abnormalities in rat retinal blood flow . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK64___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK64___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK64___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK64___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK64___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .", "Effect of beta - escin sodium on endothelial cells proliferation , migration and apoptosis . beta - Escin , the major active compound in extracts of the horse chestnut Aesculus hippocastanum seed , has shown clinically significant activity in chronic venous insufficiency ( CVI ) . Our previous studies had shown that beta - escin sodium inhibited angiogenesis in chick chorioallantoic membrane ( P62158 ) and in aortic disk assay . In this study , we explored the direct effect of beta - escin sodium on proliferation , migration and apoptosis in human umbilical vein endothelial cells ( HUVECs ) and ECV304 cells . Sulforhodamine B ( P50991 ) assay showed that beta - escin sodium ( 10 , 20 , 40 microg / ml ) inhibited endothelial cells ( ECs ) proliferation dose - dependently . beta - escin sodium also induced ECs apoptosis at 40 microg / ml . Cell migration was evaluated by an improved wound assay : barren spot assay . And the direct effect on cell motility excluding influence of cell proliferation was examined by High Content Screening ( HCS , Cellomics ) assay . The data indicated that beta - escin sodium suppressed ECs migration and cell motility . Western blot results suggested that beta - escin sodium acts on ECs possibly by increasing expression of thrombospondin - 1 ( P07996 - 1 ) , and decreasing expression of P17252 and activation of Q8TCB0 / 42 mitogen - activated protein kinase ( P29323 ) and p38 mitogen - activated protein kinase ( p38 MAPK ) . Our findings give the evidence that beta - escin sodium might have potential anti - angiogenic activity via its direct effects on ECs .", "Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK48___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .", "Activation of P09917 and related cell membrane lipoperoxidation in hemodialysis patients . Lipid peroxidation was shown at the membrane level in peripheral blood cells of patients hemodialyzed on cuprophan dialyzers , and was mainly attributable to the generation of conjugated hydroperoxides in the lipid bilayer . The oxidative index ( i . e . , the A234 / 205 ratio ) of membrane lipids was 3 . 2 - fold higher in hemodialysis patients than in healthy control subjects , and also the level of leukotriene B4 was significantly increased ( up to 1 . 7 - fold over control ) . Both membrane peroxidation and release of leukotriene B4 were linked to upregulation of P09917 activity ( up to 2 . 4 - fold over control ) and expression at the protein level ( up to 1 . 9 - fold ) . DB00163 , the most important lipophilic antioxidant , prevented both membrane peroxidation and release of leukotriene B4 by inhibiting P09917 activity without affecting enzyme expression . Similar results were observed in patients hemodialyzed on polymethylmetacrylate membranes , but in this case the activation of P09917 was less pronounced . The use of a purified P09917 demonstrated that vitamin E was a reversible inhibitor of enzyme activity ( IC50 = 35 +/- 4 microM ) , further characterized as noncompetitive ( Ki = 30 +/- 3 microM ) . Taken together , the results reported here shed some light on the mechanism responsible for the oxidative damage in hemodialysis . Moreover , the beneficial effect of vitamin E described here may have relevance for the therapy of patients with kidney disease .", "A novel hydroxamic acid derivative , MHY218 , induces apoptosis and cell cycle arrest through downregulation of NF - κB in HCT116 human colon cancer cells . Colorectal cancer ( CRC ) is one of the most common malignant diseases and frequent cause of cancer deaths in the world . In spite of the significant advances in conventional therapeutic approaches to CRC , most patients ultimately die of their disease . There is a need to develop novel preventive approaches for this malignancy . This study was carried out to investigate the anticancer effect of MHY218 , a hydroxamic acid derivative , in HCT116 human colon cancer cells . Treatment of cells with MHY218 resulted in growth inhibition and induction of apoptosis in a concentration - dependent manner . MHY218 induced G2 / M phase arrest in the cell cycle progression which was observed by flow cytometry analysis , and a decrease in the protein expression of cyclin B1 and its activating partners Cdc25C and Cdc2 . MHY218 also caused an increase in the expression levels of P38936 ( P38936 / CIP1 ) , a G2 / M phase inhibitor , in a p53 - independent pathway . The induction of apoptosis was observed by decreased viability , DNA fragmentation , cleavage of poly ( ADP - ribose ) polymerase , alteration in the ratio of Bax / Bcl - 2 protein expression , and activation of caspase - 3 , - 8 and - 9 . In addition , MHY218 treatment showed downregulation of the expression levels of the transcription factor nuclear factor - kappa B ( NF - κB ) in the nucleus , which has been reported to be implicated in the apoptotic cell death of several types of cancer cells , suppression of P01375 - α - induced NF - κB activation , inhibition of cyclooxygenase - 2 expression , repression of matrix metalloproteinase - 9 activation and decrease of P09917 in a concentration - dependent manner . These results suggest that MHY218 may be a useful candidate to be used in the chemoprevention and / or treatment of colon cancer .", "Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . ___MASK48___ non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .", "DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin - dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .", "DB00163 and drug metabolism . Tocopherols and tocotrienols are metabolized by side chain degradation initiated by cytochrome P450 ( CYP ) - catalyzed omega - hydroxylation followed by beta - oxidation . Whereas DB00163 is only poorly metabolized , high amounts of the final products , carboxyethyl hydroxychroman ( CEHC ) , are found from other tocols in HepG2 cells and in human urine . P08684 and P78329 were suggested to be involved in tocopherol degradation . P08684 metabolizes most of the drugs and is induced by many of its substrates via the activation of the pregnane X receptor ( O75469 ) . Also tocopherols and in particular tocotrienols induce the expression of a O75469 - driven reporter gene and the expression of endogenous P08684 and P20815 which is supported by sporadic publications spread over the last 30 years . The potential interference of vitamin E with drug metabolism is discussed in the light of related complications evoked by herbal remedies .", "Pharmacogenetics of asthma . PURPOSE OF REVIEW : Patient response to the asthma drug classes , bronchodilators , inhaled corticosteroids and leukotriene modifiers , are characterized by a large degree of heterogeneity , which is attributable in part to genetic variation . Herein , we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs . RECENT FINDINGS : Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short - acting and long - acting beta - agonists are related to the Gly16Arg genotype for the P07550 . More recent studies including genome - wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous beta - agonist use . Genetic determinants of the safety of long - acting beta - agonist require further study . Variants in P34998 , Q9UL17 , and P06734 contribute to variability in response for lung function , airways responsiveness , and exacerbations in patients taking inhaled corticosteroids . Variants in P09917 , P09960 , Q16873 , P33527 , Q9NS75 , and O94956 contribute to variability in response to leukotriene modifiers . SUMMARY : Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome - wide association studies . Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine .", "DB00163 , P09917 and oxidative stress in haemodialysis patients : facts , not fancies .", "Novel combination treatments targeting chronic myeloid leukemia stem cells . Chronic myeloid leukemia ( CML ) is currently considered incurable in most patients . Stem cell transplantation , an accepted curative option for which extensive experience has been gained , is limited by high morbidity and mortality rates , particularly in older patients . Tyrosine kinase inhibitors targeting P11274 - P00519 are widely used and induce remission in a high proportion of patients , but resistance and incomplete response to these agents portends eventual relapse and disease progression . Although P11274 - P00519 inhibitors eradicate most CML cells , they are largely ineffective against the reservoir of quiescent leukemic stem cells ( LSCs ) . Thus a strong medical need exists for therapies that effectively eradicate LSCs and is currently a focus of extensive research . To date , evidence obtained from in vitro studies , animal models , and clinical CML specimens suggests that an effective approach may be to partner existing P11274 - P00519 inhibitors with compounds targeting key stem cell molecular effectors , including Wnt / β - catenin , hedgehog pathway components , histone deacetylase ( HDAC ) , transforming growth factor - β ( TGF - β ) , O60674 , promyelocytic leukemia protein , and arachidonate P09917 ( P09917 ) . Novel combinations may sensitize LSCs to P11274 - P00519 inhibitors , thereby overcoming resistance and creating the possibility of improving disease outcome beyond the current standard of care .", "Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .", "P01375 - alpha and X - linked adrenoleukodystrophy . The two most common forms of X - linked adrenoleukodystrophy ( X - P33897 ) , the childhood cerebral form ( CCER ) and the adult form , adrenomyeloneuropathy ( Q9BXJ7 ) , arise from the same mutations in the X - P33897 gene at Xq28 . These two forms are distinguished by the degree of cerebral inflammation . Segregation analysis suggests that an autosomal modifying gene may be a major determinant of phenotype in X - P33897 . Thus , a modifying gene could be involved in initiating or promoting the inflammatory response . In this study we detected a difference in tumor necrosis factor - alpha ( P01375 ) bioactivity , but not P01375 protein levels , in serum from some advanced CCER patients . Early - stage CCER patients and Q9BXJ7 patients were in the normal range . Allelic differences in P01375 or levels of soluble P01375 receptor did not account for bioactivity differences or phenotypic heterogeneity in X - P33897 .", "[ Effect of tocopherol and tocopherol quinone complexes with proteins on activity of leukotriene B4 lipoxygenase ] . While estimating the effect of tocopherol , tocopherylquinone and their complexes with the tocopherol - binding proteins from the rat liver cytosole on arachidonate P09917 from peritoneal - lymphocytes and soybean linoleate - P09917 DB00163 and especially its complex with tocopherol - binding protein was defined to inhibit the activity of both vegetative - and animal nature - lipoxygenase .", "Overexpression of cytochrome P450 4F2 in mice increases 20 - hydroxyeicosatetraenoic acid production and arterial blood pressure . P78329 ( P78329 ) activity is thought to be a factor in the pathogenesis of hypertension through its bioactive metabolite 20 - hydroxyeicosatetraenoic acid ( 20 - HETE ) . We previously found that a gain - in - function P78329 variant in a Chinese cohort was associated with elevated urinary 20 - HETE and hypertension . To further explore this association we generated a transgenic mouse model expressing P78329 driven by a modified mouse kidney androgen - regulated protein promoter . This heterologous promoter regulated the expression of luciferase and his - tagged P78329 in transfected P29320 293 cells . In the kidney of transgenic mice , P78329 was localized to renal proximal tubule epithelia and was expressed at a higher level than in control mice , leading to increased urinary 20 - HETE excretion . Assessment of P78329 activity by an arachidonic acid hydroxylation assay showed that 20 - HETE production was significantly higher in kidney microsomes of transgenic mice compared to control mice , as was their systolic blood pressure . There was a positive correlation of blood pressure with urinary 20 - HETE levels . Our results show that increased expression of P78329 in mice enhanced 20 - HETE production and elevated blood pressure .", "Participation of signaling pathways in the derepression of luteinizing hormone receptor transcription . The luteinizing hormone receptor ( LHR ) transcription is subject to an epigenetic regulatory mode whereby the proximal Sp1 site acts as an anchor to recruit histone deacetylases ( HDAC ) 1 / 2 and the Sin3A co - repressor complex . This results in promoter - localized histone hypo - acetylation that contributes to the silencing of LHR transcriptional expression . Chromatin changes resulting from site - specific acetylation and methylation of histones regulate LHR gene expression . The HDAC inhibitor P32119 - induced cell - specific phosphatase release from the promoter , which serves as an ' on ' mechanism for Sp1 phosphorylation by phosphatidylinositol 3 - kinase / protein kinase Czeta ( PI3K / PKCzeta ) at Ser641 , leading to P28749 repressor derecruitment and LHR transcriptional activation . The methylation status of the promoter provides another layer of modulation in a cell - specific manner . Maximal derepression of the LHR gene is dependent on complete DNA demethylation of the promoter in conjunction with histone hyperacetylation and release of repressors ( P28749 and HDAC / Sin3A ) . Independently , the P17252 / Erk pathway , participates in LHR gene expression through induction of Sp1 phosphorylation at DB00133 site ( s ) other than Ser641 . This causes dissociation of the Q13547 / mSin3A from the promoter , recruitment of Q00403 and Pol II , and transcriptional activation . Collectively , these findings demonstrate that LHR gene expression at the transcriptional level is regulated by complex and diverse networks , in which coordination and interactions between these regulatory effectors are crucial for silencing / activation of LHR expression .", "The effect of DB00163 on monocyte proatherogenic activity . Atherosclerosis is the leading cause of morbidity and mortality in Westernized populations . The monocyte is a crucial cell in the genesis of the atherosclerotic lesion and is present during all stages of atherosclerosis . alpha - Tocopherol ( AT ) is the most active component of the vitamin E family and is the principal and most potent lipid - soluble antioxidant in plasma and LDL . With regard to monocyte function , AT supplementation ( 1200 IU / d ) has been shown to decrease release of reactive oxygen species , lipid oxidation , release of cytokines such as interleukin - 1ss ( IL - 1ss ) and tumor necrosis factor - alpha ( P01375 ) and decrease adhesion of monocytes to human endothelium . The mechanism of inhibition of superoxide and lipid oxidation by monocytes appears to be via inhibition of protein kinase C ( PKC ) , the decrease in IL - 1ss and P01375 release by inhibition of P09917 and the inhibition of monocyte - endothelial cell adhesion via decrease in adhesion molecules on monocytes , CD11b and VLA - 4 and by decreasing DNA - binding activity of nuclear transcription factor kappaB . Thus , in addition to the decrease in oxidative stress resulting from AT supplementation , as evidenced by decreased F ( 2 )- isoprostanes and LDL oxidizability , AT is anti - inflammatory and exerts beneficial antiatherogenic effects on cells crucial in atherogenesis such as monocytes .", "DB00091 inhibits leukotriene production in intact RBL - 1 cells without inhibiting leukotriene biosynthetic enzymes . The effects of cyclosporin A ( Q13216 ) on arachidonic acid ( AA ) metabolism were investigated in intact rat basophilic leukemia - 1 ( RBL - 1 ) cells and cell lysates . DB01373 ionophore ( A23187 ) - stimulated synthesis of cysteinyl leukotrienes ( LTC4 , LTD4 , and LTE4 ) , LTB4 , and 5 - hydroxyeicosatetraenoic acid ( 5 - HETE ) in intact cells in the absence or presence of Q13216 was measured by reversed - phase high - performance liquid chromatography ( HPLC ) . Q13216 inhibited the production of cysteinyl LTs , LTB4 , and 5 - HETE in intact cells in a dose - dependent manner . The synthesis of cysteinyl LTs , LTB4 , and 5 - HETE was also measured after the incubation of cell lysates with free AA in the absence or presence of Q13216 . Q13216 did not inhibit synthesis of cysteinyl LTs , but rather stimulated production of LTB4 and 5 - HETE in cell lysate . A23187 - stimulated release of incorporated [ 3H ] AA from intact cells was not inhibited by Q13216 . Q13216 did not inhibit the synthesis of cysteinyl LTs and LTB4 when cells incubated with P09960 as the substrate . These results indicate that the inhibitory effects of Q13216 on the synthesis of LTs and 5 - HETE in intact cells are attributable to a modulatory action on a step in the series of intracellular events that includes the activation of P09917 , which are initiated by Ca2 + influx and end in the release of metabolites from the cell membrane , rather than to a direct inhibitory action on enzymes in the LT biosynthetic pathway .", "Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages . Low density lipoproteins ( LDL ) can be oxidatively modified in vitro by macrophages and certain other cell types so that macrophages will take them up much faster . This process may be important in the formation of cholesterol - laden foam cells derived from macrophages in atherosclerotic lesions . In this study , we have shown that certain flavonoids , plant constituents found in the diet , are potent inhibitors of the modification of 125I - labelled LDL by macrophages , with IC50 values in the micromolar range ( e . g . morin and fisetin 1 microM ; quercetin and gossypetin 2 microM ) . The potencies of individual flavonoids in inhibiting LDL modification did not correlate with their previously determined potencies as inhibitors of P09917 and cyclo - oxygenase . The modification of LDL by macrophages exhibits a lag period of about 4 - 6 hr before enhanced uptake is detected . During this time , there is a rapid depletion in its content of DB00163 ( an endogenous antioxidant found in lipoproteins ) followed by a large increase in the level of hydroperoxides . The flavonoids conserved the DB00163 content of LDL and delayed the onset of detectable lipid peroxidation . Flavonoids also inhibited the cell - free oxidation of LDL mediated by CuSO4 . These findings raise the possibility that flavonoids may protect LDL against oxidation in atherosclerotic lesions and may therefore be natural anti - atherosclerotic components of the diet , although this will depend to a large extent on their pharmacokinetics .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "The helix - loop - helix protein Id - 1 and a retinoblastoma protein binding mutant of SV40 T antigen synergize to reactivate DNA synthesis in senescent human fibroblasts . Normal somatic cells of higher organisms do not divide indefinitely . After a finite number of divisions , normal cells irreversibly cease proliferation by a process termed replicative or cellular senescence . Replicative senescence is controlled by multiple , dominant - acting genes about which very little is known . The only genes known to reactivate DNA synthesis in senescent cells are viral oncogenes encoding proteins that bind and inactivate the p53 and retinoblastoma ( P06400 ) tumor suppressor proteins . SV40 T antigen is the best studied of these viral oncoproteins . T [ P04264 ] is a T antigen point mutant that selectively is defective in binding P06400 and the P06400 - related proteins P28749 and Q08999 . We show that T [ P04264 ] stimulated quiescent human fibroblasts to synthesize DNA nearly as well as wild - type T but was incapable of stimulating senescent cells . We tested several growth regulatory genes that are repressed in senescent cells for ability to restore activity to T [ P04264 ] . These included c - fos , c - jun , Id - 1 , Id - 2 , Q01094 , and cdc2 . Only the helix - loop - helix ( HLH ) protein , Id - 1 , restored the ability of T [ P04264 ] to reactivate DNA synthesis in senescent cells . This activity of Id - 1 was not shared by Id - 2 , a related protein , and depended on an intact HLH domain . It did not appear that Id - 1 interacted directly with P06400 or P28749 . Constitutive Id - 1 expression failed to rescue proliferating cells from growth inhibition by P06400 , P28749 , or Q08999 , and failed to interact with P06400 in the yeast two hybrid system . Because Id proteins negatively regulate basic - HLH ( bHLH ) transcription factors , we suggest that senescent cells express one or more bHLH factor that cooperates with P06400 , or P06400 - related proteins , to suppress proliferation .", "Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK10___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK10___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .", "Inhibition of carboxylesterases in SH - SY5Y human and NB41A3 mouse neuroblastoma cells by organophosphorus esters . Carboxylesterases ( CbxE ) can be inhibited by organophosphorus esters ( OPs ) without causing clinical evidence of toxicity . CbxE are thought to protect the critical enzyme acetylcholinesterase ( P22303 ) from OP inhibition in animals . CbxE and P22303 are both present in neuroblastoma cells , but , even though these cells have potential to be an in vitro model of OP toxicity , the effect of OPs on CbxE and the relationship of CbxE inhibition and P22303 inhibition have not yet been examined in these cells . Therefore , this study examined concentration - related OP - induced inhibition of CbxE in human SH - SY5Y and mouse NB41A3 neuroblastoma cells with 11 active esterase inhibitors : paraoxon , malaoxon , chlorpyrifos - oxon , tolyl saligenin phosphate ( P07996 ) , phenyl saligenin phosphate ( PSP ) , diisopropyl phosphorofluoridate ( ___MASK10___ ) , mipafox , dichlorvos , trichlorfon , dibutyryl dichlorovinyl phosphate ( DBVP ) , and dioctyl dichlorovinyl phosphate ( DOVP ) . All could inhibit CbxE , although the enzyme was less likely to be inhibited than P22303 following exposure to 9 of the test compounds in the human cell line and to all 11 of the test compounds in the murine cell line . Species differences in concentration - related inhibitions of CbxE were evident . When cells were exposed first to an OP with a low IC50 toward CbxE ( PSP ) , followed by an OP with high affinity for P22303 ( paraoxon or malaoxon ) , inhibitions of CbxE and P22303 were additive . This indicated that CbxE did not protect P22303 from OP - induced inhibition in this cell culture model .", "Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK84___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .", "Some antioxidants inhibit , in a co - ordinate fashion , the production of tumor necrosis factor - alpha , IL - beta , and P05231 by human peripheral blood mononuclear cells . Some antioxidants , including butylated hydroxyanisole ( BHA ) , tetrahydropapaveroline ( THP ) , nordihydroguiauretic acid , and 10 , 11 - dihydroxyaporphine ( DB01708 ) , were found to be potent inhibitors of the production of tumor necrosis factor ( P01375 ) - alpha , P01584 , and P05231 by human peripheral blood mononuclear cells ( PBMC ) stimulated by lipopolysaccharide ( LPS ) ( IC50s in the low micromolar range ) . Inhibition of cytokine production was gene selective and not due to general effects on protein synthesis . Inhibition of cytokine production by PBMC was observed also when other inducers were used ( staphylococci , silica , zymosan ) . Much higher concentrations of other antioxidants -- including ascorbic acid , trolox , DB00163 , butylated hydroxytoluene , and the P09917 inhibitor zileuton -- did not affect the production of these cytokines . The active compounds did not inhibit IL - 1 - induced production of P05231 in fibroblasts , showing the cell selectivity of the effect . Antioxidant - mediated inhibition of cytokine production was correlated with low levels of the corresponding messenger RNAs . Nuclear run - on experiments showed that THP inhibited transcription of the P01584 gene . THP decreased the concentration of the transcription factors NF - kappa B and AP - 1 detected in nuclear extracts of PBMC cultured in the presence or absence of LPS . THP and DB01708 markedly decreased the levels of P01375 and P01584 in the circulation of mice following LPS injection . Thus antioxidants vary widely in potency as inhibitors of the activation of transcription factors and of the transcription of genes for pro - inflammatory cytokines . Coordinate inhibition of the transcription of genes for inflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock .", "The 80th anniversary of vitamin E : beyond its antioxidant properties . Molecules provided with an antioxidant function may have additional properties , the latter being sometimes of greater importance than the former . In the last ten years , DB00163 has revealed precise cellular functions , some of which are independent of its antioxidant / radical scavenging ability . At the posttranslational level , DB00163 inhibits protein kinase C and P09917 and activates protein phosphatase 2A and diacylglycerol kinase . Some genes ( P16671 , alpha - TTP , alpha - tropomyosin , and collagenase ) are affected by DB00163 at the transcriptional level . alpha - Tocopherol also induces inhibition of cell proliferation , platelet aggregation and monocyte adhesion . These effects are unrelated to the antioxidant activity of vitamin E , but rather are believed to be a result of specific interactions of vitamin E with components of the cell , e . g . proteins , enzymes and membranes . This review focuses on novel non - antioxidant functions of DB00163 and discusses the possibility that many of the effects previously attributed to the antioxidant functions can also be explained by non - antioxidant mechanisms ." ]

[ "___MASK10___", "___MASK20___", "___MASK33___", "___MASK48___", "___MASK64___", "___MASK65___", "___MASK78___", "___MASK84___", "___MASK98___" ]

[ "Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK91___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .", "Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK8___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK8___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK8___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .", "New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK75___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .", "Potential utility of telmisartan , an angiotensin II type 1 receptor blocker with peroxisome proliferator - activated receptor - gamma ( P37231 ) - modulating activity for the treatment of cardiometabolic disorders . The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus . There is widespread agreement that the renin - angiotensin system ( DB01367 ) plays a pivotal role in the pathogenesis of insulin resistance and cardiovascular disease in diabetes . Indeed , large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular end - organ protection . Thus the blockade of the DB01367 may be a promising strategy for the treatment of the patients with the metabolic syndrome . Although several types of angiotensin II type 1 ( AT ( 1 ) ) receptor blockers ( ARBs ) are commercially available for the treatment of patients with hypertension , we have recently found that telmisartan ( DB00966 ) could have the strongest binding affinity to AT ( 1 ) receptor . Further , telmisartan is reported to act as a partial agonist of peroxisome proliferator - activated receptor - gamma ( P37231 ) . These observations suggest that , due to its unique P37231 - modulating activity , telmisartan may be one of the most promising sartans for the treatment of cardiometabolic disorders . In this paper , we reviewed the potential utility of telmisartan in insulin resistance and vascular complications in diabetes .", "Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .", "Akt - dependent heme oxygenase - 1 induction by NS - 398 in P13671 glial cells : a potential role for CO in prevention of oxidative damage from hypoxia . We investigated whether increased heme oxygenase ( HO ) - 1 activity by NS - 398 is responsible for protection against hypoxia - induced damage in P13671 cells . The expression of P09601 was analyzed by Western blot and cell viability was analyzed by lactate dehydroxygease ( LDH ) activity . NS - 398 increased P09601 expression in a concentration - and time - dependent manner during both normoxia and hypoxia ( 95 % N ( 2 )/ 5 % CO ( 2 ) ) , but the latter was much more sensitive . Because induction of P09601 occurred due to hypoxia itself , NS - 398 seemed to potentiate the expression of P09601 . The reduced cell viability due to hypoxia was significantly reversed by either NS - 398 or [ Ru ( CO )( 3 )( Cl )( 2 )]( 2 ) , a CO - donor . Zinc protophorphrin ( ZnPPIX ) , a P09601 inhibitor , inhibited the protective effect of NS - 398 against hypoxia . Treatment with glucose oxidase ( Q9UJM8 , 20 mU / ml ) increased ROS production and caused apoptotic death , as assayed by DCFH - DA and TUNEL , respectively . NS - 398 significantly reduced Q9UJM8 - induced cell death and ROS production ; these effects were reversed by pre - treatment with oxyhemoglobin ( HbO ( 2 ) ) , a CO / NO scavenger , or ZnPPIX . Finally , NS - 398 increased P37231 luciferase activity in transiently P37231 transfected P13671 cells , which was antagonized by ZnPPIX . NS - 398 increased phosphorylation of Akt , and LY - 294002 , a specific PI ( 3 ) kinase inhibitor , inhibited NS - 398 - induced P09601 expression . Taken together , we conclude that therapeutic use of NS - 398 in the treatment of oxidative stress - oriented neuronal disorders would be beneficial through dual actions : P09601 induction and P35354 inhibition .", "Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK57___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK57___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .", "[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK12___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .", "Peroxisome proliferator - activated receptor - gamma : novel therapeutic target linking adiposity , insulin resistance , and atherosclerosis . P01308 resistance and obesity is a common health problem in the industrialized world . As a result of the availability of high - calorie food and a reduction in energy expenditure , maladaptive metabolic processes may interfere with the action of insulin and increase susceptibility for the development of atherosclerotic cardiovascular diseases . With the advent of peroxisome proliferator - activated receptors ( PPARs ) , the mechanisms of this maladaptation and its relationship to insulin resistance syndrome components have become less obscure , promising new therapeutic approaches for this common problem . In this review we first focus on the molecular structure and cellular mechanisms of action of these receptors and then discuss how P37231 , a Q07869 isoform , provides a link between adiposity , insulin resistance , and atherosclerosis .", "Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK100___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .", "[ ___MASK69___ sodium ( Photofrin - II ) ] . ___MASK69___ sodium ( ___MASK69___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK69___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .", "Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK88___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK88___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .", "P37231 agonist down - regulates Q16552 expression in a murine model of allergic airway inflammation . P37231 ( PPARgamma ) plays a critical role in the control of airway inflammation . Recently , Q16552 has been found to be implicated in many immune and inflammatory responses , including airway inflammation . However , no data are available concerning the effect of PPARgamma on Q16552 production in airway inflammatory diseases . In this study , we used a mouse model of asthma to evaluate the effect of two PPARgamma agonists , rosiglitazone or pioglitazone , on Q16552 expression in allergic airway disease . After OVA inhalation , mice developed the typical pathophysiological features of asthma , and the expression of Q16552 protein and mRNA in the lungs was increased . Administration of rosiglitazone or pioglitazone reduced the pathophysiological features of asthma and decreased the increased Q16552 protein and mRNA expression after OVA inhalation . In addition , the attenuating effect of PPARgamma agonist on allergic airway inflammation and bronchial hyperresponsiveness is abrogated by coadministration of rIL - 17 . This study also showed that the inhibition of Q16552 activity with anti - Q16552 Ab remarkably reduced the increased numbers of inflammatory cells of the airways , airway hyperresponsiveness , and the increased levels of P05112 , P05113 , and P35225 in bronchoalveolar lavage fluid and OVA - specific IgE in serum . In addition , we found that administration of rosiglitazone or pioglitazone decreased the increased NF - kappaB activity and that a NF - kappaB inhibitor , BAY 11 - 7085 , substantially reduced the increased Q16552 protein levels in the lung tissues after OVA inhalation . These findings suggest that the therapeutic effect of PPARgamma in asthma is partly mediated by regulation of Q16552 expression via NF - kappaB pathway .", "Pro - P08253 activation by the PPARgamma agonist , ciglitazone , induces cell invasion through the generation of ROS and the activation of P29323 . P37231 ( PPARgamma ) is a nuclear receptor modulating a variety of biological functions including cancer cell proliferation and differentiation . However , the role of PPARgamma and its ligands in tumor invasion is unclear . To evaluate a possible role for PPARgamma ligands in tumor invasion , we examined whether PPARgamma agonists including pioglitazone , troglitazone , rosiglitazone , and ciglitazone could affect the activity of matrix metalloproteinases ( MMPs ) in the HT1080 cell line , a well - studied and well - characterized cell line for MMP research . The gelatin zymography assay showed that ciglitazone activated pro - P08253 significantly . In addition , ciglitazone increased the expression of P08253 , which was accompanied by an increase of membrane type 1 - MMP ( P50281 ) expression . The PPARgamma antagonist , GW9662 attenuated the ciglitazone - induced PPARgamma activation but it did not affect the pro - P08253 activation by ciglitazone , suggesting that the action of ciglitazone on the pro - P08253 activation bypassed the PPARgamma pathway . Antioxidants and various inhibitors of signal transduction were used to investigate the mechanism of ciglitazone - induced pro - P08253 activation . We found that the sustained production of reactive oxygen species ( ROS ) was required for pro - P08253 activation by ciglitazone . We also found that PB98059 , an inhibitor of MEK - P29323 , significantly blocked ciglitazone - induced pro - P08253 activation and that extracellular signal - regulated kinase ( P29323 ) was hyperphosphorylated by ciglitazone . Moreover , cell invasion was significantly increased by ciglitazone in the HT1080 cell lines , whereas cell motility was not affected . This study suggests that ciglitazone - induced pro - P08253 activation increases PPARgamma - independent tumor cell invasion through ROS production and P29323 activation in some types of cancer cells .", "P14210 enhanced proliferation and differentiation of dental pulp cells . P14210 ( P14210 ) is mesenchymal - derived growth factor acting through a transmembrane tyrosine kinase receptor , c - met . P14210 has multiple effects on different cells . However , its function in dentinogenesis remains unclear . In this study , the expression of P14210 in human dental pulp cells ( DPCs ) in vitro was studied by immunostaining and RT - PCR . The effect of P14210 on DPCs proliferation was determined by MTT , while its effect on cell differentiation was analyzed using ALPase activity , and further confirmed with ALP and Q9NZW4 mRNA and protein expression . Immunostaining revealed that P14210 was found mainly in the cytoplasm of DPCs . RT - PCR analysis showed that both P14210 and c - met were expressed from the DPCs . Exogenous addition of P14210 enhanced proliferation and differentiation of DPCs by up - regulating CREB , P54762 - 1 , and P37231 . U0126 , an P29323 / MAPK inhibitor , inhibited the effects of P14210 on DPCs . It was concluded that P14210 stimulated both proliferation and differentiation of DPCs , at least partially through the P29323 / MAPK pathway .", "A field synopsis and meta - analysis of genetic association studies in peripheral arterial disease : The CUMAGAS - PAD database . In an electronic search of the literature , the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease ( PAD ) . They created a comprehensive database of all eligible studies , collecting detailed genetic and bioinformatics data on each polymorphism . Data from eligible studies were synthesized using meta - analysis techniques . Gene variants were classified into distinct pathophysiologic pathways , and their potential involvement in PAD pathogenesis was determined . Forty - one publications that examined 44 gene polymorphisms were included . For 37 polymorphisms , the variant form had a functional effect . Twenty - three polymorphisms in 22 potential PAD candidate genes ( F2 , P02675 , P42898 , P05106 , P12821 , AGT , P05231 , P13500 , P05362 , P16581 , P14780 , P37231 , P03956 , P35611 , Q9H244 , P11150 , Q13093 , Q8WTV0 , P08254 , P55157 , P08519 , P32297 ) showed a significant association in individual studies . Eighty - eight percent of the studies had statistical power of less than 50 % , and in 15 studies the genotype distribution in the control group did not conform to Hardy - Weinberg equilibrium . Data on 12 polymorphisms ( P12259 1691 G / A , P42898 677C / T , F2 20210 G / A , P05106 1565 T / C , P12821 I / D , AGT 704C / T , AGT - 6G / A , AGT 733C / T , P05231 - 174 G / C , P14780 - 1562C / T , P05362 1462A / G , P32297 831C / T ) were synthesized , and a positive association was found for 3 ( P05231 - 174 G / C , P05362 1462A / G , P32297 831C / T ) .", "Telmisartan , its potential therapeutic implications in cardiometabolic disorders . There is a growing body of evidence that the renin - angiotensin system ( DB01367 ) plays a pivotal role in the pathogenesis of cardiovascular diseases . Indeed , large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular - organ protection . Although several types of angiotensin II type 1 ( AT ( 1 ) ) receptor blockers ( ARBs ) are commercially available for the treatment of patients with hypertension , we have recently found that telmisartan ( DB00966 ) could have the strongest binding affinity to AT ( 1 ) receptor . Telmisartan will be a promising cardiometabolic sartan due to its unique peroxisome proliferator - activated receptor - gamma ( P37231 ) - inducing properties as well . In this review , we focused on telmisartan , and discussed its potential therapeutic implications in cardiometabolic disorders .", "Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK18___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .", "Thiazolidinediones : effects on insulin resistance and the cardiovascular system . Thiazolidinediones ( TZDs ) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years . They may delay the development of type 2 diabetes in individuals at high risk of developing the condition , and have been shown to have potentially beneficial effects on cardiovascular risk factors . TZDs act as agonists of peroxisome proliferator - activated receptor - gamma ( P37231 ) primarily in adipose tissue . P37231 receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue , increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor - alpha ( P01375 ) , plasminogen activator inhibitor - 1 ( P05121 ) and interleukin - 6 ( P05231 ) . Clinically , TZDs have been shown to reduce measures of atherosclerosis such as carotid intima - media thickness ( CIMT ) . However , in spite of beneficial effects on markers of cardiovascular risk , TZDs have not been definitively shown to reduce cardiovascular events in patients , and the safety of rosiglitazone in this respect has recently been called into question . Dual Q07869 / gamma agonists may offer superior treatment of insulin resistance and cardioprotection , but their safety has not yet been assured .", "Transforming growth factor - beta ( TGF - beta ) activates cytosolic phospholipase A2alpha ( cPLA2alpha ) - mediated prostaglandin E2 ( PGE ) 2 / EP1 and peroxisome proliferator - activated receptor - gamma ( P37231 ) / Smad signaling pathways in human liver cancer cells . A novel mechanism for subversion of TGF - beta - induced mitoinhibition . Transforming growth factor - beta ( TGF - beta ) potently inhibits the growth of human epithelial cells . However , neoplastic epithelial cells become resistant to TGF - beta - mediated mitoinhibition , and the mechanisms for this alteration during tumorigenesis are not fully understood . This study was designed to determine whether there is an association between the cytosolic phospholipase A2alpha ( cPLA2alpha ) - controlled eicosanoid metabolism and the growth response to TGF - beta in human liver cancer cells . TGF - beta treatment induced simultaneous Smad - mediated gene transcription and phosphorylation of cPLA2alpha . Whereas Smad activation inhibited tumor cell growth , phosphorylation of P47712 alpha promoted growth and counteracted Smad - mediated mitoinhibition . TGF - beta1 failed to prevent the growth of cells with high basal expression of cPLA2alpha , but inhibition of P47712 alpha , cyclooxygenase - 2 ( P35354 ) , or EP1 receptor restored mitoinhibition by TGF - beta1 in these cells . These results suggest that resistance of tumor cells to TGF - beta - mediated mitoinhibition involves activation of cPLA2alpha / P35354 / EP1 signaling . Furthermore , the TGF - beta1 - induced Smad transcriptional activity and mitoinhibition were blocked by overexpression of cPLA2alpha or peroxisome proliferator - activated receptor - gamma ( P37231 ) but enhanced by depletion of cPLA2alpha or P37231 . These findings , along with the observations that cPLA2alpha activates P37231 and that P37231 binds P84022 , illustrate novel cPLA2alpha / P35354 / EP1 and cPLA2alpha / P37231 / Smad signaling pathways that counteract the mitoinhibition by TGF - beta in human cancer cells .", "Significance of Q14764 and P37231 Expression in Lipomatous Soft Tissue Tumors . BACKGROUND : Molecular mechanism of differentiation in lipogenic tumor is still unknown in detail . P01130 - related protein ( Q14764 ) and peroxisome proliferator - activated receptor gamma ( P37231 ) , representative regulatory molecules of lipogenic differentiation , have been reported today as multi - functional molecules and to modulate tumorigenesis in various kind of cancer . To date , diagnostic and therapeutic significance of the expression of these molecules in lipogenic tumors are not defined . METHODS : The immunohistochemical expression status of Q14764 and P37231 in various grades of 54 lipogenic tumors was analyzed . Correlation between the expression levels and the differentiation of the tumors was confirmed . For statistical analyses , the Kruskal - Wallis test , the Steel - Dwass test and the Mann - Whitney U test were used . RESULTS : Q14764 and P37231 expression was detected in 50 ( 92 . 6 % ) and 44 ( 81 . 5 % ) cases , respectively . The expression level in Q14764 was significantly higher in cases with well differentiated liposarcoma , pleomorphic liposarcoma and dedifferentiated liposarcoma than in lipoma . Compared with lipoma or well differentiated liposarcoma , significant elevation in expression level of P37231 was confirmed in myxoid liposarcoma , pleomorphic liposarcoma , dedifferentiated liposarcoma and the differentiated area of dedifferentiated liposarcoma . CONCLUSION : The up - regulation of Q14764 and P37231 in higher grade cases , i . e . less differentiated tumors than in low grade cases was shown , suggesting the candidate role of these molecules as tumor progression modulators rather than regulatory molecules of differentiation in lipogenic tumors ." ]

[ "___MASK100___", "___MASK12___", "___MASK18___", "___MASK57___", "___MASK69___", "___MASK75___", "___MASK88___", "___MASK8___", "___MASK91___" ]

[ "Downregulation of protein tyrosine phosphatase Q12923 alters cell cycle and upregulates invasion - related genes in prostate cancer cells . Q12923 , a non - receptor type protein tyrosine phosphatase , has been involved in the regulation of apoptosis and invasiveness of various tumour cell types , but its role in prostate cancer remained to be investigated . We report here that downregulation of Q12923 by small interfering RNA in PC3 cells decreases cell proliferation and concomitantly reduces the expression of cell cycle - related proteins such as cyclins E and B1 , P12004 , O95997 and phospho - histone H3 . Q12923 downregulation also increases the invasion ability of PC3 cells through Matrigel coated membranes . cDNA array of Q12923 - silenced PC3 cells versus control cells showed an upregulation of invasion - related genes such as uPA , Q03405 , tPA , P05121 , integrin α6 and osteopontin . This increased expression was also confirmed in Q12923 - silenced DU145 prostate cancer cells by quantitative real time PCR and western blot . These findings suggest that Q12923 is an important mediator of central cellular processes such as proliferation and invasion .", "Genotyping of patients with sporadic and radiation - associated meningiomas . Ionizing radiation is the most established risk factor for meningioma formation . Our aim was to evaluate the main effect of selected candidate genes on the development of meningioma and their possible interaction with ionizing radiation in the causation of this tumor . The total study population included 440 cases and controls : 150 meningioma patients who were irradiated for tinea capitis in childhood , 129 individuals who were similarly irradiated but did not develop meningioma , 69 meningioma patients with no previous history of irradiation , and 92 asymptomatic population controls . DNA from peripheral blood samples was genotyped for single nucleotide polymorphisms ( SNP ) in 12 genes : P35240 , P18887 , O43542 , P13010 , P18074 , Ki - ras , p16 , cyclin D1 , P60484 , P12830 , P01137 , and P37173 . SNP analysis was done using the MassArray system ( Sequenom , San Diego , CA ) and computerized analysis by SpectroTYPER . Logistic regressions were applied to evaluate main effect of each gene on meningioma formation and interaction between gene and radiation . Intragenic SNPs in the Ki - ras and P18074 genes were associated with meningioma risk ( odds ratio , 1 . 76 ; 95 % confidence interval , 1 . 07 - 2 . 92 and odds ratio , 1 . 68 ; 95 % confidence interval , 1 . 00 - 2 . 84 , respectively ) . A significant interaction was found between radiation and cyclin D1 and p16 SNPs ( P for interaction = 0 . 005 and 0 . 057 , respectively ) . Our findings suggest that Ki - ras and P18074 SNPs are possible markers for meningioma formation , whereas cyclin D1 and p16 SNPs may be markers of genes that have an inverse effect on the risk to develop meningioma in irradiated and nonirradiated populations .", "P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK87___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .", "[ The effect of bunazosin vs captopril on hemodynamic and neurohumoral parameters in patients with congestive heart failure ] . The hemodynamic parameters ( right atrial pressure , mean pulmonary artery pressure , pulmonary capillary wedge pressure , cardiac index , heart rate , blood pressure ) and neurohumoral responses ( alpha - P01160 , plasma renin activity , aldosterone , angiotensin II ) of ___MASK28___ , oral P12821 inhibitor , and Bunazosin , oral alpha 1 - blocker , were investigated in 28 patients with congestive heart failure at rest and after exercise . These data were analysed in both acute and chronic phases . 1 ) Acute effect . ___MASK28___ produced significant improvement of neurohumoral factors at rest and also after exercise . Bunazosin reduced alpha - P01160 , but other neurohumoral factors did not change . Bunazosin produced significant hemodynamic improvement both at rest and after exercise . 2 ) Chronic effect . ___MASK28___ produced significant hemodynamic improvement both at rest and after exercise . Improvement of neurohumoral factors in acute phase was also preserved at chronic phase . On Bunazosin , improvement of hemodynamics at acute phase was also preserved at chronic phase without deterioration of neurohumoral factors .", "The thyroid hormone receptor β induces DNA damage and premature senescence . There is increasing evidence that the thyroid hormone ( TH ) receptors ( THRs ) can play a role in aging , cancer and degenerative diseases . In this paper , we demonstrate that binding of TH DB00279 ( triiodothyronine ) to P10828 induces senescence and deoxyribonucleic acid ( DNA ) damage in cultured cells and in tissues of young hyperthyroid mice . DB00279 induces a rapid activation of Q13315 ( ataxia telangiectasia mutated ) / PRKAA ( adenosine monophosphate - activated protein kinase ) signal transduction and recruitment of the NRF1 ( nuclear respiratory factor 1 ) and P10828 to the promoters of genes with a key role on mitochondrial respiration . Increased respiration leads to production of mitochondrial reactive oxygen species , which in turn causes oxidative stress and DNA double - strand breaks and triggers a DNA damage response that ultimately leads to premature senescence of susceptible cells . Our findings provide a mechanism for integrating metabolic effects of THs with the tumor suppressor activity of P10828 , the effect of thyroidal status on longevity , and the occurrence of tissue damage in hyperthyroidism .", "The peroxisome proliferator - activated receptor ( Q07869 ) β / δ agonist GW501516 inhibits P05231 - induced signal transducer and activator of transcription 3 ( P40763 ) activation and insulin resistance in human liver cells . AIM / HYPOTHESIS : P05231 induces insulin resistance by activating signal transducer and activator of transcription 3 ( P40763 ) and upregulating the transcription of its target gene O14543 . Here we examined whether the peroxisome proliferator - activated receptor ( Q07869 ) β / δ agonist GW501516 prevented activation of the P05231 - P40763 - suppressor of cytokine signalling 3 ( O14543 ) pathway and insulin resistance in human hepatic HepG2 cells . METHODS : Studies were conducted with human HepG2 cells and livers from mice null for Pparβ / δ ( also known as Ppard ) and wild - type mice . RESULTS : GW501516 prevented P05231 - dependent reduction in insulin - stimulated v - akt murine thymoma viral oncogene homologue 1 ( AKT ) phosphorylation and in P35568 and Q9Y4H2 protein levels . In addition , treatment with this drug abolished P05231 - induced P40763 phosphorylation of Tyr⁷⁰⁵ and Ser⁷²⁷ and prevented the increase in O14543 caused by this cytokine . Moreover , GW501516 prevented P05231 - dependent induction of extracellular - related kinase 1 / 2 ( P27361 / 2 ) , a serine - threonine protein kinase involved in serine P40763 phosphorylation ; the livers of Pparβ / δ - null mice showed increased Tyr⁷⁰⁵ - and Ser⁷²⁷ - P40763 as well as phospho - P27361 / 2 levels . Furthermore , drug treatment prevented the P05231 - dependent reduction in phosphorylated AMP - activated protein kinase ( AMPK ) , a kinase reported to inhibit P40763 phosphorylation on Tyr⁷⁰⁵ . In agreement with the recovery in phospho - AMPK levels observed following GW501516 treatment , this drug increased the AMP / DB00171 ratio and decreased the DB00171 / ADP ratio . CONCLUSIONS / INTERPRETATION : Overall , our findings show that the PPARβ / δ activator GW501516 prevents P05231 - induced P40763 activation by inhibiting P27361 / 2 phosphorylation and preventing the reduction in phospho - AMPK levels . These effects of GW501516 may contribute to the prevention of cytokine - induced insulin resistance in hepatic cells .", "A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .", "Prenatal exposure to bisphenol A promotes angiogenesis and alters steroid - mediated responses in the mammary glands of cycling rats . Prenatal exposure to Q03001 disturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to chemical challenges administered long after Q03001 exposure . Our aim was to assess the effect of prenatal Q03001 exposure on mammary gland angiogenesis and steroid hormone pathways in virgin cycling rats . Pregnant Wistar rats were exposed to either 25 or 250 g / kg / day ( 25 and 250 Q03001 , respectively ) or to vehicle . Female offspring were autopsied on postnatal day ( P01160 ) 50 or 110 . Ovarian steroid serum levels , the expression of steroid receptors and their co - regulators Q9Y6Q9 and Q9Y618 in the mammary gland , and angiogenesis were evaluated . At P01160 50 , all Q03001 - treated animals had lower serum levels of progesterone , while estradiol levels remained unchanged . The higher dose of Q03001 increased mammary ERα and decreased Q9Y6Q9 expression at P01160 50 and P01160 110 . Q9Y618 protein levels were similar among groups at P01160 50 , whereas at P01160 110 , animals exposed to 250 Q03001 showed a lower Q9Y618 expression . Interestingly , in the control and 25 Q03001 groups , Q9Y618 increased from P01160 50 to P01160 110 . At P01160 50 , an increased vascular area associated with higher P15692 expression was observed in the 250 Q03001 - treated rats . At P01160 110 , the vascular area was still increased , but P15692 expression was similar to that of control rats . The present results demonstrate that prenatal exposure to Q03001 alters the endocrine environment of the mammary gland and its angiogenic process . Increased angiogenesis and altered steroid hormone signals could explain the higher frequency of pre - neoplastic lesions found later in life . This article is part of a Special Issue entitled ' Endocrine disruptors ' .", "Effects of lurasidone on executive function in common marmosets . Cognitive impairment is one of the major symptoms of schizophrenia , and is considered largely due to dysfunctions in the prefrontal cortex ( P27918 ) . ___MASK8___ , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 , 5 - Q13049 and P08908 receptors has been reported to have superior efficacy in rodents ' models of cognitive impairment . However , the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non - human primates . In this study , we investigated the effect of lurasidone on executive function , which is one of the cognitive domains , in common marmosets and compared the results to those of other antipsychotics . The effects of lurasidone , haloperidol , olanzapine , risperidone , quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours ( ORD ) task . Before drug treatment , marmosets ' success rates in the easy trial of the test were almost 90 % . However , maximum success in the difficult trial of the task reached only 50 % after 8 days of training . DB00502 , olanzapine and risperidone decreased correct performance even in the easy trial of the task . All drugs , except lurasidone , impaired success rate in the difficult trial . On the other hand , lurasidone dose - dependently increased marmosets ' success rates in the difficult trial with significant effect at 10mg / kg . In conclusion , we have shown in this study that lurasidone , unlike conventional antipsychotics , improves cognition associated with executive function in common marmosets . These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics .", "Nuclear receptor coregulators are new players in nervous system development and function . Steroid / thyroid hormones and their cognate nuclear receptors ( NRs ) play important roles in nervous system development and function . The spatial and temporal gene expression that is regulated by NRs in the nervous system requires transcriptional intermediary coregulators , designated as coactivators and corepressors . These coregulators enhance or repress transcriptional activity of NRs and modulate their target gene transcription . Recent progress has largely advanced our understanding of the molecular mechanisms by which NR coregulators function in the nervous system . This article summarizes our current knowledge about the molecular mechanisms , expression patterns , and biological functions of NR coactivators , such as the P52701 steroid receptor coactivator family , CBP , p300 , P51532 , Q15648 , P20142 - 1alpha , Q8NI08 , NIX1 , and E6 - AP , as well as corepressors such as NCoR and Q9Y618 . Accumulated findings suggest that the functional spectrum of NR coregulators is much broader than was initially speculated , and these coregulators likely contribute to many physiological aspects of nervous system development and function .", "Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK26___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .", "Focal brain inflammation and autism . Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases . Autism spectrum disorders ( P51689 ) are characterized by social and learning disabilities that affect as many as 1 / 80 children in the USA . There is still no definitive pathogenesis or reliable biomarkers for P51689 , thus significantly curtailing the development of effective therapies . Many children with P51689 regress at about age 3 years , often after a specific event such as reaction to vaccination , infection , stress or trauma implying some epigenetic triggers , and may constitute a distinct phenotype . P51689 children respond disproportionally to stress and are also affected by food and skin allergies . P06850 ( P06850 ) is secreted under stress and together with neurotensin ( NT ) stimulates mast cells and microglia resulting in focal brain inflammation and neurotoxicity . NT is significantly increased in serum of P51689 children along with mitochondrial DNA ( mtDNA ) . NT stimulates mast cell secretion of mtDNA that is misconstrued as an innate pathogen triggering an auto - inflammatory response . The phosphatase and tensin homolog ( P60484 ) gene mutation , associated with the higher risk of P51689 , which leads to hyper - active mammalian target of rapamycin ( P42345 ) signalling that is crucial for cellular homeostasis . P06850 , NT and environmental triggers could hyperstimulate the already activated P42345 , as well as stimulate mast cell and microglia activation and proliferation . The natural flavonoid luteolin inhibits P42345 , mast cells and microglia and could have a significant benefit in P51689 .", "Segregation analysis of tetra - and pentanucleotide short tandem repeat polymorphisms : deviation from Mendelian expectations . Short tandem repeat ( STR ) polymorphisms are powerful tools for linkage studies , chromosome mapping and population analysis . The instability of these microsatellite regions is a prevailing event in several tumors and human genetic diseases and , despite various reports associating instability - related genes and meiosis control , the dynamics of these STR regions in normal cells / individuals has frequently been disregarded . Having previously assayed somatic instability in gastric cancer for some tetra - and pentanucleotide STRs and given the increased application of this type of marker for routine forensic expertise , we report the results of an extensive analysis of segregation in nuclear families of a normal population for the same loci . No mutations were detected in 2374 parent / offspring allelic transfers at TH01 , P07202 , VWA31 / A , MBPB , and P01730 STR loci . Nonsignificant differences were found between gene frequencies of parental and offspring generations . However , the segregation analysis revealed significant deviation from Mendelian expectations for : VWA31 / A locus - alleles 19 , 17 and 14 and TH01 locus - allele 6 . In particular , parental meiosis strongly favored specific allele transmission , depending upon the sex of the offspring . Specific mating types are apparently responsible for most of these abnormal segregations . These results suggest selective factors working either at the gametic or zygotic levels .", "Administration of amitriptyline attenuates noise - induced hearing loss via glial cell line - derived neurotrophic factor ( P39905 ) induction . Antidepressant treatments have been described to induce neurotrophic factors ( NTFs ) and reverse the cell loss observed in rodent stress models . Amitriptyline ( AT ) , a tricyclic antidepressant agent , has been reported in recent studies to induce glial cell line - derived neurotrophic factor ( P39905 ) synthesis and release in rat P13671 glioblastoma cells . P39905 has shown protection against acoustic trauma in previous studies . Therefore , we investigated whether AT could induce P39905 synthesis in the cochlea and attenuate cochlea damage against acoustic trauma . We used Hartley guinea pigs and injected AT ( 30 mg / kg ) or saline into the peritoneum . Subjects were exposed to 117 dB SPL octave band noise centered at 4 kHz for 24 h . Noise - induced hearing loss ( NIHL ) was assessed with auditory brain stem response ( Q12979 ) at 4 , 8 and 16 kHz measured prior to the injection , 3 days and 7 days after noise exposure . For histological assessment , we observed the sensory epithelium using a surface preparation technique and assessed the quantitative hair cell ( HC ) damage . We evaluated P39905 synthesis with or without intense noise exposure at 3 , 12 and 24 h after the administration of AT in the cochlea using Western blot analysis . P39905 expression was shown 3 h and 12 h after the injection without noise , whereas with noise the P39905 expression lasted for 24 h . The AT - administrated group showed significantly reduced Q12979 threshold shift and less HC damage than the saline - administrated group . These findings suggest that the administration of AT - induced P39905 levels in the cochlea and attenuated cochlea damage from NIHL .", "cDNA microarray reveals signaling pathways involved in hormones expression of human pituitary . Pituitary , a master gland of neuroendocrine system , secretes hormones that orchestrate many physiological processes , under the regulation of multiple signaling pathways . To investigate the genes involved in hormones expression of human pituitary , homemade cDNA microarray containing 14 , 800 human genes / ESTs were used to profile the gene expression in both fetal and adult pituitaries . Seven hundred and twelve known genes changed over 2 - fold between the both tissues . Of which , 23 genes were changed with hormones expression in aging were confirmed by RT - PCR , not only the known regulators such as Pit1 , P43694 , P11474 , GABA - A , and EMK , but also LOC55884 , P51452 , Q9H307 , and O43598 , which had not been reported to be involved in the hormones expression . Correspondingly , the mRNAs of GH , PRL , P01189 , P01222 , DB00094 - beta , and LH - beta , was increased as much as 6 - to 20 - fold in adult pituitary than those in fetal pituitary , by real - time quantitative RT - PCR assay . In addition , the mRNAs of signaling pathways , such as DB02527 - PKA - CREB , PI3K - Akt , and PKA - P29323 were further investigated . Of them , it was only DB02527 - PKA - CREB pathway , but not PI3K - Akt and PKA - P29323 have the same expressing pattern as hormones . It suggested that cDNA microarray is highly advantages to profile the differential expressed genes that were involved in hormones expression of human pituitary , but it might ignore some responding proteins regulated posttranscriptionally .", "The alkylating carcinogen N - methyl - N '- nitro - N - nitrosoguanidine activates the plasminogen activator inhibitor - 1 gene through sequential phosphorylation of p53 by Q13315 and ATR kinases . The alkylating agent MNNG is an environmental carcinogen that causes DNA lesions leading to cell death . We previously demonstrated that MNNG induced the transcriptional activity of the plasminogen activator inhibitor - 1 ( P05121 ) gene in a p53 - dependent manner . However , the mechanism ( s ) linking external MNNG stimulation and P05121 gene induction remained to be elucidated . Here , we show that Q13315 and ATR kinases , but not DNA - PK , which participate in DNA damage - activated checkpoints , regulate the phosphorylation of p53 at serine 15 in response to MNNG cell treatment . Using Q13315 - deficient cells , Q13315 was shown to be required for early phosphorylation of serine 15 in response to MNNG , whereas catalytically inactive ATR selectively interfered with late phase serine 15 phosphorylation . In contrast , DNA - PK - deficient cells showed no change in the MNNG - induced serine 15 phosphorylation pattern . In agreement with this , sequential activation of Q13315 and ATR kinases was also required for adequate induction of the endogenous P05121 gene by MNNG . Finally , we showed that cells derived from P05121 - deficient mice were more resistant to MNNG - induced cell death than normal cells , suggesting that p53 - dependent P05121 expression partially mediated this effect . Since P05121 is involved in the control of tumor invasiveness , our finding that MNNG induces P05121 gene expression via Q13315 / ATR - mediated phosphorylation of p53 sheds new insight on the role of these DNA damage - induced cell cycle checkpoint kinases .", "Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .", "Novel non - genomic signaling of thyroid hormone receptors in thyroid carcinogenesis . The thyroid hormone receptors ( TRs ) are transcription factors that mediate the pleiotropic activities of the thyroid hormone , DB00279 . Four DB00279 - binding isoforms , TRalpha1 , TRbeta1 , TRbeta2 , and TRbeta3 , are encoded by two genes , P10827 and P10828 . Mutations and altered expression of TRs have been reported in human cancers . A targeted germ - line mutation of the Thrbeta gene in the mouse leads to spontaneous development of follicular thyroid carcinoma ( TRbeta ( PV / PV ) mouse ) . The TRbetaPV mutant has lost DB00279 - binding activity and displays potent dominant negative activity . The striking phenotype of thyroid cancer exhibited by TRbeta ( PV / PV ) mice has recently led to the discovery of novel non - genomic actions of TRbetaPV that contribute to thyroid carcinogenesis . These actions involve direct physical interaction of TRbetaPV with cellular proteins , namely the regulatory subunit of the phosphatidylinositol 3 - kinase ( p85alpha ) , the pituitary tumor transforming gene ( O95997 ) and beta - catenin , that are critically involved in cell proliferation , motility , migration , and metastasis . Thus , a TRbeta mutant ( TRbetaPV ) , via a novel mode of non - genomic action , acts as an oncogene in thyroid carcinogenesis .", "Interactions of STAT5b - RARalpha , a novel acute promyelocytic leukemia fusion protein , with retinoic acid receptor and P40763 signaling pathways . Signal transducer and activator of transcription ( P35610 ) 5b - retinoic acid receptor ( RAR ) alpha is the fifth fusion protein identified in acute promyelocytic leukemia ( APL ) . Initially described in a patient with all - trans retinoic acid ( DB00755 ) - unresponsive disease , STAT5b - RARalpha resulted from an interstitial deletion on chromosome 17 . To determine the molecular mechanisms of myeloid leukemogenesis and maturation arrest in STAT5b - RARalpha (+) APL and its unresponsiveness to DB00755 , we examined the effect of STAT5b - RARalpha on the activity of myeloid transcription factors including RARalpha / retinoid X receptor ( RXR ) alpha , P40763 , and P42229 as well as its molecular interactions with the nuclear receptor corepressor , Q9Y618 , and nuclear receptor coactivator , Q9Y6Q9 . STAT5b - RARalpha bound to retinoic acid response elements ( RAREs ) both as a homodimer and as a heterodimer with RXRalpha and inhibited wild - type RARalpha / RXRalpha transactivation . Although STAT5b - RARalpha had no effect on ligand - induced STAT5b activation , it enhanced interleukin 6 - induced P40763 - dependent reporter activity , an effect shared by other APL fusion proteins including promyelocytic leukemia - RARalpha and promyelocytic leukemia zinc finger ( Q05516 ) - RARalpha . Q9Y618 was released from STAT5b - RARalpha / Q9Y618 complexes by DB00755 at 10 (- 6 ) M , whereas Q9Y6Q9 became associated with STAT5b - RARalpha at 10 (- 7 ) M . The coiled - coil domain of STAT5b was required for formation of STAT5b - RARalpha homodimers , for the inhibition of RARalpha / RXRalpha transcriptional activity , and for stability of the STAT5b - RARalpha / Q9Y618 complex . Thus , STAT5b - RARalpha contributes to myeloid maturation arrest by binding to RARE as either a homodimer or as a heterodimer with RXRalpha resulting in the recruitment of Q9Y618 and inhibition of RARalpha / RXRalpha transcriptional activity . In addition , STAT5b - RARalpha and other APL fusion proteins may contribute to leukemogenesis by interaction with the P40763 oncogene pathway .", "MLCK - dependent exchange and actin binding region - dependent anchoring of ZO - 1 regulate tight junction barrier function . The perijunctional actomyosin ring contributes to myosin light chain kinase ( MLCK ) - dependent tight junction regulation . However , the specific protein interactions involved in this process are unknown . To test the hypothesis that molecular remodeling contributes to barrier regulation , tight junction protein dynamic behavior was assessed by fluorescence recovery after photobleaching ( P42345 ) . MLCK inhibition increased barrier function and stabilized ZO - 1 at the tight junction but did not affect claudin - 1 , occludin , or actin exchange in vitro . Pharmacologic MLCK inhibition also blocked in vivo ZO - 1 exchange in wild - type , but not long MLCK (-/-) , mice . Conversely , ZO - 1 exchange was accelerated in transgenic mice expressing constitutively active MLCK . In vitro , ZO - 1 lacking the actin binding region ( Q12979 ) was not stabilized by MLCK inhibition , either in the presence or absence of endogenous ZO - 1 . Moreover , the free Q12979 interfered with full - length ZO - 1 exchange and reduced basal barrier function . The free Q12979 also prevented increases in barrier function following MLCK inhibition in a manner that required endogenous ZO - 1 expression . In silico modeling of the P42345 data suggests that tight junction - associated ZO - 1 exists in three pools , two of which exchange with cytosolic ZO - 1 . Transport of the Q12979 - anchored exchangeable pool is regulated by MLCK . These data demonstrate a critical role for the ZO - 1 Q12979 in barrier function and suggest that MLCK - dependent ZO - 1 exchange is essential to this mechanism of barrier regulation .", "___MASK83___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .", "Variations in the exome of the LNCaP prostate cancer cell line . BACKGROUND : The LNCaP cell line is widely used as a model for prostate cancer . However , information on protein - changing mutations , genetic heterogeneity and genetic ( in ) stability is largely lacking for these cells . METHODS : Next - generation sequencing of the LNCaP exome revealed many single nucleotide variants ( SNVs ) . To help identify the mutations that are most likely drivers of the oncogenic process , we developed an in silico protocol , which can be adapted for other exome analyses . RESULTS : We detected 1 , 802 non - synonymous SNVs and 218 small insertions and deletions in the LNCaP exome . We confirm the known mutations in the androgen receptor and the P60484 gene , but most other mutations remained undescribed until now . The presence of 38 out of 42 SNVs was confirmed in monoclonal as well as in polyclonal LNCaP derivatives . Moreover , most variants were also detectable in LNCaP mRNA . CONCLUSIONS : We provide an extensive database of genetic variations in the protein - coding part of the genome of LNCaP cells , which should be taken into consideration when using LNCaP cells or its derivatives as models for prostate cancer . From the analysis of several LNCaP - derived cultures and clones , we can confirm that the cell line is heterozygous for a large number of variants and that both the variant and the wild - type allele can be simultaneously expressed as mRNA . The fact that the SNVs in the P12830 , P11802 , Notch1 , and PlexinB1 genes are absent in some of the subclones strongly indicates a degree of genetic instability .", "The v - ErbA oncoprotein quenches the activity of an erythroid - specific enhancer . v - ErbA is a mutated variant of thyroid hormone receptor ( TRalpha / P10827 ) borne by the Avian Erythroblastosis virus causing erythroleukemia . TRalpha is known to activate transcription of specific genes in the presence of its cognate ligand , DB00279 hormone , while in its absence it represses it . v - ErbA is unable to bind ligand , and hence is thought to contribute to leukemogenesis by actively repressing erythroid - specific genes such as the carbonic anhydrase II gene ( CA II ) . In the prevailing model , v - ErbA occludes liganded TR from binding to its cognate elements and constitutively interacts with the corepressors NCoR / Q9Y618 . We previously identified a v - ErbA responsive element ( VRE ) within a P24855 hypersensitive region ( Q5VYS8 ) located in the second intron of the CA II gene . We now show that Q5VYS8 fulfils all the requirements for a genuine enhancer that functions independent of its orientation and position with a profound erythroid - specific activity in normal erythroid progenitors ( T2ECs ) and in leukemic erythroid cell lines . We find that the Q5VYS8 enhancer activity is governed by two adjacent GATA - factor binding sites . v - ErbA as well as unliganded TR prevent Q5VYS8 activity by nullifying the positive function of factors bound to GATA - sites . However , v - ErbA , in contrast to TR , does not convey active repression to silence the transcriptional activity intrinsic to a heterologous tk promoter . We propose that depending on the sequence and context of the binding site , v - ErbA contributes to leukemogenesis by occluding liganded TR as well as unliganded TR thereby preventing activation or repression , respectively .", "Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK82___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK82___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .", "Changes in Guinea pig cochlear hair cells after sound conditioning and noise exposure . Sound conditioning has reduced noise - induced hearing loss in experimental mammalian animals and in clinical observation . Forty guinea pigs were grouped as : A , control ; B , conditioning noise exposure group ; C , high level noise exposure group ; and D , conditioning noise exposure followed by a high level noise exposure group . Auditory brainstem response thresholds were measured . The cochlear sensory epithelia surface was observed microscopically . P62158 , F - actin and heat shock protein 70 ( HSP70 ) in hair cells were immunohistochemistrically stained . The intracellular free calcium was stained for confocal microscopy . The Q12979 threshold shift after noise exposure was higher in group C than D , and showed a quicker and better recovery in group D than C . Stereocilia loss and the disarrangement of outer hair cells were observed , with the greatest changes seen in group C , followed by groups D and B . The most intensive immunohistochemical intracellular expressions of calmodulin , F - actin , and HSP70 were found in group D , followed by groups C , B and A . The highest intensity of the fluorescent intracellular free Ca2 + staining in the isolated outer hair cells was observed in group C . The Q12979 and morphological studies confirmed the protective effect from noise trauma of sound conditioning . The protective mechanism of hair cells during sound conditioning was enforced through the increase of cellular cytoskeleton proteins and through the relieving of intracellular calcium overloading caused by the traumatic noise .", "Transforming growth factor - beta1 induces tumor stroma and reduces tumor infiltrate in cervical cancer . Cervical carcinomas consist of tumor cell nests surrounded by varying amounts of intratumoral stroma containing different quantities and types of immune cells . Besides controlling ( epithelial ) cell growth , the multifunctional cytokine transforming growth factor - beta ( 1 ) ( TGF - beta ( 1 ) ) is involved in the formation of stroma and extracellular matrix ( Q13201 ) and in immunosuppression . Several malignancies are known to be associated with enhanced production of TGF - beta ( 1 ) , repression or mutation of TGF - beta transmembrane receptors , or mutations at the postreceptor intracellular signaling pathway . The aim of our study was to investigate the role of tumor cell - derived TGF - beta ( 1 ) on the amount of intratumoral stroma ; the deposition of collagen IV , fibronectin , and laminin ; and the tumor infiltrate in cervical carcinoma . The expression of TGF - beta ( 1 ) mRNA in 108 paraffin - embedded cervical carcinomas was detected by mRNA in situ hybridization . Immunohistochemistry was used to investigate the amount of tumor stroma and Q13201 proteins and the extent of the tumor infiltrate . P00747 activator inhibitor - 1 ( P05121 ) protein expression in tumor cells was determined to verify the biological activity of TGF - beta ( 1 .) Cytoplasmatic TGF - beta ( 1 ) mRNA expression in tumor cells was significantly correlated with the amount of intratumoral stroma and the deposition of collagen IV . TGF - beta ( 1 ) mRNA expression in every tumor was accompanied by P05121 expression , indicating biological activity of TGF - beta ( 1 ) . An inverse relationship between TGF - beta ( 1 ) mRNA expression in tumor cells and the extent of the tumor infiltrate was demonstrated . Our results indicate that cervical cancer cells affect the amount and the composition of the intratumoral stroma and the tumor infiltrate by the production and secretion of TGF - beta ( 1 ) .", "P10828 is essential for development of auditory function . Congenital thyroid disorders are often associated with profound deafness , indicating a requirement for thyroid hormone ( DB00279 ) and its receptors in the development of hearing . Two DB00279 receptor genes , Tr alpha and Tr beta are differentially expressed , although in overlapping patterns , during development . Thus , the extent to which they mediate unique or redundant functions is unclear . We demonstrate that Tr beta - deficient ( Thrb -/- ) mice exhibit a permanent deficit in auditory function across a wide range of frequencies , although they show no other overt neurological defects . The auditory - evoked brainstem response ( Q12979 ) in Thrb -/- mice , although greatly diminished , displayed normal waveforms , which suggested that the primary defect resides in the cochlea . Although hypothyroidism causes cochlear malformation , there was no evidence of this in Thrb -/- mice . These findings suggest that Tr beta controls the maturation of auditory function but not morphogenesis of the cochlea . Thrb -/- mice provide a model for the human endocrine disorder of resistance to thyroid hormone ( RTH ) , which is typically associated with dominant mutations in Tr beta . However , deafness is generally absent in RTH , indicating that dominant and recessive mutations in Tr beta have different consequences on the auditory system . Our results identify Tr beta as an essential transcription factor for auditory development and indicate that distinct Tr genes serve certain unique functions .", "Attenuated P08908 receptor signaling in brains of suicide victims : involvement of adenylyl cyclase , phosphatidylinositol 3 - kinase , Akt and mitogen - activated protein kinase . Positron emission tomography studies in major depression show reduced serotonin ( 5 - HT ) 1A receptor antagonist - binding potentials in many brain regions including occipital cortex . The functional meaning of this observation in terms of signal transduction is unknown . We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of P08908 receptor activation . The diagnosis was established by means of psychological autopsy using Diagnostic and Statistical Manual of Mental Disorders ( DSM ) III - R criteria . Measurements of [ 35S ] GTPgammaS binding to Galphai / o in the occipital cortex of suicide victims and matched controls revealed a blunted response in suicide subjects and a decrease in the coupling of P08908 receptor to adenylyl cyclase . No significant group differences were detected in the expression levels of Galphai / o , Galphaq / 11 or Galphas proteins , or in the activity of DB02527 - dependent protein kinase A . Studies of a parallel transduction pathway downstream from P08908 receptor activation demonstrated a decrease in the activity of phosphatidylinositol 3 - kinase and its downstream effector Akt , as well as an increase in P60484 ( phosphatase and tensin homolog deleted on chromosome 10 ) , the phosphatase that hydrolyzes phosphatidylinositol 3 , 4 , 5 - triphosphate . Finally , the activation of extracellular signal - regulated kinases 1 and 2 was attenuated in suicide victims . These data suggest that the alterations in agonist - stimulated P08908 receptor activation in depressed suicide victims are also manifest downstream from the associated G protein , affecting the activity of second messengers in two P08908 receptor transduction pathways that may have implications for cell survival .", "MicroRNAs in thyroid cancer . CONTEXT : Traditionally , factors predisposing to diseases are either genetic ( \" nature \" ) or environmental , also known as lifestyle - related ( \" nurture \" ) . Papillary thyroid cancer is an example of a disease where the respective roles of these factors are surprisingly unclear . EVIDENCE ACQUISITION : Original articles and reviews summarizing our current understanding of the role of microRNA in thyroid tumorigenesis are reviewed and evaluated . CONCLUSION : The genetic predisposition to papillary thyroid cancer appears to consist of a variety of gene mutations that are mostly either of low penetrance and common or of high penetrance but rare . Moreover , they likely interact with each other and with environmental factors . The culpable genes may not be of the traditional , protein - coding type . A limited number of noncoding candidate genes have indeed been described , and we propose here that the failure to find mutations in traditional protein - coding genes is not coincidental . Instead , a more likely hypothesis is that changes in the expression of multiple regulatory RNA genes , e . g . microRNAs , may be a major mechanism . Our review of the literature strongly supports this notion in that a polymorphism in one microRNAs ( miR - 146a ) predisposes to thyroid carcinoma , whereas numerous other microRNAs are involved in signaling ( mainly P60484 / PI3K / AKT and DB00279 / P10828 ) that is central to thyroid carcinogenesis .", "Induction of platelet - derived growth factor B / DB00102 by the v - erbA oncogene in glial cells . The v - erbA oncogene codes for a mutated form of the thyroid hormone receptor TR / P10827 . Thyroid hormone ( triiodothyronine , DB00279 ) regulates glial functions such as myelination and both astrocytes and oligodendrocytes have been shown to express thyroid hormone receptors ( TRs ) . To study putative effects of v - erbA on glial precursors , we have expressed it in a glial clonal cell line established from early embryonal mouse brain . We have found that v - erbA increases cell survival in serum - free conditions . Moreover , v - erbA - expressing cells show a substantial growth in the presence of insulin or P05019 , whereas normal and TR / c - erbA - over - expressing cells progressively degenerate . By Northern blotting , immunofluorescence , immunoprecipitation , and neutralization experiments , we show that v - erbA actions are mediated by an increase in the levels of PDGF B / DB00102 mRNA and protein . We used anti - PDGF receptor and anti - phosphotyrosine antibodies to show the constitutive activation of PDGF receptors in B3 . 1 + v - erbA cells , and neutralizing anti - PDGF antibodies to demonstrate that v - erbA enhances the secretion of active PDGF into the culture medium . Our data indicate that v - erbA induces PDGF B / DB00102 , a factor involved in the generation of gliomas , the most common central nervous system tumor in humans .", "Expression of epithelial cell adhesion molecule and pituitary tumor transforming gene in adamantinomatous craniopharyngioma and its correlation with recurrence of the tumor . Craniopharyngiomas are benign tumors of the sellar region generally associated with endocrine disorders and often locally aggressive . The reliable criteria for predicting the tumor behavior are still lacking . It has been suggested that proliferative potential of the tumor cells is necessary for recurrence . The aim of this study was to evaluate the activity and correlation of epithelial cell adhesion molecule ( P16422 ) and pituitary tumor transforming gene ( O95997 - 1 ) immunoexpression that is possibly related to relapse in 40 patients with adamantinomatous craniopharyngioma . The study involved clinical and pathologic analysis . Of the subjects , 49 % were females and 51 % were males . The mean age of the patients was 37 years . Relapsing rate at 5 years was 46 % and for death was 22 . 5 % . Histologically , whorl - like arrays and dense or hypercellular stellate reticulum cells were correlated with recurrence . Epithelial P62158 and O95997 - 1 were also higher in stellate reticulum cells and in whorl - like arrays . Both were higher in recurrence / regrowth tumors than in primary one . The PTGG - 1 expression in craniopharyngioma may suggest hypophyseal metaplasia . The P16422 and O95997 - 1 expression in craniopharyngioma could be used as prediction markers of relapsing tumor . It has been suggested that proliferative potential of the tumor cells is necessary for recurrence .", "Changes of thyroid hormone levels and related gene expression in zebrafish on early life stage exposure to triadimefon . In this study , zebrafish was exposed to triadimefon . Thyroid hormones levels and the expression of related genes in the hypothalamic - pituitary - thyroid ( Q9HD23 ) axis , including thyroid - stimulating hormone ( P01222 ) , deiodinases ( dio1 and dio2 ) and the thyroid hormone receptor ( thraa and thrb ) were evaluated . After triadimefon exposure , increased DB00451 can be explained by increased thyroid - stimulating hormone ( P01222 ) . The conversion of DB00451 to DB00279 ( deiodinase type I - dio1 ) was decreased , which reduced the DB00279 level . P10828 ( thrb ) mRNA levels were significantly down - regulated , possibly as a response to the decreased DB00279 levels . The overall results indicated that triadimefon exposure could alter gene expression in the Q9HD23 axis and that mechanisms of disruption of thyroid status by triadimefon could occur at several steps in the synthesis , regulation , and action of thyroid hormones .", "Nuclear translocation of Q02750 triggers a complex T cell response through the corepressor silencing mediator of retinoid and thyroid hormone receptor . Q02750 phosphorylates P27361 / 2 and regulates T cell generation , differentiation , and function . Q02750 has recently been shown to translocate to the nucleus . Its nuclear function is largely unknown . By studying human P01730 T cells , we demonstrate that a low level of Q02750 is present in the nucleus of P01730 T cells under basal conditions . T cell activation further increases the nuclear translocation of Q02750 . Q02750 interacts with the nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptor ( Q9Y618 ) . Q02750 reduces the nuclear level of Q9Y618 in an activation - dependent manner . Q02750 is recruited to the promoter of c - Fos upon TCR stimulation . Conversely , Q9Y618 is bound to the c - Fos promoter under basal conditions and is removed upon TCR stimulation . We examined the role of Q9Y618 in regulation of T cell function . Small interfering RNA - mediated knockdown of Q9Y618 results in a biphasic effect on cytokine production . The production of the cytokines P60568 , P05112 , P22301 , and IFN - γ increases in the early phase ( 8 h ) and then decreases in the late phase ( 48 h ) . The late - phase decrease is associated with inhibition of T cell proliferation . The late - phase inhibition of T cell activation is , in part , mediated by P22301 that is produced in the early phase and , in part , by β - catenin signaling . Thus , we have identified a novel nuclear function of Q02750 . Q02750 triggers a complex pattern of early T cell activation , followed by a late inhibition through its interaction with Q9Y618 . This biphasic dual effect most likely reflects a homeostatic regulation of T cell function by Q02750 .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "Developmental expression of plasminogen activator inhibitor - 1 associated with thrombopoietin - dependent megakaryocytic differentiation . P00747 activator inhibitor - 1 ( P05121 ) is present in the platelet alpha - granule and is released on activation . However , there is some debate as to whether the megakaryocyte and platelet synthesize P05121 , take it up from plasma , or both . We examined the expression of P05121 in differentiating megakaryocytic progenitor cells ( UT - 7 ) and in P28906 (+)/ CD41 (-) cells from cord blood . UT - 7 cells differentiated with thrombopoietin ( P07202 ) resembled megakaryocytes ( UT - 7 / P07202 ) with respect to morphology , ploidy , and the expression of glycoprotein IIb - IIIa . P05121 messenger RNA ( mRNA ) expression was upregulated and P05121 protein synthesized in the UT - 7 / P07202 cells accumulated in the cytoplasm without being released spontaneously . In contrast , erythropoietin ( EPO ) - stimulated UT - 7 cells ( UT - 7 / EPO ) did not express P05121 mRNA after stimulation with P07202 because they do not have endogenous c - Mpl . After cotransfection with human wild - type c - mpl , the cells ( UT - 7 / EPO - P40238 ) responded to phorbol 12 - myristate 13 - acetate ( PMA ) , tumor necrosis factor - alpha ( P01375 ) , and interleukin - 1beta ( IL - 1beta ) with enhanced P05121 mRNA expression within 24 to 48 hours . However , induction of P05121 mRNA in UT - 7 / EPO - P40238 cells by P07202 required at least 14 - days stimulation . UT - 7 / EPO cells expressing c - Mpl changed their morphology and the other characteristics similar to the UT - 7 / P07202 cells . P07202 also differentiated human cord blood P28906 (+)/ CD41 (-) cells to P28906 (-)/ CD41 (+) cells , generated morphologically mature megakaryocytes , and induced the expression of P05121 mRNA . These results suggest that both P05121 mRNA and de novo P05121 protein synthesis is induced after differentiation of immature progenitor cells into megakaryocytes by P07202 .", "Thyroid hormone status interferes with estrogen target gene expression in breast cancer samples in menopausal women . We investigated thyroid hormone levels in menopausal BrC patients and verified the action of triiodothyronine on genes regulated by estrogen and by triiodothyronine itself in BrC tissues . We selected 15 postmenopausal BrC patients and a control group of 18 postmenopausal women without BrC . We measured serum P07202 - AB , DB00024 , FT4 , and estradiol , before and after surgery , and used immunohistochemistry to examine estrogen and progesterone receptors . BrC primary tissue cultures received the following treatments : ethanol , triiodothyronine , triiodothyronine plus 4 - hydroxytamoxifen , 4 - hydroxytamoxifen , estrogen , or estrogen plus 4 - hydroxytamoxifen . Genes regulated by estrogen ( P01135 , P01137 , and P06401 ) and by triiodothyronine ( Q07011 , P22004 , and P10827 ) in vitro were evaluated . DB00024 levels in BrC patients did not differ from those of the control group ( 1 . 34 ± 0 . 60 versus 2 . 41 ± 1 . 10 μ U / mL ) , but FT4 levels of BrC patients were statistically higher than controls ( 1 . 78 ± 0 . 20 versus 0 . 95 ± 0 . 16 ng / dL ) . P01135 was upregulated and downregulated after estrogen and triiodothyronine treatment , respectively . DB00279 increased P06401 expression ; however 4 - hydroxytamoxifen did not block triiodothyronine action on P06401 expression . DB04468 , alone or associated with triiodothyronine , modulated gene expression of Q07011 , P22004 , and P10827 , similar to triiodothyronine treatment . Thus , our work highlights the importance of thyroid hormone status evaluation and its ability to interfere with estrogen target gene expression in BrC samples in menopausal women .", "Interactions between the ovary and the local P05019 axis modulate mammary development in prepubertal heifers . The objective was to determine the effects of ovariectomy and epithelial - stromal interactions on mammary development and local expression of P05019 and IGF - binding protein ( IGFBP ) mRNA in prepubertal heifers . An epithelium - free ( ' cleared ' ) fat pad ( P27918 ) was prepared in two glands in each of 14 Holstein heifers , aged 1 - 3 Months . Eight of the calves were also ovariectomized . Serum concentrations of GH , P05019 and prolactin were not affected by ovariectomy . At 6 Months of age , calves were killed to provide mammary samples of parenchyma , P27918 and intact fat pad ( MFP ) . Total mammary mass was reduced in ovariectomized calves ( 130 +/- 21 g vs 304 +/- 25 g ; P < 0 . 001 ) , and in several cases parenchymal tIssue was essentially absent . Uterus weight was also reduced by ovariectomy ( 14 . 5 +/- 3 . 8 g vs 30 . 4 +/- 4 . 5 g ; P < 0 . 05 ) . In support of our hypothesis that local P05019 mediates prepubertal mammary development , mRNA expression of P05019 was lower in ovariectomized than in control calves ( 62 . 1 +/- 7 . 8 vs 91 . 6 +/- 7 . 8 arbitrary units ; P < 0 . 05 ) . Specific binding of P05019 to mammary parenchymal microsomes was also reduced by ovariectomy ( 377 +/- 142 vs 868 +/- 82 c . p . m . ; P < 0 . 01 ) , suggesting decreased sensitivity to P05019 . Expression of P17936 and P24593 mRNA were not influenced by ovariectomy . Expression of P05019 , P17936 and P24593 mRNA did not differ between P27918 and MFP , suggesting that expression of these factors was not influenced by interactions between stroma and developing epithelium . Overall , the data suggested that interactions between the ovary and the local P05019 axis act to optimize the availability and effectiveness of P05019 within the gland to stimulate mammary growth .", "The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK8___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK8___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .", "Placental expression of insulin - like growth factor - I , fibroblast growth factor - basic , and neural cell adhesion molecule in preeclampsia . OBJECTIVE : To investigate placental expression of insulin - like growth factor - I ( P05019 ) , fibroblast growth factor - basic ( FGF - b ) , and neural cell adhesion molecule ( N - P62158 ) in preeclampsia . STUDY DESIGN : An immunohistochemical analysis using P05019 , FGF - b , and N - P62158 antibodies was conducted on 4 % paraformaldehyde - fixed placental tissues of preeclamptic patients ( N = 14 ) and normotensive pregnant subjects ( N = 10 ) . Immunostaining patterns of chorionic villi and amniochorionic membranes were assessed . RESULTS : Significantly increased FGF - b and N - P62158 immunoreactivities in cytotrophoblasts and increased FGF - b immunoreactivity in capillary endothelium of chorionic villi of preeclamptic subjects were noted . Significantly increased FGF - b and decreased N - P62158 immunoreactivities in extravillous trophoblasts and decidual cells of amniochorionic membranes obtained from preeclamptic subjects were demonstrated . Additionally , a significantly increased P05019 immunoreactivity was shown in decidual cells of preeclamptic cases . CONCLUSION : Investigation of the regional distribution of P05019 , FGF - b , and N - P62158 at the maternal - fetal interface establishes a better understanding of cell - specific altered growth processes , which may be associated with the pathogenesis of preeclampsia .", "___MASK28___ reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin - converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU / ml ) , tissue plasminogen activator ( t - PA ) antigen ( ng / ml ) , and serum P12821 activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37 . 5 mg daily ) and compared them with the values in 15 placebo - treated patients chosen at random . Blood sampling was performed at 07 . 00 h . In the captopril - treated group , serum P12821 activity decreased significantly , from 14 . 0 +/- 0 . 8 to 11 . 5 +/- 1 . 2 IU / L 24 h after captopril therapy ( p < 0 . 01 ) , and those of P05121 activity and t - PA antigen also decreased significantly - from 11 . 9 +/- 2 . 8 to 5 . 5 +/- 2 . 2 IU / ml ( p < 0 . 02 ) and from 9 . 9 +/- 1 . 0 to 7 . 5 +/- 0 . 9 ng / ml ( p < 0 . 05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t - PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .", "P10828 mutants : Dominant negative regulators of peroxisome proliferator - activated receptor gamma action . Thyroid hormone ( DB00279 ) and peroxisome proliferators have overlapping metabolic effects in the maintenance of lipid homeostasis . Their actions are mediated by their respective receptors : thyroid hormone receptors ( TR ) and peroxisome proliferator - activated receptors ( Q07869 ) . We recently found that a dominantly negative TRbeta mutant ( PV ) that causes a genetic disease , resistance to thyroid hormone , acts to repress the ligand ( troglitazone )- mediated transcriptional activity of PPARgamma in cultured thyroid cells . This finding suggests that TRbeta mutants could crosstalk with PPARgamma - signaling pathways . The present study explored the molecular mechanisms by which PV represses the PPARgamma transcriptional activity . Gel - shift assays show that the PV , similar to wild - type TRbeta , bound to the peroxisome proliferator response element ( PPRE ) as homodimers and heterodimers with PPARgamma or the retinoid X receptor ( RXR ) , thereby competing with PPARgamma for binding to PPRE and for sequestering RXR . Association of PPRE - bound PV with corepressors [ e . g . , nuclear receptor corepressor ( NCoR ) ] that led to transcriptional repression was independent of DB00279 and troglitazone . Chromatin immunoprecipitation assay further demonstrated that , despite the presence of ligands , NCoR was recruited to PPRE - bound PV on a PPARgamma - target gene , the lipoprotein lipase , in vivo , suggesting the dominant action of PV on PPARgamma - mediated transcriptional activity . Thus , the dominant negative action of PV is not limited on the wild - type TRs . The findings that TRbeta mutants affect PPARgamma functions through dominant negative action provide insights into the molecular mechanisms by which TR regulates the PPARgamma - target genes involved in metabolic pathways , lipid homeostasis , and carcinogenesis .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "___MASK26___ overcomes gefitinib resistance in P01116 mutant human non - small cell lung carcinoma cells . The exact influence of statins on gefitinib resistance in human non - small cell lung cancer ( NSCLC ) cells with P01116 mutation alone or P01116 / P42336 and P01116 / P60484 comutations remains unclear . This work found that transfection of mutant P01116 plasmids significantly suppressed the gefitinib cytotoxicity in Calu3 cells ( wild - type P01116 ) . Gefitinib disrupted the Kras / PI3K and Kras / Raf complexes in Calu3 cells , whereas not in Calu3 P01116 mutant cells . These trends were corresponding to the expression of pAKT and pERK in gefitinib treatment . ___MASK26___ ( 1 μM ) plus gefitinib treatment inhibited proliferation , promoted cell apoptosis , and reduced the AKT activity in P01116 mutant NSCLC cells compared with gefitinib alone . ___MASK26___ ( 5 μM ) further enhanced the gefitinib cytotoxicity through concomitant inhibition of AKT and P29323 activity . ___MASK26___ could interrupt Kras / PI3K and Kras / Raf complexes , leading to suppression of AKT and P29323 activity . Similar results were also obtained in comutant P01116 / P60484 or P01116 / P42336 NSCLC cells . Furthermore , mevalonate administration reversed the effects of atorvastatin on the Kras / Raf and Kras / PI3K complexes , as well as AKT and P29323 activity in both A549 and Calu1 cells . The in vivo results were similar to those obtained in vitro . Therefore , mutant P01116 - mediated gefitinib insensitivity is mainly derived from failure to disrupt the Kras / Raf and Kras / PI3K complexes in P01116 mutant NSCLC cells . ___MASK26___ overcomes gefitinib resistance in P01116 mutant NSCLC cells irrespective of P42336 and P60484 statuses through inhibition of P04035 - dependent disruption of the Kras / Raf and Kras / PI3K complexes .", "DB00156 2609 phosphorylation of the DNA - dependent protein kinase is a critical prerequisite for epidermal growth factor receptor - mediated radiation resistance . The P01133 receptor ( P00533 ) contributes to tumor radioresistance , in part , through interactions with the catalytic subunit of DNA - dependent protein kinase ( DNA - PKc ) , a key enzyme in the nonhomologous end joining DNA repair pathway . We previously showed that P00533 - P78527 interactions are significantly compromised in the context of activating mutations in P00533 in non - small cell lung carcinoma ( NSCLC ) and human bronchial epithelial cells . Here , we investigate the reciprocal relationship between phosphorylation status of P78527 and P00533 - mediated radiation response . The data reveal that both the kinase activity of P78527 and radiation - induced phosphorylation of P78527 by the ataxia telangiectasia - mutated ( Q13315 ) kinase are critical prerequisites for P00533 - mediated radioresponse . DB00160 substitutions at seven key serine / threonine residues in P78527 or inhibition of P78527 by NU7441 completely abrogated P00533 - mediated radioresponse and blocked P00533 binding . Q13315 deficiency or Q13315 inhibition with KU55933 produced a similar effect . Importantly , alanine substitution at an Q13315 - dependent P78527 phosphorylation site , T2609 , was sufficient to block binding or radioresponse of P00533 . However , mutation of a P78527 autophosphorylation site , S2056 had no such effect indicating that P78527 autophosphorylation is not necessary for P00533 - mediated radioresponse . Our data reveal that in both NSCLCs and human bronchial epithelial cells , activating mutations in P00533 specifically abolished the P78527 phosphorylation at T2609 , but not S2056 . Our study underscores the critical importance of a reciprocal relationship between P78527 phosphorylation and P00533 - mediated radiation response and elucidates mechanisms underlying mutant P00533 - associated radiosensitivity in NSCLCs .", "Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK64___ and Tissue P00747 Activator in Occluded Arteries .", "Gene expression profiling of human kidneys undergoing laparoscopic donor nephrectomy . BACKGROUND AND OBJECTIVES : The objective was to compare gene expression profiles of 6 kidneys from open donor nephrectomy with 6 kidneys removed after laparoscopic donor nephrectomy and several hours of carbon dioxide pneumoperitoneum with DNA microarrays and identify small - molecule drugs . METHODS : The gene expression profile GSE3297 was downloaded from the Gene Expression Omnibus database , and the differentially expressed genes were identified by a bioinformatics approach . First , Osprey software was used to construct a differentially expressed gene associated network . Then , DAVID ( Database for Annotation , Visualization , and Integrated Discovery ) and FuncAssociate were used to perform functional analyses . Finally , the Connectivity Map was used to screen for small - molecule drugs . RESULTS : A total of 285 differentially expressed genes were identified , including 148 down - regulated genes and 137 up - regulated genes . In addition , the differentially expressed genes in the most significant Gene Ontology term were P55212 , P01116 , O15524 , P03372 , P01222 , P02452 , and P50281 . Furthermore , several differentially expressed genes , including P42224 , P42226 , Q07890 , and O15524 , participated in the most remarkable Janus kinase - signal transducer and activator of transcription signaling pathway . Finally , luteolin -- with the highest score ( 0 . 887 ) -- was identified as the small - molecule drug . CONCLUSIONS : Our data show an altered renal transcriptome induced by several hours of carbon dioxide pneumoperitoneum and laparoscopic surgery characterized by up - regulation of genes associated with acute inflammation , apoptosis , and immune injury , which could potentially result in renal injury and an enhanced immune response in the recipient after transplant .", "[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK64___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .", "___MASK74___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK74___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK74___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK74___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK74___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .", "Replacement of dietary soy protein isolate with concentrates of soy 7S or 11S globulin has minimal or no effects on plasma lipoprotein profiles and biomarkers of coronary risk in monkeys . Effects of soy peptide fractions on risk factors for coronary heart disease are unknown . We compared the effects of a soy protein isolate , a soy 7S fraction concentrate and a soy 11S fraction concentrate on total plasma cholesterol , HDL cholesterol , LDL + VLDL cholesterol and triacylglycerol in adult male cynomolgus monkeys . Effects on biomarkers of coronary risk [ soluble P16581 , vascular cell - adhesion molecule - 1 ( P19320 ) , monocyte chemoattractant protein - 1 ( P13500 ) , transforming growth factor beta - 1 ( P01137 ) and plasminogen activator inhibitor - 1 ( P05121 ) ] were also determined . Relative to a soy - and isoflavone - free diet ( casein and lactalbumin as the source of protein ) , soy protein isolate had the predicted favorable effects on plasma lipoproteins , i . e . , reductions in total and VLDL + LDL cholesterol ( 8 and 14 % , respectively ) ( P ' s < 0 . 05 ) and a 41 % increase in HDL ( P < 0 . 05 ) . Effects of 7S and 11S on these variables were less favorable . In fact , there was a 7 % increase in total plasma cholesterol concentration ( P < 0 . 05 ) in monkeys fed 7S that was accounted for primarily by an increase in VLDL + LDL cholesterol . There was no effect of any protein source on cardiovascular biomarkers . Replacement of dietary soy protein isolate with concentrated 7S or 11S does not result in improvement of plasma lipoprotein profiles or cardiovascular biomarkers in monkeys .", "Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK46___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .", "P01308 increases the abundance of the growth hormone receptor in liver and adipose tissue of periparturient dairy cows . After parturition , increased growth hormone ( GH ) secretion is important to preserve the metabolic homeostasis of energy - deficient dairy cows . Elevated plasma GH promotes lipid mobilization from adipose tissue , but paradoxically , is associated with depressed concentration of insulin - like growth factor - I ( P05019 ) , a growth factor produced in a GH - dependent fashion in liver . Primary factors regulating GH responses of liver and adipose tissue are poorly understood in periparturient dairy cows . Consistent with insulin being such a factor , its plasma concentration declined concomitantly with net energy balance ( EB ) and with plasma P05019 in a group of 9 periparturient dairy cows . To test the role of insulin in regulating cellular determinants of GH responsiveness , hyperinsulinemic - euglycemic clamps were performed on 6 dairy cows in late pregnancy ( 28 d prepartum ) before the reductions in EB , insulin , and P05019 were initiated , and when they were completed in early lactation ( 10 d postpartum ) . Infusion of insulin nearly doubled the plasma concentration of P05019 ( P < 0 . 001 ) and hepatic levels of P05019 mRNA during both states ( P < 0 . 05 ) . In liver , these responses were associated with increased abundance of the P10912 protein ( P10912 ; P < 0 . 05 ) , whereas the abundance of intracellular mediators of GH actions ( O60674 , P42229 , or P40763 ) remained unaffected . P01308 also doubled P10912 abundance in adipose tissue ( P < 0 . 01 ) , indicating that this effect is not liver specific . These results raise the possibility that insulin regulates the efficiency of GH signaling in liver and adipose tissue of dairy cows by acting as a rheostat of P10912 synthesis .", "Inhibitory effects of DB06663 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo . DB01285 ( DB01285 ) production by pituitary corticotroph adenomas is the main cause of Cushing ' s disease . A drug that targets pituitary DB01285 - secreting adenomas would aid treatment of Cushing ' s disease . ___MASK83___ , a somatostatin receptor type 2 ( P30874 ) - preferring somatostatin analogue , has no effect on DB01285 secretion in patients with Cushing ' s disease . The multiligand DB06663 ( pasireotide ) displays a much higher affinity for P30872 and P35346 than octreotide and suppresses DB01285 secretion in cultures of human corticotroph tumors to a greater extent than octreotide . In the present in vitro and in vivo study , we determined the effect of DB06663 on DB01285 production and cell proliferation of AtT - 20 corticotroph tumor cells . DB06663 decreased proopiomelanocortin ( P01189 ) mRNA levels in AtT - 20 cells and DB01285 levels in the culture medium of these cells , suggesting that DB06663 suppresses DB01285 synthesis and secretion in corticotroph tumor cells . DB06663 also decreased cell proliferation and both cyclic adenosine monophosphate response element - binding protein and Akt phosphorylation in AtT - 20 cells . P35346 knockdown inhibited the DB06663 - induced decreases in cell proliferation . Fluorescence - activated cell sorting analyses revealed that DB06663 did not attenuate cell cycle progression . Tumor weight in mice xenografted with AtT - 20 cells and treated with DB06663 was significantly lower than in AtT - 20 - xenografted control mice . DB06663 also significantly decreased plasma DB01285 levels , and P01189 and pituitary tumor transforming gene mRNA levels in the tumor cells . Thus , DB06663 inhibits DB01285 production and corticotroph tumor cell proliferation in vitro and in vivo .", "___MASK83___ is the favorable alternative for cisplatin resistance reversal of ovarian cancer in vitro and in nude mice in vivo . This study aimed to observe the effects of octreotide ( O75051 ) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo . MTT method and flow cytometry were used to investigate the effect of cisplatin , O75051 or the combination of these two compounds on the proliferation and apoptosis of SKOV3 - O60220 cells . The size and weight of xenograft tumors from the nude mice model were measured . Real - time PCR was used to detect the mRNA expression of P30874 , P08183 , Q92887 , Q86UG4 - pi and P00533 in SKOV3 / O60220 cells following the different treatment . At the concentration of 2 . 5 - 20 g / ml , O75051 significantly reduced IC50 ( p < 0 . 05 ) and promoted apoptosis ( p < 0 . 05 ) of SKOV3 - O60220 cells ' response to cisplatin . Unchanged expression was found in P30874 on the SKOV3 / O60220 cell in vitro after O75051 treatment , but increased expression in vivo ( p < 0 . 05 ) . O75051 increased Q86UG4 - pi expression ( p < 0 . 05 ) and reduced Q92887 and P00533 expression ( p < 0 . 05 ) in a dose - dependent manner . The similar results were obtained in mice in vivo experiment , except the reduced expression of Q86UG4 - pi . It is suggested that O75051 could inhibit ovarian cancer proliferation and promote apoptosis , via the cell surface P30874 , and reverse cisplatin resistance through inhibition of Q92887 , P00533 , and even Q86UG4 - pi expressions .", "Molecular classification of papillary thyroid carcinoma : distinct P15056 , DB01367 , and P07949 / PTC mutation - specific gene expression profiles discovered by DNA microarray analysis . Thyroid cancer poses a significant clinical challenge , and our understanding of its pathogenesis is incomplete . To gain insight into the pathogenesis of papillary thyroid carcinoma , transcriptional profiles of four normal thyroids and 51 papillary carcinomas ( PCs ) were generated using DNA microarrays . The tumors were genotyped for their common activating mutations : P15056 V600E point mutation , P07949 / Q13635 and 3 rearrangement and point mutations of P01116 , P01112 and P01111 . Principal component analysis based on the entire expression data set separated the PCs into three groups that were found to reflect tumor morphology and mutational status . By combining expression profiles with mutational status , we defined distinct expression profiles for the P15056 , P07949 / PTC and DB01367 mutation groups . Using small numbers of genes , a simple classifier was able to classify correctly the mutational status of all 40 tumors with known mutations . One tumor without a detectable mutation was predicted by the classifier to have a P07949 / PTC rearrangement and was shown to contain one by fluorescence in situ hybridization analysis . Among the mutation - specific expression signatures were genes whose differential expression was a direct consequence of the mutation , as well as genes involved in a variety of biological processes including immune response and signal transduction . Expression of one mutation - specific differentially expressed gene , P07202 , was validated at the protein level using immunohistochemistry and tissue arrays containing an independent set of tumors . The results demonstrate that mutational status is the primary determinant of gene expression variation within these tumors , a finding that may have clinical and diagnostic significance and predicts success for therapies designed to prevent the consequences of these mutations ." ]

[ "___MASK26___", "___MASK28___", "___MASK46___", "___MASK64___", "___MASK74___", "___MASK82___", "___MASK83___", "___MASK87___", "___MASK8___" ]

[ "[ ___MASK36___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK36___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .", "___MASK91___ - mediated cyclooxygenase - 2 expression via epidermal growth factor receptor / Q15717 interaction enhances the aggressiveness of triple - negative breast cancer cells . ___MASK91___ , a dual epidermal growth factor receptor ( P00533 ) / human epidermal growth factor receptor 2 ( P04626 ) kinase inhibitor , showed clinical benefits in advanced P04626 - positive breast cancer patients . Because some triple - negative breast cancers ( TNBCs ) frequently overexpress P00533 , the antitumor activity of lapatinib in such diseases was also tested . However , the results showed a worse event - free survival rate . It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells . In this study , our results demonstrated that lapatinib facilitated axillary and lung metastases of triple - negative MDA - MB - 231 breast cancer cells without affecting their viability , leading to worse survival in orthotopic xenograft mice . The lapatinib - increased motility was attributed by the elevation of P00533 through the downregulation of microRNA - 7 and by the subsequent overexpression of cyclooxygenase - 2 ( P35354 ) . Strikingly , independent of its kinase activity , the elevated P00533 at least partly stabilized P35354 expression by enhancing the binding of Q15717 to P35354 mRNA . Our results suggest that lapatinib may increase the migration and invasion of MDA - MB - 231 cells by upregulating P00533 and P35354 through the downregulation of microRNA - 7 , providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib - based treatment . These findings also shed new light on the molecular mechanism of P35354 mRNA stabilization by P00533 in a kinase - independent manner .", "___MASK49___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK49___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .", "Antiinflammatory effect of lactic acid bacteria : inhibition of cyclooxygenase - 2 by suppressing nuclear factor - kappaB in Raw264 . 7 macrophage cells . Lactobacillus casei 3260 ( L . casei 3260 ) was evaluated in relation to the inflammatory response mediated by lipopolysaccharide ( LPS ) - induced nuclear factor - kappaB ( NF - kappaB ) and cyclooxygenase - 2 ( P35354 ) expression in Raw264 . 7 macrophage cells . The treatment of Raw264 . 7 cells with L . casei 3260 significantly inhibited the secretion of tumor necrosis factor - alpha ( P01375 ) and prostaglandins E2 ( DB00917 ) , followed by suppression of P35354 . To clarify the molecular mechanism , the inhibitory effect of L . casei 3260 on the NF - kappaB signaling pathway was examined based on the luciferase reporter activity . Although the treatment of Raw264 . 7 cells with L . casei 3260 did not affect the transcriptional activity of NF - kappaB , it did inhibit NF - kappaB activation , as determined by the cytosolic p65 release and degradation of I - kappaBalpha . Therefore , these findings suggest that the suppression of P35354 through inhibiting the NF - kappaB activation by LPS may be associated with the antiinflammatory effects of L . casei 3260 on Raw264 . 7 cells .", "Effect of cyclooxygenase inhibitors on the P06850 - induced pituitary - adrenocortical activity during crowding stress . The aim of the present study was to determine the effect of social stress and significance of prostaglandins ( PG ) generated by constitutive and inducible cyclooxygenase ( P23219 and P35354 ) in the stimulation of hypothalamic - pituitary - adrenal ( Q9Y251 ) axis by corticotropin releasing hormone ( P06850 ) under basal and social crowding stress conditions . The stressed rats were crowded in groups of 24 to a cage for 3 or 7 days , whereas the control animals were haused in groups of 7 to a cage of the same size . The activity of Q9Y251 axis was determined by measuring plasma DB01285 and serum corticosterone levels 1 h after i . p . P06850 administration . Inhibitors of P23219 , piroxicam ( 0 . 2 , 2 . 0 , and 5 . 0 mg / kg ) , and P35354 , compound NS - 398 ( 0 . 2 and 2 . 0 mg / kg ) , were administered i . p . 15 min prior to P06850 ( 0 . 1 microg / kg i . p . ) to control or crowded rats . The obtained results indicate that social stress for 3 and 7 days markedly intensifies the stimulatory action of P06850 on DB01285 secretion . Neither piroxicam nor NS - 398 induce any significant effect on the P06850 - elicited DB01285 and corticosterone secretion in non - stressed or crowded rats . Therefore , PG generated by P23219 or P35354 do not participate to a significant extent in the stimulation of Q9Y251 axis by P06850 under either basal conditions or during crowding stress . These results also indicate that the stimulatory action of P06850 on DB01285 secretion is not only completely resistant to desensitization but is sensitized during social crowding stress . The results contrast with a significant involvement of PG in the vasopressin - induced stimulation of Q9Y251 response during crowding stress .", "Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case - control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population - based case - control study . We examined nutrient density - adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0 . 026 ) , cooked by pan - frying ( trend P = 0 . 035 ) , and cooked until well - done ( trend P = 0 . 013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0 . 023 ) . A gene - by - diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0 . 008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .", "___MASK95___ induces apoptosis through p53 / P38936 - dependent pathway and increases P12830 expression through downregulation of HDAC / Q15910 . ___MASK95___ ( MTX ) is a dihydrofolate reductase ( P00374 ) inhibitor widely used as an anticancer drug in different kinds of human cancers . Here we investigated the anti - tumor mechanism of MTX against non - small cell lung cancer ( NSCLC ) A549 cells . MTX not only inhibited in vitro cell growth via induction of apoptosis , but also inhibited tumor formation in animal xenograft model . RNase protection assay ( RPA ) and RT - PCR demonstrated its induction of p53 target genes including DR5 , P38936 , Puma and Noxa . Moreover , MTX promoted p53 phosphorylation at Ser15 and acetylaion at Lys373 / 382 , which increase its stability and expression . The apoptosis and inhibition of cell viability induced by MTX were dependent on p53 and , partially , on P38936 . In addition , MTX also increased P12830 expression through inhibition of histone deacetylase ( HDAC ) activity and downregulation of polycomb group protein enhancer of zeste homologue 2 ( Q15910 ) . Therefore , the anticancer mechanism of MTX acts through initiation of p53 - dependent apoptosis and restoration of P12830 expression by downregulation of HDAC / Q15910 .", "Temporal and pharmacological characterization of angiostatin release and generation by human platelets : implications for endothelial cell migration . Platelets play an important role in thrombosis and in neo - vascularisation as they release and produce factors that both promote and suppress angiogenesis . Amongst these factors is the angiogenesis inhibitor angiostatin , which is released during thrombus formation . The impact of anti - thrombotic agents and the kinetics of platelet angiostatin release are unknown . Hence , our objectives were to characterize platelet angiostatin release temporally and pharmacologically and to determine how angiostatin release influences endothelial cell migration , an early stage of angiogenesis . We hypothesized anti - platelet agents would suppress angiostatin release but not generation by platelets . Human platelets were aggregated and temporal angiostatin release was compared to vascular endothelial growth factor ( P15692 ) . Immuno - gold electron microscopy and immunofluorescence microscopy identified α - granules as storage organelles of platelet angiostatin . Acetylsalicylic acid , MRS2395 , P08514 / IIIa blocking peptide , and aprotinin were used to characterize platelet angiostatin release and generation . An endothelial cell migration assay was performed under hypoxic conditions to determine the effects of pharmacological platelet and angiostatin inhibition . Compared to P15692 , angiostatin generation and release from α - granules occurred later temporally during platelet aggregation . Consequently , collagen - activated platelet releasates stimulated endothelial cell migration more potently than maximally - aggregated platelets . Platelet inhibitors prostacyclin , S - nitroso - glutathione , acetylsalicylic acid , and P08514 / IIIa blocking peptide , but not a Q9H244 inhibitor , suppressed angiostatin release but not generation . Suppression of angiostatin generation in the presence of acetylsalicylic acid enhanced platelet - stimulated endothelial migration . Hence , the temporal and pharmacological modulation of platelet angiostatin release may have significant consequences for neo - vascularization following thrombus formation .", "Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK36___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK95___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .", "Thrombin inhibits migration of human hepatic myofibroblasts . Several lines of data recently pointed out a role of the serine proteinase thrombin in liver fibrogenesis , but its mechanism of action is unknown . The aim of this study was to evaluate the effect of thrombin on the migration of human liver myofibroblasts . We show here that thrombin inhibits both basal migration and platelet - derived growth factor ( PDGF ) - BB - induced migration of myofibroblasts . By using a thrombin antagonist , a protease - activated receptor ( PAR ) - 1 mimetic peptide , and a P25116 antibody , we show that this effect is dependent on the catalytic activity of thrombin and on P25116 activation . Thrombin ' s effect on basal migration was dependent on cyclooxygenase 2 ( P35354 ) activation because it was blocked by the P35354 inhibitors NS - 398 and nimesulide , and pharmacological studies showed that it was relayed through prostaglandin E ( 2 ) and its EP ( 2 ) receptor . On the other hand , thrombin - induced inhibition of DB00102 - induced migration was not dependent on P35354 . We show that thrombin inhibits PDGF - induced Akt - 1 phosphorylation . This effect was consecutive to inhibition of PDGF - beta receptor activation through active dephosphorylation . Thus thrombin , through two distinct mechanisms , inhibits both basal - and DB00102 - induced migration of human hepatic liver myofibroblasts . The fine tuning of myofibroblast migration may be one of the mechanisms used by thrombin to regulate liver fibrogenesis .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "The protective effect of rebamipide on paracellular permeability of rat gastric epithelial cells . BACKGROUND : Barrier function in gastric epithelial cells is essential for the gastric defence mechanism against acid back - diffusion into the mucosal layer . Our previous study indicated that trans - epithelial resistance ( Q9NZ01 ) of rat gastric epithelial cells was rapidly increased when the cells were exposed to acid . This response to acid was diminished by indometacin . AIM : Evaluate the effects of a mucoprotective agent , rebamipide , on the nonsteroidal anti - inflammatory drug ( NSAID ) - induced increase of gastric epithelial permeability . METHODS : Rat gastric epithelial cells were plated on tissue culture inserts . Cells were exposed to a NSAID ( indometacin , 10 - 7 M ) . Trans - epithelial permeability was measured by Q9NZ01 and diffusion rate of 14C - mannitol . The effect of rebamipide was evaluated by measuring Q9NZ01 . Endogenous prostaglandin E2 ( DB00917 ) production in culture medium was also measured . RESULTS : DB00328 gradually and significantly decreased Q9NZ01 and increased 14C - manitol permeability . Rebamipide reversed the indometacin - induced changes in epithelial permeability and induced DB00917 synthesis . This induction was blocked by either indometacin or a Cyclooxygenase ( P36551 ) - 2 specific inhibitor . CONCLUSIONS : P36551 inhibitors such as indometacin inhibit regulation of epithelial permeability by reducing DB00917 . P23219 has an important role in the gastric defense mechanism . Rebamipide suppressed an indometacin - induced increase in gastric epithelial permeability by increasing DB00917 levels in a P35354 dependent manner .", "P04150 - mediated regulation of P14780 gene expression in human ovarian surface epithelial cells . OBJECTIVE : To obtain proof - of - concept that locally produced anti - inflammatory steroids suppress ovulation - associated extracellular matrix proteases in human ovarian surface epithelial ( OSE ) cells . DESIGN : Primary OSE cell cultures treated with interleukin - 1alpha ( IL - 1alpha ) ( 500 pg / mL ) as proxy for inflammation , with / without anti - inflammatory steroid ( cortisol or progesterone [ P ] , 0 . 01 - 1 . 0 microM ) . SETTING : Academic medical center . PATIENT ( S ) : Sixteen premenopausal women ( 29 - 46 years ) undergoing surgery for nonmalignant gynecological conditions . MAIN OUTCOME MEASURE ( S ) : Semiquantitative extracellular matrix protease gene expression profiling with verification by real - time quantitative reverse transcription polymerase chain reaction ( qRT - PCR ) and gelatinase zymography . RESULT ( S ) : Treatment with IL - 1alpha stimulated messenger RNA ( mRNA ) expression of several ovulation - associated matrix metalloproteinase genes by OSE cell cultures , including gelatinase B ( P14780 ) but not gelatinase A ( P08253 ) . The IL - 1alpha - stimulated P14780 mRNA production was suppressed by cortisol but not P . ___MASK49___ but not P also dose - dependently suppressed IL - 1alpha - stimulated P14780 gelatinase activity and this effect was blocked by the glucocorticoid receptor antagonist DB00834 . CONCLUSION ( S ) : In human OSE cells , stimulation of P14780 gene expression and proteolytic activity by IL - 1alpha is suppressed by anti - inflammatory cortisol through a glucocorticoid receptor - mediated mechanism . Because IL - 1alpha also generates cortisol formation in OSE by stimulating cortisone reductase activity , these results support a role for intracrine cortisol in minimizing proteolytic damage to the OSE at ovulation .", "[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK48___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .", "Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK78___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK78___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK78___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK78___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK78___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK78___ increased the protein expression of hepatic P05181 and ___MASK78___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK78___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK78___ and RFP - induced hepatotoxicity .", "DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . ___MASK95___ ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .", "High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK79___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .", "[ Anticoagulants of primary haemostasis ] . Inhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases . Established antiplatelet agents use different pharmacological targets for this role . Acetyl salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of P23219 . DB00208 or clopidogrel are ADP - Q9H244 receptor antagonists . Tirofiban , abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb / IIIa receptor which is activated at the surface of platelets preceding the final step of their aggregation . The mechanism of dipyridamole is based on the inhibition of adenosine uptake and of phosphodiesterase - 5 . Efforts are made to improve antiplatelet therapy with the aim to find agents with favorable clinical outcome and lower bleeding risk . Current clinical studies focus on a new generation of ADP receptor antagonists ( prasugrel , cangrelor and ticagrelor ) as successors of ticlopidine and clopidogrel after coronary arterial interventions . Developments using platelet targets different from established drugs are thrombin receptor antagonists ( like SCH530348 ) or thromboxane receptor antagonists ( like S18886 / terutroban ) in patients with cerebrovascular events . Results from recent experimental studies could lead to new strategies for antiplatelet therapy ( like inhibition of GP Ib receptor , GP VI receptor , platelet - leukocyte interaction , factor XII and others ) in the future .", "miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro . Decidualization is a morphological and biochemical transformation of endometrial stromal fibroblast into differentiated decidual cells , which is critical for embryo implantation and pregnancy establishment . The complex regulatory networks have been elucidated at both the transcriptome and the proteome levels , however very little is known about the post - transcriptional regulation of this process . miRNAs regulate multiple physiological pathways and their de - regulation is associated with human disorders including gynaecological conditions such as endometriosis and preeclampsia . In this study we profile the miRNAs expression throughout human endometrial stromal ( hESCs ) decidualization and analyze the requirement of the miRNA biogenesis enzyme Dicer during this process . A total of 26 miRNAs were upregulated and 17 miRNAs downregulated in decidualized hESCs compared to non - decidualized hESCs . Three miRNAs families , miR - 181 , miR - 183 and miR - 200 , are down - regulated during the decidualization process . Using miRNAs target prediction algorithms we have identified the potential targets and pathways regulated by these miRNAs . The knockdown of Dicer has a minor effect on hESCs during in vitro decidualization . We have analyzed a battery of decidualization markers such as cell morphology , P01236 , P08833 , P55773 and P35625 secretion as well as P31260 , P35354 , SP1 , C / EBPß and Q12778 expression in decidualized hESCs with decreased Dicer function . We found decreased levels of P31260 and altered intracellular organization of actin filaments in Dicer knockdown decidualized hESCs compared to control . Our results provide the miRNA signature of hESC during the decidualization process in vitro . We also provide the first functional characterization of Dicer during human endometrial decidualization although surprisingly we found that Dicer plays a minor role regulating this process suggesting that alternative biogenesis miRNAs pathways must be involved in human endometrial decidualization .", "Altered expression of beta - catenin , P12830 , cycloxygenase - 2 , and p53 protein by ovine intestinal adenocarcinoma cells . Around 1 . 6 % of sheep in New Zealand develop small - intestinal adenocarcinomas . These neoplasms typically develop widespread metastases . The common development of these neoplasms and their subsequent behavior suggests that sheep could be a useful animal model of human colonic cancer . However , for an animal model of human disease to be relevant , similar genetic mutations should be present . Genetic mutations within human colonic cancers frequently result in expression of cycloxygenase - 2 ( P35354 ) , loss of membranous expression of beta - catenin and P12830 , and accumulation of p53 protein within the neoplastic cells . Immunohistochemistry was used to investigate the presence of these 4 proteins within 26 ovine intestinal adenocarcinomas . Loss of membranous beta - catenin reactivity was observed in 14 of 26 ovine intestinal adenocarcinomas ( 54 % ) . The loss of membranous beta - catenin reactivity was accompanied by cytoplasmic and nuclear reactivity in 2 neoplasms . Loss of P12830 was observed within 8 of 26 neoplasms ( 31 % ) . Neoplastic cell expression of P35354 was observed in 12 of 26 neoplasms ( 46 % ) , whereas cells within 3 of 26 neoplasms ( 11 % ) contained visible p53 protein . In conclusion , all 4 proteins that commonly have altered expression in human colonic cancers were also altered in a proportion of the ovine intestinal adenocarcinomas . These results provide additional evidence that sheep could be useful for the study of human colonic cancer .", "Evaluation of pharmacological profile of meloxicam as an anti - inflammatory agent , with particular reference to its relative selectivity for cyclooxygenase - 2 over cyclooxygenase - 1 . We studied the anti - inflammatory activity of meloxicam on rat carrageenin - induced pleurisy and its toxicity for rat gastric mucosa , relative to its in vitro inhibitory potency against partially purified cyclooxygenase ( P36551 ) - 1 and P35354 preparations in order to clarify the pharmacological profile of the compound as an anti - inflammatory agent . In rat carrageenin - induced pleurisy , the plasma exudation rate peaked at 5 h , at which time P35354 was detectable in cells from the pleural exudate . Meloxicam and piroxicam ( 1 and 3 mg / kg ) and NS - 398 ( 3 mg / kg ) showed almost equal anti - inflammatory potency against 5 - hour pleurisy . A single oral administration of the compounds caused a dose - dependent increase in the number of rats with gastric mucosal erosion . The ED50 value for meloxicam ( 5 . 92 mg / kg ) was significantly higher than that for piroxicam ( 1 . 76 mg / kg ) , indicating that meloxicam is safer . DB00328 showed intermediate safety ( 2 . 59 mg / kg ) . In in vitro experiments , indometacin inhibited P23219 about 1 . 7 times more potently than P35354 . NS - 398 inhibited P35354 with an IC50 of 0 . 32 microM , but never affected P23219 activity , even at 100 microM . In the same assay system , meloxicam inhibited P35354 about 12 times more selectively than P23219 . Piroxicam , however , inhibited both isoforms almost equally . These results indicate that meloxicam is a potent anti - inflammatory agent with low gastric toxicity . One reason for its in vivo pharmacological profile may be related to its relative selectivity for P35354 over P23219 . Thus , meloxicam may belong to a group of P35354 selective anti - inflammatory agents with a better safety profile than conventional P23219 and P35354 nonselective anti - inflammatory agents .", "P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK67___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .", "___MASK32___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .", "Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .", "[ Effects of octreotide on necrosis of hepatocellular carcinoma xenografts in nude mice ] . BACKGROUND AND OBJECTIVE : ___MASK32___ , a kind of somatostatin analogue , may inhibit the growth of hepatocellular carcinoma ( HCC ) . This study was to investigate the mechanism of inducing necrosis of HCC xenografts in nude mice by octreotide . METHODS : The proliferation of HepG2 cells was determined by MTT assay . Nude mice bearing HepG2 xenografts were treated with octreotide [ 100 microg times ; ( kg times ; d ) (- 1 ) ] or normal saline ( as control ) for eight weeks . The necrosis of HCC was estimated by histology . Vascular endothelial growth factor ( P15692 ) was detected by immunohistochemistry . Somatostatin receptor 2 ( P30874 ) was quantified by Western blot and located with immunohistochemistry . RESULTS : The proliferation of HepG2 cells was not obviously affected by 24 - hour treatment of octreotide ( 0 . 1 - 1000 nmol / L ) in vitro . The tumor weight was significantly heavier in octreotide group than in control group [ ( 7 . 15 +/- 2 . 96 ) g vs . ( 4 . 21 +/- 3 . 11 ) g , P < 0 . 05 ] , while the proportion of necrotic volume was significantly higher in octreotide group than in control group [ ( 81 . 86 +/- 0 . 05 ) % vs . ( 43 . 75 +/- 0 . 06 ) % , P < 0 . 05 ] . In contrast with control group , P15692 was undetected in the xenografts in octreotide group . P30874 expression in xenograft sinusoids was similar in both groups . CONCLUSION : With active proliferation of HCC cells , octreotide can induce necrosis in HCC xenografts only through the inhibition of angiogenesis mediated by P30874 in the tumor .", "DB00328 ameliorates high glucose - induced proliferation and invasion via modulation of e - cadherin in pancreatic cancer cells . DB00328 , an inhibitor of cyclooxygenase - 2 ( P35354 ) , has been shown to exert anticancer effects in a variety of cancers . However , the effect and mechanism of indometacin on high glucose ( HG ) - induced proliferation and invasion of pancreatic cancer ( PC ) cells remain unclear . Multiple lines of evidence suggest that a large portion of pancreatic cancer ( PC ) patients suffer from either diabetes or HG which contributing PC progression . In this study , we report that indometacin down - regulated HG - induced proliferation and invasion via up - regulating P12830 but not P35354 in PC cells . Additionally , the P12830 transcriptional repressors , Snail and Slug , were also involved in the process . Furthermore , the proliferation and invasion of PC cells , incubated in HG medium and treated with indometacin were significantly increased when P12830 was knocked down ( Si - E - cad ) . Moreover , the protein levels of P08253 , P14780 , and P15692 were increased in PC cells transfected with Si - E - cad . Finally , the activation of the PI3K / AKT / GSK - 3β signaling pathway was demonstrated to be involved in indometacin reversing HG - induced cell proliferation and invasion in PC cells . In conclusion , these results suggest that indometacin plays a key role in down - regulating HG - induced proliferation and invasion in PC cells . Our findings indicate that indometacin could be used as a novel therapeutic strategy to treat PC patients who simultaneously suffer from diabetes or HG .", "Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .", "Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .", "Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK79___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK79___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease ." ]

[ "___MASK32___", "___MASK36___", "___MASK48___", "___MASK49___", "___MASK67___", "___MASK78___", "___MASK79___", "___MASK91___", "___MASK95___" ]

[ "Cytochromes P450 are differently expressed in normal and varicose human saphenous veins : linkage with varicosis . The expression of cytochrome P450 ( CYP ) enzymes and cyclo - oxygenases ( P36551 ) was investigated in human saphenous veins by reverse transcription - polymerase chain reaction analysis . Non - varicose veins were obtained from patients undergoing aortocoronary bypass grafting , whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins . In non - varicose veins , Q16678 , CYP2C , P05181 and Q02928 were detected , whereas P51589 , P20815 , P23219 and P35354 were detected almost exclusively in varicose veins . P78329 was not detectable . Except for Q02928 , the levels of individual CYP mRNA were higher in varicose veins than in control veins . Smooth muscle cell volume , determined by a colour image - analysis system , was increased approximately 1 . 5 - fold in varicose veins . Because CYPs and COXs produce various vasoactive compounds , increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology . Then , CYP or P36551 modulators may be potentially active in the treatment of chronic venous insufficiency .", "Effects of nitric oxide synthase inhibition with or without cyclooxygenase - 2 inhibition on resting haemodynamics and responses to exendin - 4 . BACKGROUND AND PURPOSE : Interactions between the NO system and the cyclooxygenase systems may be important in cardiovascular regulation . Here we measured the effects of acute cyclooxygenase - 2 inhibition ( with parecoxib ) , alone and in combination with NOS inhibition ( with NG - nitro - L - arginine methyl ester ( L - NAME ) ) , on resting cardiovascular variables and on responses to the glucagon - like peptide 1 agonist , exendin - 4 , which causes regionally - selective vasoconstriction and vasodilatation . EXPERIMENTAL APPROACH : Rats were instrumented with flow probes and intravascular catheters to measure regional haemodynamics in the conscious , freely moving state . L - NAME was administered as a primed infusion 180 min after administration of parecoxib or vehicle , and exendin - 4 was given 60 min after the onset of L - NAME infusion . KEY RESULTS : DB08439 had no effect on resting cardiovascular variables or on responses to L - NAME . Exendin - 4 caused a pressor response accompanied by tachycardia , mesenteric vasoconstriction and hindquarters vasodilatation . DB08439 did not affect haemodynamic responses to exendin - 4 , but L - NAME inhibited its hindquarters vasodilator and tachycardic effects . When combined , L - NAME and parecoxib almost abolished the hindquarters vasodilatation while enhancing the pressor response . CONCLUSIONS AND IMPLICATIONS : P35354 - derived products do not affect basal haemodynamic status in conscious normotensive rats , or influence the NO system acutely . The inhibitory effects of L - NAME on the hindquarters vasodilator and tachycardic effects of exendin - 4 are consistent with a previous study that showed those events to be beta - adrenoceptor mediated . The additional effect of parecoxib on responses to exendin - 4 in the presence of L - NAME , is consistent with other evidence for enhanced involvement of vasodilator prostanoids when NO production is reduced .", "Amelioration of meconium - induced acute lung injury by parecoxib in a rabbit model . P35354 ( P35354 ) plays important roles in various inflammatory conditions and is significantly increased in meconium - induced lung injury . We investigated the effects of parecoxib on meconium - induced acute lung injury ( ALI ) in rabbits . Twenty - four rabbits were randomized into sham , control , and parecoxib groups . Rabbits in the control and parecoxib groups underwent tracheal instillation of meconium , followed by intravenous injection of saline or parecoxib and 4 h of ventilation . The airway pressure , dynamic compliance , and ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen ( PaO2 / FiO2 ratio ) were recorded at baseline ( T0 ) and 4 h after instillation ( T1 - DB00451 ) . The lung tissue wet - to - dry weight ratio ; neutrophil percentage ; and total protein , tumor necrosis factor - α ( P01375 - α ) , interleukin ( IL ) - 1β , P10145 , prostaglandin E2 , and malondialdehyde levels in bronchoalveolar lavage fluid ( BALF ) were evaluated . The myeloperoxidase activity , P35354 expression , and degree of histopathologic injury in lung tissue were also analyzed . The airway pressure , compliance , and PaO2 / FiO2 ratio were significantly improved by parecoxib after meconium instillation . The lung wet - to - dry weight ratio , total protein level , and neutrophil percentage in BALF were lowest in the parecoxib group . The P01375 - α , IL - 1β , P10145 , prostaglandin E2 , and malondialdehyde levels in the BALF were lowest in the parecoxib group . The P35354 expression and myeloperoxidase activity in lung tissue were significantly reduced by parecoxib . The degree of lung injury was also reduced . In conclusions : DB08439 effectively ameliorates respiratory function and attenuates meconium - induced ALI . These effects are correlated with prostaglandin E2 and P35354 inhibition .", "Effects of retroviral - mediated P08183 expression on hematopoietic stem cell self - renewal and differentiation in culture . Ex vivo expansion of hematopoietic stem cells would be useful for bone marrow transplantation and gene therapy applications . Toward this goal , we have investigated whether retrovirally - transduced murine stem cells could be expanded in culture with hematopoietic cytokines . Bone marrow cells were transduced with retroviral vectors expressing either the human multidrug resistance 1 gene ( HaMDR1 ) , a variant of human dihydrofolate reductase ( HaDHFR ) , or both P08183 and P00374 in an internal ribosomal entry site ( IRES ) - containing bicistronic vector ( HaMID ) . Cells were then expanded for 15 days in cultures stimulated with interleukin ( IL ) - 3 , P05231 , and stem cell factor . When very low marrow volumes were injected into lethally irradiated recipient mice , long - term reconstitution with 100 % donor cells was seen in all mice injected with HaMDR1 - or HaMID - transduced cells . By contrast , engraftment with HaDHFR - or mock - transduced cells ranged from partial to undetectable despite injection of significantly larger marrow volumes . In addition , mice transplanted with expanded HaMDR1 - or HaMID - transduced stem cells developed a myeloproliferative disorder that was characterized by an increase in abnormal peripheral blood leukocytes . These results show that P08183 - transduced stem cells can be expanded in vitro with hematopoietic cytokines , but indicate that an increased stem cell division frequency can lead to stem cell damage .", "The effect of TSPP - mediated photodynamic therapy and DB08439 in experimental tumours . AIMS : The study investigated the effects of the combined treatment DB08439 ( Pcox ) and 5 , 10 , 15 , 20 - tetra - sulphonato - phenyl - porphyrin ( TSPP )- mediated photodynamic therapy on Walker 256 carcinosarcoma . MAIN METHODS : Five groups of male Wistar rats were used : the control group , treated with TSPP , group 2 , irradiated 24 h thereafter , group 3 , treated with Pcox and irradiated 24 h thereafter , groups 4 and 5 treated with combined therapies , TSPP and Pcox before irradiation , and Pcox 24 h after TSPP and irradiation respectively . Tumour inflammation , growth and non - growth factors , apoptosis / necrosis rate and oxidative / nitrosative stress markers were investigated . KEY FINDINGS : Malondialdehyde levels and cyclooxygenase ( P36551 ) - 2 expression increased significantly in the group treated with Pcox after TSPP - PDT when compared with TSPP + IR group ( p < 0 . 05 , p < 0 . 001 respectively ) , in correlation with a decrease in glutathione levels ( p < 0 . 05 ) . The quantification of apoptosis , based on the TUNEL - assay , and necrosis rate revealed an increase of apoptotic / necrotic index in the same group ( p < 0 . 05 ) . On the other hand , Pcox administered before irradiation showed a significant increase in both vascular endothelial growth factor ( P15692 ) and P35354 levels ( p < 0 . 05 ) and in nitric oxide production ( p < 0 . 01 ) , when compared with the control group . SIGNIFICANCE : The administration of Pcox after TSPP - mediated PDT showed promising antitumoural effects , leading to an increase in oxidative and nitrosative stress as well as apoptosis / necrosis rate in tumour tissue . These results show that combined regimens that involve selective P35354 inhibitors administration after irradiation may improve the therapeutic effectiveness of PDT .", "The P35354 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy . The enzyme cyclooxygenase - 2 ( P35354 ) , which catalyzes the production of pro - inflammatory prostaglandins , is induced in the brain after various insults , thus contributing to brain inflammatory processes involved in the long - term consequences of such insults . Mounting evidence supports that inflammation may contribute to epileptogenesis and neuronal injury developing after brain insults . Anti - inflammatory treatments , such as selective P35354 inhibitors , may thus constitute a novel approach for anti - epileptogenesis or disease - modification after brain injuries such as head trauma , cerebral ischemia or status epilepticus ( SE ) . However , recent rat experiments with prophylactic administration of two different P35354 inhibitors after SE resulted in conflicting results . In the present study , we evaluated whether treatment with parecoxib , a pro - drug of the highly potent and selective P35354 inhibitor valdecoxib , alters the long - term consequences of a pilocarpine - induced SE in rats . DB08439 was administered twice daily at 10 mg / kg for 18 days following SE . Five weeks after termination of treatment , spontaneous recurrent seizures were recorded by continuous video / EEG monitoring . Prophylactic treatment with parecoxib prevented the SE - induced increase in prostaglandin E ( 2 ) and reduced neuronal damage in the hippocampus and piriform cortex . However , the incidence , frequency or duration of spontaneous seizures developing after SE or the behavioral and cognitive alterations associated with epilepsy were not affected by parecoxib . Only the severity of spontaneous seizures was reduced , indicating a disease - modifying effect . These results substantiate that P35354 contributes to neuronal injury developing after SE , but inhibition of P35354 is no effective means to modify epileptogenesis .", "DB08439 does not suppress thromboxane synthesis in newborn piglets with group B streptococcal sepsis . Group B streptococci ( GBS ) cause fatal sepsis in newborns . Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension . In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP - 3 receptor gene expression . Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP - 3 receptor in infected lung tissue , parecoxib did not suppress urine levels of thromboxane like indometacin . We presume that P35354 inhibition in GBS sepsis is associated with enhanced thrombogenicity .", "Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK24___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .", "The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK62___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK62___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK62___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK62___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .", "Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .", "DB08439 as an alternative in P35354 hypersensitivity . The group of non - steroidal anti - inflammatory drugs ( NSAIDs ) is commonly involved in hypersensitivity reactions . In clinical practice the physician is often faced with the need to choose an alternative anti - inflammatory agent for a patient who has suffered a hypersensitivity reaction to a NSAID . The most common approach to choosing the safest NSAID is to perform a challenge test . DB08439 is the first injectable P35354 selective inhibitor indicated for the treatment of acute postoperative pain . The authors report the case of a patient with a history of cutaneous adverse reactions to different classes of NSAIDs , including selective P35354 inhibitors , who underwent and tolerated challenge with parecoxib .", "Toll - like receptor expression in human keratinocytes : nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll - like receptor 2 but not toll - like receptor 4 or platelet activating factor receptor dependent . Cultured primary human keratinocytes were screened for their expression of various members of the toll - like receptor ( TLR ) family . Keratinocytes were found to constitutively express Q15399 , O60603 , O15455 , O60602 , and Q9NR96 but not O00206 , Q9Y2C9 , Q9NYK1 , Q9NR97 , or Q9BXR5 as shown by polymerase chain reaction analysis . The expression of the crucial receptor for signaling of staphylococcal compounds O60603 was also confirmed by immunohistochemistry , in contrast to O00206 , which showed a negative staining pattern . Next , we analyzed the activation of the proinflammatory nuclear transcription factor kappaB by Staphylococcus aureus strain 8325 - 4 . Using nuclear extract gel shifts , RelA staining , and luciferase reporter transfection plasmids we found a clear induction of nuclear factor kappaB translocation by the bacteria . This translocation induced the transcription of nuclear factor kappaB controlled genes such as inducible nitric oxide synthetase , P35354 , and interleukin - 8 . Transcription of these genes was followed by production of increased amounts of interleukin - 8 protein and NO . Inhibition experiments using monoclonal antibodies and the specific platelet activating factor receptor inhibitor CV3988 showed that nuclear factor kappaB activation by S . aureus was O60603 but not O00206 or platelet activating factor receptor dependent . In line , the purified staphylococcal cell wall components lipoteichoic acid and peptidoglycan , known to signal through O60603 , also showed nuclear factor kappaB translocation in human keratinocytes , indicating a crucial role of the staphylococcal cell wall in the innate immune stimulation of human keratinocytes . These results help to explain the complex activation of human keratinocytes by S . aureus and its cell wall components in various inflammatory disorders of the skin .", "Motility - induced but not vasoactive intestinal peptide - induced increase in luminal alkalinization in rat duodenum is dependent on luminal Cl (-) . AIM : to investigate whether the motility - and the vasoactive intestinal peptide ( P01282 ) - induced increase in luminal alkalinization in the duodenum is dependent on luminal Cl (-) . METHODS : experiments were performed in anaesthetized rats in vivo . The proximal duodenum was perfused luminally with an isotonic solution , containing zero or low Cl (-) and the effects on luminal alkalinization , motility , fluid flux and epithelial permeability were determined . DB08439 , a P35354 inhibitor , was used to induce duodenal contractions . RESULTS : control rats lacked duodenal wall contractions while parecoxib - treated ones exhibited contractions throughout the experiment . Most animals had a net fluid absorption during the perfusion with isotonic NaCl . DB01174 alkalinization was about 100 % higher in parecoxib - treated rats than in controls . Cl (-) - free solutions did not affect epithelial permeability or motility but decreased luminal alkalinization by ≥ 50 % and decreased net fluid absorption in both control and parecoxib - treated animals . Reduction in luminal Cl (-) decreased alkalinization in a concentration - dependent manner . The parecoxib - induced increase in alkalinization was markedly reduced in the absence of luminal Cl (-) . P01282 increased luminal alkalinization and induced fluid secretion . The lack of luminal Cl (-) did not affect the P01282 - induced increase in alkalinization but reduced fluid secretion . CONCLUSIONS : the parecoxib - induced increase in luminal alkalinization is highly dependent on luminal Cl (-) and it is proposed that P35354 inhibition , via induction of duodenal motility , enhances HCO ( 3 ) ( - ) efflux through stimulation of apical Cl (-) / HCO ( 3 ) ( - ) exchange in duodenal epithelial cells . Although the P01282 - induced stimulation of fluid secretion is partly dependent on luminal Cl (-) , the P01282 - induced increase in luminal alkalinization is not .", "Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK69___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .", "Effects of parecoxib on plasma protein extravasation and c - fos expression in the rat . OBJECTIVE : We aimed to investigate the effects of the cyclooxygenases - 2 ( P35354 ) inhibitor parecoxib on meningeal plasma protein extravasation ( PPE ) and on c - fos expression in the nucleus trigeminalis caudalis in an animal model of trigeminovascular activation . Background .- Recent reports about the efficacy of P35354 inhibitors in migraine treatment suggest the involvement of P35354 in migraine pathophysiology . So far , studies on the role of P35354 in animal models of migraine are lacking . METHODS : Unilateral electrical stimulation of the trigeminal ganglion was performed in anesthetized male Sprague Dawley rats . We assessed PPE in the ipsilateral dura mater and expression of c - fos within the ipsilateral trigeminal nucleus caudalis ( P24821 ) under control conditions and after pretreatment with parecoxib . RESULTS : DB08439 significantly attenuated PPE in the rat dura mater . The PPE ratio under control conditions ( 1 . 73 +/- 0 . 19 ( mean +/- SD ) ) was reduced by 58 . 9 +/- 30 % after pretreatment with 10 mg / kg parecoxib and by 78 . 1 +/- 23 % after pretreatment with 50 mg / kg . c - fos experiments : Compared with vehicle , all doses of parecoxib ( 1 mg / kg , 10 mg / kg , 50 mg / kg ) significantly reduced the number of c - fos positive cells in the ipsilateral P24821 ( P < . 05 ) . The number of c - fos positive cells in the ipsilateral P24821 was 50 +/- 2 . 7 ( mean +/- SEM ) under control conditions and 9 . 1 +/- 0 . 6 after pretreatment with 50 mg / kg parecoxib . CONCLUSION : Our study results suggest that P35354 is involved in neurogenic inflammation of the rat dura mater . Moreover , the study points to a role of P35354 inhibitors in trigeminal nociception at the second - order level .", "Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK37___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .", "DB08439 has non - significant long - term effects on bone healing in rats when administered for a short period after fracture . INTRODUCTION : Selective and non - selective cyclo - oxygenase ( P36551 ) inhibitors impair bone healing by inhibiting prostaglandin synthesis . The purpose of this study was to evaluate the long - term effect of parecoxib , a selective P35354 inhibitor , on bone healing in rats , when it is applied in a pattern similar to clinical treatment patterns , that is , in a high dose and for a short period after bone fracture . METHOD : Closed non - displaced mid - diaphyseal fractures in the middle of the left femoral shaft were generated in each animal . In the study group , parecoxib sodium ( 1 . 06 mg / kg ) was administered intra - peritoneally every day for 7 days . In the control group , normal saline was administered intra - peritoneally every day for 7 days . In both groups fracture healing ( bone union and callus formation ) was evaluated with X - rays 28 and 42 days after surgery . RESULTS : Bone healing was lower in the study group ( 60 vs . 80 % in the control group 28 days after fracture and 80 vs . 90 % 42 days after fracture ) but this difference was not statistically significant ( P > 0 . 05 ) . CONCLUSION : DB08439 does not have a significant long - term effect on bone healing in rats , when it is administered in a high dose and for a short period after bone fracture .", "Pre - clinical evaluation of an in vitro selection protocol for the enrichment of transduced P28906 + cell - derived human dendritic cells . The efficient genetic modification of P28906 + cell - derived dendritic cells ( DC ) will provide a significant advancement towards the development of immunotherapy protocols for cancer , autoimmune disorders and infectious diseases . Recent reports have described the transduction of P28906 + cells via retrovirus - and lentivirus - based gene transfer vectors and subsequent differentiation into functional DC . Since there is significant apprehension regarding the clinical uses of HIV - based vectors , in this report , we compare a murine leukemia virus ( MLV ) - and a human immunodeficiency virus ( HIV ) - based bicistronic vector for gene transfer into human P28906 + cells and subsequent differentiation into mature DC . Each vector expressed both EGFP and the dominant selectable marker P00374 ( L22Y ) allowing for the enrichment of marked cells in the presence of the antifolate drug trimetrexate ( TMTX ) . Both MLV - based and HIV - based vectors efficiently transduced cytokine mobilized human peripheral blood P28906 + cells . However , in vitro expansion and differentiation in the presence of GM - P04141 , P01375 , Flt - 3L , P21583 and P05112 resulted in a reduction in the percentage of DC expressing the transgene . Selection with TMTX during differentiation increased the percentage of marked DC , resulting in up to 79 % ( MLV vector ) and up to 94 % ( lentivirus - vector ) transduced cells expressing EGFP without loss of DC phenotype . Thus , MLV - based vectors and in vitro selection of transduced human DC show great promise for immunotherapy protocols .", "Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .", "P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK8___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK8___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .", "DB08439 suppresses P35638 and Foxo1 nuclear translocation , but increases P11021 levels in a rat model of focal ischemia . DB08439 , a novel P35354 inhibitor , functions as a neuroprotective agent and rescues neurons from cerebral ischemic reperfusion injury - induced apoptosis . However , the molecular mechanisms underlying parecoxib neuroprotection remain to be elucidated . There is growing evidence that endoplasmic reticulum ( ER ) stress plays an important role in neuronal death caused by brain ischemia . However , very little is known about the role of parecoxib in mediating pathophysiological reactions to ER stress induced by ischemic reperfusion injury . Therefore , in the present study , we investigated whether delayed administration of parecoxib attenuates brain damage via suppressing ER stress - induced cell death . Adult male Sprague - Dawley rats were administered parecoxib ( 10 or 30 mg kg (- 1 ) , IP ) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion ( MCAO ) for three consecutive days . The expressions of glucose - regulated protein 78 ( P11021 ) and oxygen - regulated protein 150 ( Q9Y4L1 ) and P35638 ( P35638 ) and forkhead box protein O 1 ( Foxo1 ) in cytoplasmic and nuclear fraction were determined by Western blotting . The levels of caspase - 12 expression were checked by immunohistochemistry analysis , served as a marker for ER stress - induced apoptosis . DB08439 significantly suppressed cerebral ischemic injury - induced nuclear translocation of P35638 and Foxo1 and attenuated the immunoreactivity of caspase - 12 in ischemic penumbra . Furthermore , the protective effect of delayed administration of parecoxib was accompanied by an increased P11021 and Q9Y4L1 expression . Therefore , our study suggested that elevation of P11021 and Q9Y4L1 , and suppression of P35638 and Foxo1 nuclear translocation may contribute to parecoxib - mediated neuroprotection during ER stress responses .", "Thrombosis is reduced by inhibition of P23219 , but unaffected by inhibition of P35354 , in an acute model of platelet activation in the mouse . BACKGROUND : Clinical use of selective inhibitors of cyclooxygenase ( P36551 ) - 2 appears associated with increased risk of thrombotic events . This is often hypothesised to reflect reduction in anti - thrombotic prostanoids , notably P06744 ( 2 ) , formed by P35354 present within endothelial cells . However , whether P35354 is actually expressed to any significant extent within endothelial cells is controversial . Here we have tested the effects of acute inhibition of P36551 on platelet reactivity using a functional in vivo approach in mice . METHODOLOGY / PRINCIPAL FINDINGS : A non - lethal model of platelet - driven thromboembolism in the mouse was used to assess the effects of aspirin ( 7 days orally as control ) diclofenac ( 1 mg . kg (- 1 ) , i . v . ) and parecoxib ( 0 . 5 mg . kg (- 1 ) , i . v . ) on thrombus formation induced by collagen or the thromboxane ( TX ) A ( 2 )- mimetic , U46619 . The P36551 inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo . Collagen and U46619 caused in vivo thrombus formation with the former , but not latter , sensitive to oral dosing with aspirin . Diclofenac inhibited P23219 and P35354 ex vivo and reduced thrombus formation in response to collagen , but not U46619 . DB08439 inhibited only P35354 and had no effect upon thrombus formation caused by either agonist . CONCLUSIONS / SIGNIFICANCE : Inhibition of P23219 by diclofenac or aspirin reduced thrombus formation induced by collagen , which is partly dependent upon platelet - derived TXA ( 2 ) , but not that induced by U46619 , which is independent of platelet TXA ( 2 ) . These results are consistent with the model demonstrating the effects of P23219 inhibition in platelets , but provide no support for the hypothesis that acute inhibition of P35354 in the circulation increases thrombosis .", "Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .", "Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK49___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .", "P35354 inhibition attenuates endotoxin - induced downregulation of organic anion transporters in the rat renal cortex . Renal excretion of organic anions such as DB00345 is reduced during severe sepsis and following ischemia / reperfusion injury . In order to better define the pathophysiology of sepsis - associated renal tubular dysfunction we measured the effect of lipopolysaccharide on renocortical organic anion transporter ( P04181 ) expression in the rat . DB00917 ( DB00917 ) downregulates OATs in vitro , therefore , we also evaluated the effect of the cyclooxygenase ( P36551 ) - 2 inhibitor parecoxib on this process . Endotoxemia caused a time - and dose - dependent decrease of Q4U2R8 and Q8TCC7 expression that paralleled increased renocortical P35354 expression and DB00917 formation . Pretreatment with parecoxib decreased endotoxin - stimulated PGE ( 2 ) formation . DB08439 attenuated Q4U2R8 and Q8TCC7 gene repression in the rat kidney following endotoxin treatment and during ischemia / reperfusion - induced acute renal injury . P35354 inhibition improved the creatinine clearance in lipopolysaccharide - treated rats but not after ischemia / reperfusion - induced acute renal injury . The decreased clearance of DB00345 in rats following endotoxin - or ischemia / reperfusion - induced renal injury was improved by parecoxib . Our findings show that P35354 derived prostanoids downregulate OATs during lipopolysaccharide - induced acute renal injury .", "[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK86___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .", "DB08439 . Pharmacia corp . Pharmacia ( formerly Monsanto ) is developing parecoxib , an injectable P35354 inhibitor , for the management of post - surgical acute pain [ 287279 ] , [ 313957 ] . By January 1999 , the compound was in phase III trials for this indication [ 312280 ] . In October 2000 , Pharmacia submitted an NDA for parecoxib sodium for the management of acute pain to the FDA . The company anticipated a 12 - month review of the NDA [ 387654 ] but received a ' not approvable ' letter in July 2001 , indicating there were deficiencies in the filing ; at this time , Pharmacia anticipated refiling before the end of 2002 [ 415668 ] . Under a license agreement with Pharmacia Corp , parecoxib ( designated YM - 177 ) is being developed in Japan by Yamanouchi [ 392030 ] . Prior to the FDA ruling , in June 2000 , the company anticipated that the compound would be launched by 2001 [ 370466 ] . In March 2000 , Merrill Lynch predicted that parecoxib would be filed in the third quarter of 2000 [ 361969 ] , [ 382577 ] . By May 2001 , the analysts revised their predictions to launch in 2002 [ 411811 ] .", "DB08439 sodium , an injectable P35354 - specific inhibitor , does not affect unfractionated heparin - regulated blood coagulation parameters . The objective of this study was to evaluate the potential for hemostatic interaction between a full analgesic dose of parecoxib sodium ( parecoxib ) , a prodrug of the P35354 specific inhibitor valdecoxib , and unfractionated heparin ( UFH ) in healthy male subjects . This open - label , single - center study comprised two treatment periods . In treatment period I , fasted , eligible subjects ( n = 18 ) received a UFH bolus ( 4000 U ) followed by a 36 - hour UFH infusion ( start dose 10 - 14 U / kg ) . Activated partial thromboplastin time ( aPTT ) , prothrombin time ( PT ) , and platelet counts were measured at regular intervals up to 24 hours after the end of the UFH infusion . After a 2 - day washout , patients randomized to treatment period II received a full analgesic dosage of parecoxib 40 mg bid intravenously ( IV ) for 6 days ( n = 18 ) , with concomitant UFH ( same regimen as treatment period I ) on day 5 ( n = 18 ) . APTT , PT , and platelet counts were evaluated at regular intervals up to 24 hours after UFH infusion . Coadministration of parecoxib 40 mg bid IV with UFH ( treatment period II ) had no significant effect on aPTT , PT , or platelet counts , which were similar to those of participants receiving UFH alone ( treatment period I ) at all time points . These results show that a full analgesic dose of parecoxib , a P35354 - specific inhibitor available for parenteral administration , can be coadministered with UFH without affecting blood coagulation parameters . Therefore , parecoxib may be administered to patients who are receiving UFH for thromboprophylaxis .", "Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .", "Ovarian hyperstimulation syndrome inhibition by targeting P15692 , P35354 and calcium pathways : a preclinical randomized study . OBJECTIVE : The efficacy of vascular endothelial growth factor ( P15692 ) , P35354 , calcium and aromatase inhibitors in an ovarian hyperstimulation syndrome ( OHSS ) rat model was tested . METHODS : One hundred and eight female Wistar rats were randomly divided in nine groups . The control group received saline , while the OHSS group received rec - DB00094 for 4 consecutive days . The other seven groups received rec - DB00094 ( 4d ) and DB00112 twice , DB08439 daily , Verapamil daily , DB08439 daily and DB00112 twice , Verapamil daily and DB00112 twice , DB08439 and Verapamil daily , Letrozole and Meloxicam daily , respectively . All groups received also hCG at the 5th day . RESULTS : All intervention groups were characterized by reduced vascular permeability compared to the OHSS group , which in the groups of Verapamil ( DB01373 inhibition ) and DB08439 + Verapamil ( P35354 + DB01373 inhibition ) presented significant statistical difference . The Verapamil group showed the lowest corpus luteum formation , while the DB08439 ( P35354 inhibition ) , the DB08439 + Verapamil ( P35354 + DB01373 inhibition ) , the DB00112 + DB08439 ( P15692 + P35354 inhibition ) and the DB00112 + Verapamil ( P15692 + DB01373 inhibition ) groups were also characterized by lower corpus luteum numbers compared to the OHSS group . Furthermore , lower graafian follicle formation was observed in the above groups , while the ovarian weight and the hormonal profile were not significantly affected . CONCLUSIONS : Studying the different check points of the P15692 pathway , we conclude that targeting calcium pathways could be beneficial for the vascular permeability control in an OHSS animal model .", "Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following gynecologic laparotomy surgery . BACKGROUND : This study tested the hypothesis that an injectable cyclooxygenase ( P36551 ) - 2 - specific inhibitor will be at least as effective and well tolerated as a P36551 - nonspecific conventional nonsteroidal antiinflammatory drug ( NSAID ) by comparing the analgesic efficacy and tolerability of one intravenous dose of parecoxib sodium , an injectable prodrug of the novel P35354 - specific inhibitor , valdecoxib , with ketorolac and placebo in postoperative laparotomy surgery patients . Intravenous morphine , 4 mg , was studied as a positive analgesic control . METHODS : In this multicenter , double - blinded , placebo - controlled study , women experiencing moderate - to - severe pain on the first day after abdominal hysterectomy or myomectomy received one intravenous dose of parecoxib sodium , 20 or 40 mg , ketorolac , 30 mg , morphine , 4 mg , or placebo . Analgesic efficacy and tolerability were evaluated for 24 h postdose or until patients , whose pain was not adequately controlled , opted to receive rescue analgesia . RESULTS : Two hundred two patients were enrolled . All treatment groups had comparable demographics and baseline pain status . All active treatments had an equally rapid time to onset of analgesia ( 10 - 23 min ) . Overall , each parecoxib sodium dose and ketorolac were significantly superior to morphine and placebo for most measures of analgesic efficacy at most time points , including a significantly longer ( two - to threefold ) time to rescue analgesia ( P </= 0 . 05 ) . All treatments were well tolerated . CONCLUSIONS : Single intravenous doses of parecoxib sodium , 20 mg and 40 mg , have comparable analgesic effects and are well tolerated after laparotomy surgery . DB08439 sodium appears to be as effective as intravenous ketorolac , 30 mg , and superior to intravenous morphine , 4 mg .", "The role of cycloxygenase - 2 in the rodent kidney following ischaemia / reperfusion injury in vivo . The role of cyclooxygenase - 2 ( P35354 ) in the pathophysiology of renal ischaemia / reperfusion injury is still not fully understood . In order to elucidate the role of P35354 in ischaemia / reperfusion injury of the kidney , we have evaluated the effects of ischaemia / reperfusion on renal dysfunction and injury in ( i ) rats treated with either vehicle or the selective P35354 inhibitor parecoxib , and ( ii ) wild - type mice or mice in which the gene for P35354 has been deleted ( P35354 knock - out mice or P35354 (-/-) ) . Rats were subjected to bilateral renal ischaemia ( 45 min ) and reperfusion ( 6 h ) , and received parecoxib ( 20 mg / kg , i . v . ) 30 min prior to ischaemia and 3 h after the commencement of reperfusion . Serum urea , serum creatinine , serum aspartate aminotransferase , creatinine clearance and fractional excretion of sodium were all used as indicators of renal dysfunction and injury . Mice ( wild - type and P35354 (-/-) ) were subjected to bilateral renal ischaemia ( 30 min ) and reperfusion ( 24 h ) after which renal dysfunction ( serum urea and creatinine ) and renal injury was assessed by histological analysis . DB08439 significantly augmented the degree of renal dysfunction and injury caused by ischaemia / reperfusion in the rat . In addition , the degree of renal injury and dysfunction caused by ischaemia / reperfusion was also significantly augmented in P35354 (-/-) mice when compared to their wild - type littermates . These findings support the view that metabolites of P35354 protect the kidney against ischaemia / reperfusion injury , and ( ii ) that selective inhibitors of P35354 may worsen renal dysfunction and injury in conditions associated with renal ischaemia .", "Increased interleukin - 6 receptor expression in the paraventricular nucleus of rats with heart failure . Activation of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis and augmented plasma and tissue levels of P05231 are hallmarks of heart failure ( HF ) . Within the forebrain , cardiovascular homeostasis is mediated in part by the paraventricular nucleus ( PVN ) of the hypothalamus . P05231 , via binding to the P05231 receptor ( IL - 6R ) / glycoprotein 130 ( P40189 ) complex influences cellular and physiological responses . Thus , in the current study , we hypothesized that PVN IL - 6R protein and gene expression are upregulated in HF vs . sham - operated rats , whereas P40189 levels in the same tissues remain stable . Six weeks after coronary ligation surgery , hemodynamic measurements were obtained , and HF rats were divided into moderate noncongestive and severe chronic congestive groups based on cardiac indices . Plasma P05231 levels were determined and changes in gene and protein expression of IL - 6R and P40189 between sham - operated and HF rats were determined via real - time PCR and Western blot analyses , respectively . Plasma levels of P05231 were elevated in rats with severe , but not moderate , HF compared with sham - operated controls . In both moderate and severe HF rats , protein but not gene expression of IL - 6R was significantly increased in PVN tissue but not in non - PVN tissue , compared with sham - operated controls . Gene and protein levels of the P40189 subunit were not altered by HF in either tissue analyzed . Collectively , these data suggest that within the brain of HF rats , IL - 6R expression is not a global change . Rather the increased P05231 levels characteristic of HF may alter PVN - mediated physiological responses via enhanced expression of the IL - 6R .", "The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice . P00747 activation to plasmin protects from lung fibrosis , but the mechanism underlying this antifibrotic effect remains unclear . We found that mice lacking plasminogen activation inhibitor - 1 ( P05121 ) , which are protected from bleomycin - induced pulmonary fibrosis , exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 ( DB00917 ) . P00747 activation upregulated DB00917 synthesis in alveolar epithelial cells , lung fibroblasts , and lung fibrocytes from saline - and bleomycin - treated mice , as well as in normal fetal and adult primary human lung fibroblasts . This response was exaggerated in cells from Pai1 -/- mice . Although enhanced DB00917 formation required the generation of plasmin , it was independent of proteinase - activated receptor 1 ( P25116 ) and instead reflected proteolytic activation and release of P14210 with subsequent induction of P35354 . That the P14210 / P35354 / DB00917 axis mediates in vivo protection from fibrosis in Pai1 -/- mice was demonstrated by experiments showing that a selective inhibitor of the P08581 c - DB00134 increased lung collagen to WT levels while reducing P35354 protein and DB00917 levels . Of clinical interest , fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce P35354 and , therefore , unable to upregulate DB00917 synthesis in response to plasmin or P14210 . These studies demonstrate crosstalk between plasminogen activation and DB00917 generation in the lung and provide a mechanism for the well - known antifibrotic actions of the fibrinolytic pathway .", "NSAIDS inhibit in vitro O60682 chondrogenesis but not osteogenesis : implications for mechanism of bone formation inhibition in man . The non - steroidal anti - inflammatory drugs ( NSAIDs ) are widely used for analgesia but may inhibit bone formation . We investigated whether the reported NSAID effect on bone is related to inhibition of bone marrow mesenchymal stem cell ( O60682 ) proliferation and osteogenic and chondrogenic differentiation and evaluated both cyclooxygenase ( P36551 ) - 1 and P35354 specific drugs . The effects of seven P23219 and P35354 inhibitors on O60682 proliferation and osteogenic and chondrogenic differentiation were tested using Vybrant , sodium 3 '- [ 1 -( phenylaminocarbonyl )- 3 , 4 - tetrazolium ] - bis ( 4 - methoxy - 6 - nitro ) benzene sulfonic acid hydrate ( XTT ) , functional and quantitative assays of O60682 differentiation . The O60682 expression of P23219 and P35354 and prostaglandin E2 ( PGE - 2 ) levels were evaluated serially during lineage differentiation by quantitative PCR and ELISA . None of the NSAIDs at broad range of concentration ( range 10 (- 3 ) to 100 μg / ml ) significantly affected O60682 proliferation . Surprisingly , O60682 osteogenic differentiation inhibition was not evident . However , NSAIDs affected chondrogenic potential with a reduction in sulphated glycosaminoglycans ( sGAG ) content by 45 % and 55 % with diclofenac and ketorolac , respectively ( P < 0 . 05 compared to controls ) . DB08439 and meloxicam , more P35354 specific reagents inhibited sGAG to a lesser degree , 22 % and 27 % respectively ( P < 0 . 05 compared to controls ) . Cartilage pellet immunohistochemistry confirmed the above results . Pellet chondrogenesis was associated with increased P23219 expression levels but not P35354 , and P23219 specific drugs suppressed O60682 PGE - 2 more than P35354 specific inhibitors . These findings suggest that NSAIDs may inhibit bone formation via blockage of O60682 chondrogenic differentiation which is an important intermediate phase in normal endochondral bone formation .", "DB08439 for parenteral analgesia in postsurgical patients . OBJECTIVE : To review the pharmacology , pharmacokinetics , clinical efficacy and safety studies , adverse effects , drug interactions , and dosage and administration of parecoxib sodium , a selective cyclooxygenase - 2 ( P35354 ) inhibitor . DATA SOURCES : Information was obtained from MEDLINE searches of the English - language literature ( 1996 - May 2003 ) . Search terms included parecoxib , parecoxib sodium , SC - 69124A , and selective cyclooxygenase - 2 inhibitor . STUDY SELECTION AND DATA EXTRACTION : We reviewed available literature , which included abstracts , clinical trials , and data on file with the manufacturer . DATA SYNTHESIS : DB08439 sodium is a novel selective P35354 inhibitor under development for parenteral administration . It has produced efficacious analgesia following dental , gynecologic , and orthopedic surgery . The adverse effect profile has been compared with that of ketorolac ; no statistically significant differences were identified . There are no documented drug interactions when parecoxib is coadministered with midazolam , propofol , or unfractionated heparin . CONCLUSIONS : DB08439 sodium is in the final stages of Phase III trials and has a favorable safety and efficacy profile . Its place in moderate to severe postsurgical pain management will be further defined when more pharmacoeconomic and postmarketing safety data are available . Theoretical benefits are its lower potential for gastrointestinal adverse effects compared with ketorolac and lower opioid requirements after surgery .", "Effect of selective inhibition of cyclooxygenase - 2 on lipopolysaccharide - induced hyperalgesia . Lipopolysaccharide ( LPS ) is known to increase the expression and release of various pro - inflammatory mediators , including cyclooxygenase - 2 ( P35354 ) and produce hyperalgesia . It is also well known that prostaglandins ( PGs ) , synthesised both in the periphery and centrally by P36551 isoforms , play a key role in sensitisation of nociceptors and nociceptive processing . To investigate the role of P35354 in LPS - induced hyperalgesia , parecoxib , a selective P35354 - inhibiting pro - drug , was injected intravenously 30 min before assessing hyperalgesia induced by intraperitoneal or subcutaneous administration of LPS ( 50 microg / mouse or 25 microg / paw of rat , respectively ) . DB03166 - induced writhing and tail immersion assay in mice and paw withdrawal response to thermal and mechanical stimuli in rats were used to assess the effect of inhibition of P35354 on LPSinduced hyperalgesia . Animals showed significant hyperalgesic behavior 8 h after LPS injection . DB08439 ( up to 20 mg / kg , i . v . ) had no effect in the two acute nociceptive assays but showed marked antinociceptive activity in writhing and tail immersion assay in LPS - pretreated mice . Similarly , parecoxib reversed the hyperalgesia in the LPS - injected paw but not in the contralateral paw of rats . Pre - treatment with dexamethasone , an inhibitor of P35354 expression before LPS injection significantly affected the development of hyperalgesia in both mice and rats . These findings suggest that inducible P35354 derived PGs are involved in central nociceptive processing , which resulted in hyperalgesic behavior following LPS administration and inhibition of P35354 or its expression attenuated LPS - induced hyperalgesia .", "Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .", "Single - walled carbon nanotubes ( SWCNTs ) enhance DB00761 - , acetylcholine - , and serotonin - induced contractions and evoke oxidative stress on rabbit ileum . We examined the effects of intravenous administration of purified arc - discharge single - walled carbon nanotubes ( SWCNTs ) on rabbit ileum to establish the possibility of using these SWCNTs as cell markers or drug carriers for the treatment of intestinal diseases . The SWCNT purification process eliminated carbonaceous impurities and decreased the amount of metals . SWCNTs increased the contractile responses induced by DB00761 , acetylcholine ( ACh ) , and serotonin ( 5 - HT ) in rabbit ileum . Verapamil , apamin , glibenclamide , quinine and charybdotoxin reduced the contractile responses induced by ACh and 5 - HT in ileum from rabbits treated with SWCNTs , indicating that voltage - dependent Ca2 + channels and small , intermediate , and large - conductance Ca ( 2 +)- activated , DB00171 - sensitive , and voltage - dependent K + channels are involved in these effects . Atropine and hexamethonium reduced the ACh response , indicating that muscarinic and nicotinic receptors are involved in this effect . ___MASK38___ and GR 113808 reduced the 5 - HT response , indicating that serotonin 5 - Q9H205 and Q13639 receptors are involved in this effect . SWCNTs increased the malondialdehyde plus 4 - hydroxyalkenals and carbonyl levels in rabbit plasma and ileum , indicating that SWCNTs produce oxidative stress . SWCNTs did not produce relevant histological changes or modify the levels of the inflammatory mediators P35228 and P35354 in the ileum . In conclusion , this study demonstrates that the intravenous administration of SWCNTs can evoke oxidative stress and affect contractility in rabbit ileum . These effects could reduce the possibility of using the arc - discharge SWCNTs as cell markers or drug carriers to treat intestinal diseases .", "Cyclooxygenase 2 inhibition exacerbates P41181 and pAQP2 downregulation independently of V2 receptor abundance in the postobstructed kidney . Previously we demonstrated that P03950 II receptor ( AT1R ) blockade attenuates V2 receptor ( P30518 ) , P41181 , and pS256 - P41181 downregulation in the postobstructed kidney and partially reverses obstruction - induced inhibition of DB02527 generation and cyclooxygenase 2 ( P35354 ) induction . Therefore , we speculated whether the effects of AT1R blockade on P30518 and the vasopressin - regulated pathway are attributable to attenuated P35354 induction . To examine this , rats were subjected to 24 - h bilateral ureteral obstruction ( BUO ) followed by 48 - h release and treated with the P35354 inhibitor parecoxib or saline . Control rats were sham - operated . DB08439 treatment significantly reduced urine output 24 h after release of BUO whereas urine osmolality and solute - free water reabsorption was comparable between saline - and parecoxib - treated BUO rats . Immunoblotting revealed a significant decrease in P41181 and pS256 - P41181 abundance to 20 and 23 % of sham levels in parecoxib - treated BUO rats compared with 40 and 55 % of sham levels in saline - treated BUO rats . Immunohistochemistry confirmed the exacerbated P41181 and pS256 - P41181 downregulation in parecoxib - treated BUO rats . Finally , parecoxib treatment had no effect on P30518 downregulation and the inhibited , vasopressin - stimulated DB02527 generation in inner medullary membrane fractions from the postobstructed kidney . In conclusion , P35354 inhibition exacerbates P41181 and pS256 - P41181 downregulation 48 h after release of 24 - h BUO independently of P30518 abundance and vasopressin - stimulated DB02527 generation . The results indicate that P35354 inhibition does not mimic AT1R blockade - mediated effects and that AT1R - mediated P41181 regulation in the postobstructed kidney collecting duct is independent of P35354 induction .", "DB08439 and indomethacin delay early fracture healing : a study in rats . Nonsteroidal antiinflammatory drugs ( NSAIDs ) are used to reduce inflammatory response and pain . These drugs have been reported to impair bone metabolism . DB08439 , a specific P35354 inhibitor , exerts an inhibitory effect on the mineralization of fracture callus after a tibial fracture in rats . Decreased bone mineral density ( BMD ) at a fracture site may indicate impairment of early healing , casting doubt on the safety of using P35354 inhibitors during the early treatment of diaphyseal fractures . Forty - two female Wistar rats were randomly allocated to three groups . They were given parecoxib , indomethacin , or saline intraperitoneally for 7 days after being subjected to a closed tibial fracture stabilized with an intramedullary nail . Two and 3 weeks after surgery , the bone density at the fracture site was measured using dual energy xray absorptiometry ( DEXA ) . Three weeks after the operation the rats were euthanized and the healing fractures were mechanically tested in three - point cantilever bending . DB08439 decreased BMD at the fracture site for 3 weeks after fracture , indomethacin for 2 weeks . Both parecoxib and indomethacin reduced the ultimate bending moment and the bending stiffness of the healing fractures after 3 weeks . These results suggest P36551 inhibitors should be avoided in the early phase after fractures .", "DB08439 inhibits apoptosis in acute myocardial infarction due to permanent coronary ligation but not due to ischemia - reperfusion . PURPOSE : Myocardial ischemia induces cyclooxygenase 2 ( P35354 ) expression . We evaluated the effects of parecoxib , a P35354 inhibitor , in 2 different mouse models of myocardial ischemia : permanent left coronary artery ligation ( PI ) and transient ligation ( 30 minutes ischemia ) followed by reperfusion ( I / R ) . METHODS : Forty adult male Institute of Cancer Research mice underwent PI ( n = 24 ) or I / R ( n = 16 ) , followed by randomization to parecoxib ( 0 . 75 mg / kg intraperitoneal daily ) or normal saline for 7 days . RESULTS : DB08439 significantly reduced apoptosis [ 0 . 8 % vs . 3 . 4 % ( saline ) , P < 0 . 001 ] and 7 - day mortality [ 0 % vs . 57 % ( saline ) , P = 0 . 040 ] in the PI group but showed no benefit in the I / R group . DB08439 - treated mice also exhibited greater fractional shortening in the PI group [ 22 % vs . 14 % ( saline ) , P = 0 . 045 ) but not in the I / R group . DB08439 did not affect infarct size in either group . CONCLUSIONS : P35354 may play a pivotal role in mediating apoptosis in the ischemic peri - infarct myocardium that is not reperfused after infarct .", "P35354 activity transiently contributes to increased water and NaCl excretion in the polyuric phase after release of ureteral obstruction . Release of bilateral ureteral obstruction ( BUO ) is associated with reduced expression of renal aquaporins ( AQPs ) , polyuria , and impairment of urine - concentrating capacity . Recently , we demonstrated that 24 h of BUO is associated with increased cyclooxygenase ( P36551 ) - 2 expression in the inner medulla ( IM ) and that selective P35354 inhibition prevents downregulation of P41181 . In the present study , we tested the hypothesis that P35354 activity increases in the postobstructive phase and that this increase in P35354 activity contributes to polyuria and impaired urine - concentrating capacity . We examined the effect of the selective P35354 inhibitor parecoxib ( 5 mg . kg (- 1 ). day (- 1 ) via osmotic minipumps ) on renal functions and protein abundance of P41181 , Q92482 , Na - K - 2Cl cotransporter type 2 ( Q13621 ) , and Na - K - ATPase 3 days after release of BUO . At 3 days after release of BUO , rats exhibited polyuria , dehydration and urine and IM tissue osmolality were decreased . There were inverse changes of P23219 and P35354 in the IM : P35354 mRNA , protein , and activity increased , while P23219 mRNA and protein decreased . DB08439 reduced urine output 1 day after release of BUO , but sodium excretion and glomerular filtration rate were unchanged . DB08439 normalized urinary PGE ( 2 ) and P06744 ( 2 ) excretion and attenuated downregulation of P41181 and Q92482 , while phosphorylated P41181 and Q13621 remained suppressed . DB08439 did not improve urine - concentrating capacity in response to 24 h of water deprivation . We conclude that decreased Q13621 and collapse of the IM osmotic gradient , together with suppressed phosphorylated P41181 , are likely causes for the impaired urine - concentrating capacity and that P35354 activity is not likely to mediate these changes in the chronic postobstructive phase after ureteral obstruction .", "Multiple antigenic polypeptide composed of heparanase B ‑ cell epitopes shrinks human hepatocellular carcinoma in mice . The purpose of this study was to evaluate the anti ‑ growth effect of the self ‑ designed multiple antigenic polypeptide ( Q96HU1 ) vaccine comprising B ‑ cell epitopes of heparanase ( Q9Y251 ) on HCC97 ‑ H hepatocellular carcinoma ( HCC ) in mice . The polyclonal antibodies against the B ‑ cell epitopes of Q9Y251 were prepared by immunizing rabbits with freshly synthesized Q96HU1 vaccine . HCC ‑ bearing models were constructed on BALB / c nude mice . Anti ‑ Q96HU1 antibodies were administrered to the models to assess the effects on Q9Y251 activity , HCC growth , the expression of P15692 / P09038 and the value of micro ‑ vessel density ( P53602 ) . The anti ‑ Q96HU1 antibodies were harvested , purified and identified . These antibodies were able to specifically bind with the dominant epitopes of the precursor protein and large subunit monomer of Q9Y251 , decrease Q9Y251 activity , suppress the expressions of P15692 and P09038 , reduce the P53602 , and markedly shrink the HCC volume . Based on these findings , Q96HU1 vaccine based on the B ‑ cell epitopes of Q9Y251 seemed to provide theoretical evidence for further study of the synthesized Q9Y251 Q96HU1 vaccine in the treatment of HCC .", "Elevated macrophage migration inhibitory factor and decreased transforming growth factor - beta levels in major depression -- no influence of celecoxib treatment . OBJECTIVES : The involvement of an immune process in the pathophysiology of major depression disorder ( MDD ) was substantiated by studies demonstrating elevated levels of proinflammatory cytokines and prostaglandin E ( 2 ) ( PGE ( 2 ) ) . P35354 ( P35354 ) inhibitors lead to a reduced production of PGE ( 2 ) and have been shown to improve depressive symptoms . We investigated the three immune parameters macrophage migration inhibitory factor ( MIF ) , transforming growth factor - β ( TGF - β ) and soluble P08571 ( sCD14 ) in a randomized , placebo - controlled trial of the P35354 inhibitor celecoxib as add - on therapy in patients with MDD treated with reboxetine . METHODS : Thirty - two patients with depression and 20 healthy controls participated in the study . The patients were treated with reboxetine and celecoxib or placebo . Immune parameters were measured from serum at baseline , after three and five weeks using ELISA . RESULTS : Celecoxib as add - on strategy resulted in a significant reduction of Hamilton Depression Scale scores compared to placebo . Depressed patients showed significantly elevated MIF ( p < 0 . 001 ) and reduced TGF - β ( p = 0 . 006 ) concentrations at baseline . There was no difference in sCD14 - concentrations . There was no difference between the placebo and the celecoxib group and no change over time . LIMITATIONS : Limitations of the study are the relatively small sample size and lack of functional assessment of Q9Y251 axis in parallel . CONCLUSIONS : MIF is a promising new candidate in the neuro - immune interplay that may link depressive symptoms , altered immune state and Q9Y251 - axis dysregulation . Reduced levels of TGF - β replicate previous findings and support the importance of this regulatory cytokine in major depressive disorder .", "Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .", "Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .", "Modulation of mucosal permeability by vasoactive intestinal peptide or lidocaine affects the adjustment of luminal hypotonicity in rat duodenum . AIMS : To examine whether modulation of paracellular solute permeability affects the capability of the duodenum to adjust luminal osmolality . METHODS : Proximal duodenum was perfused with a hypotonic NaCl solution and effects on paracellular permeability to ( 51 ) Cr - DB00974 , motility , anion secretion , net fluid flux and perfusate osmolality determined in anaesthetized rats in the absence and presence of the P35354 inhibitor parecoxib . Vasoactive intestinal peptide ( P01282 ) was used to reduce and lidocaine to augment the hypotonicity - induced increase in paracellular permeability . RESULTS : DB01174 hypotonicity slightly increased paracellular permeability in control animals . DB08439 induced motility , increased electrolyte and fluid secretion , potentiated the hypotonicity - induced rise in paracellular permeability and enhanced the capability to adjust luminal osmolality . P01282 , given to control animals stimulated electrolyte and fluid secretion and augmented the capability to adjust luminal osmolality . Administration of P01282 to parecoxib - treated animals increased secretion further , markedly reduced the hypotonicity - induced increase in permeability but did not change the osmolality - adjusting capability . DB01174 lidocaine potentiated the hypotonicity - induced increase in permeability , reduced the hypotonicity - induced net fluid absorption and the osmolality - adjusting capability was 50 % greater than in controls . DB00281 , given to parecoxib - treated animals potentiated the hypotonicity - induced increase in permeability , reduced the hypotonicity - induced net fluid absorption but did not change the osmolality - adjusting capability . CONCLUSIONS : Vasoactive intestinal peptide reduces the osmolality - adjusting capacity of the duodenum by inhibiting paracellular solute permeability but improves this capacity by stimulating active electrolyte and fluid secretion . In contrast , lidocaine improves the osmolality - adjusting capability by augmenting paracellular solute transport but depresses it by reducing the hypotonicity - induced net fluid absorption .", "P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK8___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .", "Ca2 +/ calmodulin effects on DB02527 response in cultured chick ciliary epithelial cells . The authors investigated the influence of the elevation of intracellular Ca2 + concentration on the production of cyclic adenosine 3 ', 5 '- monophosphate ( DB02527 ) using cultured chick embryo ciliary epithelium ( CE ) . We examined the effects of calcium ionophore ( A23187 ) on DB02527 production after incubation with vasoactive intestinal peptide ( P01282 ) , isoproterenol ( ISO ) , sodium fluoride ( NaF ) or forskolin ( FSK ) . A23187 had no effect on the basal DB02527 level , or the NaF - and FSK - stimulated responses for DB02527 level ; but A23187 potentiated P01282 - and ISO - stimulated DB02527 responses . P62158 antagonist ( W - 7 ) was very effective in inhibiting the potentiating effects of A23187 on P01282 and ISO - stimulated production of DB02527 . Our present findings suggested that Ca2 +/ calmodulin may potentiate the receptor - mediated DB02527 pathway through Ca2 +/ calmodulin - dependent protein kinase in the CE .", "Increased risk of cardiovascular events with parecoxib / valdecoxib : a systematic review and meta - analysis . OBJECTIVE : To determine the risk of serious cardiovascular events associated with the use of the P35354 inhibitor valdecoxib and its prodrug parecoxib following major surgery . METHODS : A systematic review and meta - analysis of placebo - controlled randomised double - blind clinical trials of IV parecoxib followed by oral valdecoxib treatment , that presented data on serious cardiovascular events . Studies were identified from six databases including Medline and the FDA website on parecoxib / valdecoxib . The main outcome measure was major cardiovascular events . The pooled fixed effects estimates for the odds ratio for risk of cardiovascular events for the use of parecoxib / valdecoxib were calculated using the inverse variance weighting method . RESULTS : Three studies with a total of 2 , 604 subjects were included in the meta - analysis . DB08439 / valdecoxib was associated with a significantly increased risk of major cardiovascular events , with an odds ratio of 2 . 3 ( 95 % CI : 1 . 1 - 4 . 7 ) . CONCLUSION : There is an increased cardiovascular risk associated with parecoxib / valdecoxib therapy in the post - surgical situation . These findings are consistent with a class effect for P35354 inhibitors increasing the risk of cardiovascular events .", "Preconditioning of intravenous parecoxib attenuates focal cerebral ischemia / reperfusion injury in rats . BACKGROUND : Several studies suggest that cyclooxygenase - 2 ( P35354 ) contributes to the delayed progression of ischemic brain damage . This study was designed to investigate whether P35354 inhibition with parecoxib reduces focal cerebral ischemia / reperfusion injury in rats . METHODS : Ninety male Sprague - Dawley rats were randomly assigned to three groups : the sham group , ischemia / reperfusion ( I / R ) group and parecoxib group . The parecoxib group received 4 mg / kg of parecoxib intravenously via the vena dorsalis penis 15 minutes before ischemia and again at 12 hours after ischemia . The neurological deficit scores ( NDSs ) were evaluated at 24 and 72 hours after reperfusion . The rats then were euthanized . Brains were removed and processed for hematoxylin and eosin staining , Nissl staining , and measurements of high mobility group Box 1 protein ( P09429 ) and tumor necrosis factor - α ( P01375 - α ) levels . Infarct volume was assessed with 2 , 3 , 5 - triphenyltetrazolium chloride ( TTC ) staining . RESULTS : The rats in the I / R group had lower NDSs ( P < 0 . 05 ) , larger infarct volume ( P < 0 . 05 ) , lower P09429 levels ( P < 0 . 05 ) , and higher P01375 - α levels ( P < 0 . 05 ) compared with those in the sham group . DB08439 administration significantly improved NDSs , reduced infarct volume , and decreased P09429 and P01375 - α levels ( P < 0 . 05 ) . CONCLUSIONS : Pretreatment with intravenous parecoxib was neuroprotective . Its effects may be associated with the attenuation of inflammatory reaction and the inhibition of inflammatory mediators .", "Evaluation of intravenous parecoxib for the relief of acute post - surgical pain . DB08439 is a prodrug of valdecoxib , which is a potent and selective inhibitor of P35354 . Intravenous preparation of parecoxib is in Phase III clinical trials for the management of acute and severe post - surgical pain . It is the only P35354 inhibitor that is available in a parenteral formulation . Clinical results compare parecoxib with ketorolac , a NSAID , which is the only non - narcotic analgesic available in parenteral formulation that can be administered for the relief of moderate to severe acute pain . Pharmacokinetic studies have shown that parecoxib is converted to valdecoxib within a short time following administration by im . or iv . injection . In clinical trials , parecoxib compares favourably with ketorolac and produces less gastric or duodenal ulcers , the predominant adverse effect , than ketorolac . DB08439 , thus , fulfils some of the desirable characteristics of an ideal non - narcotic analgesic for severe post - surgical pain and has application in other acutely painful conditions . DB08439 is expected to be filed for approval before the end of 2000 and is expected to be introduced in the market in 2001 . It has favourable prospects for a fair share of the post - surgical pain relief market which is valued at approximately US $ 1 billion for the year 2000 .", "A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re - vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly - developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically - used drugs operating on the P00797 - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point - of - no - return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling - reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy - steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy - associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization - induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling - reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .", "Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK70___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .", "The selective cyclooxygenase - 2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats . AIM : To examine whether the prevention of post - operative duodenal ileus by treatment with parecoxib , a selective cyclooxygenase - 2 ( P35354 ) inhibitor , affects the ability of the duodenum to respond to luminal hypertonicity . METHODS : The proximal duodenums of anaesthetized rats were perfused with hypertonic NaCl solutions with osmolalities of 400 , 500 , 600 or 700 mOsm kg (- 1 ) , and the effects on mucosal permeability , motility , transepithelial net fluid flux and effluent osmolality were assessed in the absence ( control ) and presence of parecoxib . RESULTS : DB08439 - treated , but not control animals , exhibited duodenal contractions , which were reduced by the nicotinic receptor antagonists mecamylamine and hexamethonium and by perfusion with 700 mOsm kg (- 1 ) . All animals responded to luminal hypertonicity with induction of net fluid secretion , which peaked at an osmolality of 500 mOsm kg (- 1 ) . The hypertonicity - induced increases in fluid secretion were twofold greater in parecoxib - treated than in control rats and attenuated by nicotinic receptor blockade . The decrease in luminal osmolality correlated with the osmolality of the perfusion solution in both control and parecoxib - treated animals but the osmolality - adjusting capability was markedly better in the latter group . Rats exposed to duodenal luminal distension responded to hypertonicity with a greater fluid secretion and a larger decrease in luminal osmolality than control rats . Perfusion with 700 mOsm kg (- 1 ) increased mucosal permeability in parecoxib - treated animals only , an effect abolished by nicotinic receptor blockade . CONCLUSION : DB08439 markedly improved the ability of the duodenum to sense and to decrease luminal hypertonicity by a mechanism most probably involving inhibition of P35354 and stimulation of nicotinic acetylcholine receptors .", "DB08439 vs . lornoxicam in the treatment of postoperative pain after laparoscopic cholecystectomy : a prospective randomized placebo - controlled trial . BACKGROUND AND OBJECTIVE : Non - steroidal anti - inflammatory drugs are considered as an effective treatment of postoperative pain after laparoscopic cholecystectomy . P35354 inhibitors are newer drugs having less adverse effects . Data supporting their efficacy postoperatively in comparison to older non - steroidal anti - inflammatory drugs are scarce . Our study is a prospective , randomized , double - blinded , placebo - controlled trial comparing the efficacy of lornoxicam vs . parecoxib for the management of pain after laparoscopic cholecystectomy . MATERIALS AND METHODS : We enrolled 76 patients , ASA I and II , scheduled for elective laparoscopic cholecystectomy . The patients were randomized to receive before induction parecoxib 40 mg i . v . , lornoxicam 8 mg i . v . or placebo . Pain at rest and on movement was assessed using a visual analogue scale at 0 , 6 , 12 h postoperatively . Total meperidine consumption and adverse effects were also recorded . RESULTS : At 12 h , visual analogue scale scores at rest and on movement were significantly lower with parecoxib and lornoxicam compared with control ( P = 0 . 047 ) . The percentage of patients needing meperidine and the average dose of meperidine administered was significantly lower with parecoxib and lornoxicam compared with control ( P < 0 . 001 and P = 0 . 018 ) . There was no difference between parecoxib and lornoxicam . One patient receiving lornoxicam vomited . CONCLUSIONS : DB08439 40 mg i . v . and lornoxicam 8 mg i . v . were equianalgesic and both were more efficacious than placebo for the management of pain after laparoscopic cholecystectomy .", "DB08439 reduces systemic inflammation and acute lung injury in burned animals with delayed fluid resuscitation . Burn injuries result in the release of proinflammatory mediators causing both local and systemic inflammation . Multiple organ dysfunctions secondary to systemic inflammation after severe burn contribute to adverse outcome , with the lungs being the first organ to fail . In this study , we evaluate the anti - inflammatory effects of DB08439 , a parenteral P35354 inhibitor , in a delayed fluid resuscitation burned rat model . Anaesthetized Sprague Dawley rats were inflicted with 45 % total body surface area full - thickness scald burns and subsequently subjected to delayed resuscitation with Hartmann ' s solution . DB08439 ( 0 . 1 , 1 . 0 , and 10 mg / kg ) was delivered intramuscularly 20 min after injury followed by 12 h interval and the rats were sacrificed at 6 h , 24 h , and 48 h . Burn rats developed elevated blood cytokines , transaminase , creatinine , and increased lung P05164 levels . Animals treated with 1 mg / kg DB08439 showed significantly reduced plasma level of CINC - 1 , P05231 , PGEM , and lung P05164 . Treatment of 1 mg / kg DB08439 is shown to mitigate systemic and lung inflammation without significantly affecting other organs . At present , no specific therapeutic agent is available to attenuate the systemic inflammatory response secondary to burn injury . The results suggest that DB08439 may have the potential to be used both as an analgesic and ameliorate the effects of lung injury following burn .", "DB08439 impairs early tendon repair but improves later remodeling . BACKGROUND : P35354 inhibitors inhibit bone repair . HYPOTHESIS : Cyclooxygenase inhibitors might also have a negative effect on early tendon repair , although a positive effect on late tendon repair previously has been shown . STUDY DESIGN : Controlled laboratory study . METHODS : Achilles tendon transection was performed on 80 rats . Sixty rats were given daily intramuscular injections of either parecoxib ( 6 . 4 mg / kg body weight ) or saline for the first 5 days after surgery and sacrificed either at 8 or 14 days . The remaining 20 rats were given intramuscular parecoxib or saline injections from day 6 until sacrifice at 14 days . RESULTS : At 8 days , early parecoxib treatment caused a 27 % decrease in force at failure ( P = . 007 ) , a 25 % decrease in maximum stress ( P = . 01 ) , and a 31 % decrease in energy uptake ( P = . 05 ) . Stiffness and transverse area were not significantly affected . At 14 days , early parecoxib treatment caused a decrease in stiffness ( P = . 004 ) . In contrast to early treatment , late parecoxib treatment caused a 16 % decrease in cross - sectional area ( P = . 03 ) and a 29 % increase in maximum stress ( P = . 04 ) . CONCLUSIONS : During early tendon repair , a cyclooxygenase - 2 inhibitor had a detrimental effect . During remodelling , however , inflammation appears to have a negative influence , and cyclooxygenase - 2 inhibitors might be of value . CLINICAL RELEVANCE : The results suggest that cyclooxygenase - 2 inhibitors should be used with care in the early period after tendon injury .", "Constitutive cyclo - oxygenase - 2 does not contribute to the development of human visceral pain hypersensitivity . BACKGROUND AND AIMS : Central sensitisation ( CS ) , contributes to the development and maintenance of gastrointestinal pain hypersensitivity . Constitutive cyclo - oxygenase - 2 ( P35354 ) contributes to central sensitisation in somatic pain hypersensitivity but its role in mediating visceral pain hypersensitivity is unknown . We therefore conducted a study to determine if P35354 inhibition with DB00580 attenuates the development or early maintenance of CS in a validated human oesophageal pain hypersensitivity model . METHODS : Healthy volunteers were studied in two randomised , double blind , crossover studies in which pain thresholds ( PT ) to electrical stimulation were assessed in the proximal oesophagus , chest wall and foot , prior to and following a distal oesophageal acid infusion . Protocol 1 : DB00580 , ( 40 mg ) or matching placebo was given orally for 4 days prior to oesophageal acid infusion . Protocol 2 : IV DB08439 ( 40 mg ) or saline was given 120 min after oesophageal acid infusion . RESULTS : DB00580 did not prevent the induction of secondary allodynia in the proximal oesophagus nor did it attenuate it following its establishment . Chest wall PT fell following oesophageal acid but foot PT remained unchanged ; highlighting the development viscero - somatic convergence due to CS . DB00580 had no analgesic or anti - hyperalgesic effect on chest wall or foot PT . CONCLUSIONS : Neither the induction nor initial maintenance of acid induced oesophageal pain hypersensitivity is prevented by DB00580 , suggesting that constitutive spinal P35354 does not contribute to the development or early maintenance of acute visceral central sensitisation .", "Delayed administration of parecoxib , a specific P35354 inhibitor , attenuated postischemic neuronal apoptosis by phosphorylation Akt and GSK - 3β . DB08439 is a recently described novel P35354 inhibitor whose functional significance and neuroprotective mechanisms remain elusive . Therefore , in this study , we aimed to investigate whether delayed administration of parecoxib inhibited mitochondria - mediated neuronal apoptosis induced by ischemic reperfusion injury via phosphorylating Akt and its downstream target protein , glycogen synthase kinase 3β ( GSK - 3β ) . Adult male Sprague - Dawley rats were administered parecoxib ( 10 or 30 mg kg (- 1 ) , IP ) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion ( MCAO ) for three consecutive days . Cerebral infarct volume , apoptotic neuron , caspase - 3 immunoreactivity and the protein expression of p - Akt , p - GSK - 3β and Cytochrome C in cerebral ischemic cortex were evaluated at 96 h after reperfusion . DB08439 significantly diminished infarct volume and attenuated neuron apoptosis in a dose - independent manner , compared with MCAO group alone . Increased p - Akt and p - GSK - 3β was observed in the ischemic penumbra of parecoxib group after stroke . Moreover , parecoxib also reduced the release of Cytochrome C from mitochondrial into cytosol and attenuated the caspase - 3 immunoreactivity in the penumbra . Taken together , these results suggested that parecoxib ameliorated postischemic mitochondria - mediated neuronal apoptosis induced by focal cerebral ischemia in rats and this neuroprotective potential is involved in phosphorylation of Akt and GSK - 3β .", "Single doses of parecoxib sodium intravenously are as effective as ketorolac in reducing pain after oral surgery . PURPOSE : Our goal was to compare the analgesic efficacy and safety of single doses of intravenous parecoxib sodium , a prodrug of the novel cyclooxygenase ( P36551 ) - 2 - selective inhibitor valdecoxib , with intravenous ketorolac and placebo in postoperative oral surgery patients . PATIENTS AND METHODS : Eligible patients experiencing moderate to severe pain within 6 hours of surgery to extract 2 or more impacted third molars were randomized to receive a single dose of parecoxib sodium 1 , 2 , 5 , 10 , 20 , 50 , or 100 mg ; ketorolac 30 mg ; or placebo . Analgesic efficacy was assessed over a 24 - hour treatment period or until rescue analgesia was required . RESULTS : DB08439 sodium doses ( particularly 50 and 100 mg ) had a rapid onset of analgesia ( within 11 minutes ) . The analgesic efficacy of parecoxib sodium 20 to 100 mg was similar to that of ketorolac 30 mg . DB08439 sodium doses below 20 mg had suboptimal analgesic activity compared with placebo and ketorolac . A plateau of efficacy was observed at the parecoxib sodium 50 - mg dose . DB08439 sodium 50 and 100 mg had a significantly longer duration of analgesia than ketorolac 30 mg . All doses of parecoxib sodium were well tolerated . CONCLUSIONS : DB08439 sodium , a novel parenteral prodrug of the P35354 - selective inhibitor valdecoxib , is as effective and longer acting at 50 - and 100 - mg intravenous doses than a standard dose of ketorolac 30 mg intravenously . DB08439 sodium appears to be safe and well tolerated and , therefore , merits further evaluation in other models of postsurgical pain .", "DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "The pharmacokinetics and in vitro / ex vivo cyclooxygenase selectivity of parecoxib and its active metabolite valdecoxib in cats . DB08439 ( PX ) is an injectable prodrug of valdecoxib ( VX , which is a selective cyclo - oxyganase - 2 ( P35354 ) ) inhibitor licensed for humans . The aim of the present study was to evaluate pharmacokinetics and in vitro / ex vivo cyclooxygenase selectivity of PX and VX in cats . In a whole blood in vitro study , PX did not affect either P36551 enzymes whereas VX revealed a P35354 selective inhibitory effect in feline whole blood . The IC50 values of VX for P35354 and P23219 were 0 . 45 and 38 . 6 µM , respectively . Six male cats were treated with 2 . 5 mg / kg of PX by intramuscular injection . PX was rapidly converted to VX with a relatively short half - life of 0 . 4 h . VX achieved peak plasma concentration ( 2 . 79 ± 1 . 59 µg / mL ) at 7 h following PX injection . The mean residence times for PX and VX were 0 . 43 ± 0 . 15 and 5 . 94 ± 0 . 88 h , respectively . In the ex vivo study , PX showed a P35354 inhibition rate of about 70 % in samples taken at 1 , 2 , 4 and 10 h after injection , with a significant difference compared to the control . In contrast , P23219 was slightly inhibited , ranging from 0 . 7 % to 9 . 7 % of the control inhibition rate without any significant difference for 24 h after PX administration . The preliminary findings of the present research appear promising and encourage further studies to investigate whether PX can be successfully used in feline medicine ." ]

[ "___MASK24___", "___MASK37___", "___MASK38___", "___MASK49___", "___MASK62___", "___MASK69___", "___MASK70___", "___MASK86___", "___MASK8___" ]

[ "Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK100___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK100___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK100___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .", "P15391 : A multifunctional immunological target molecule and its implications for Blineage acute lymphoblastic leukemia . Over the last 20 - 30 years P15391 has gained attention as a potential target in the therapy of B - cell malignancies . In particular , targeting P15391 with the bispecific T - cell engager ( BiTE ) antibody DB09052 and T - cells modified by chimeric antigen receptors ( CAR ) has shown promising efficacy in early phase clinical trials for adults and children with precursor B - cell ALL ( P03999 - ALL ) . This review will discuss the rationale behind targeting P15391 in P03999 - ALL and its potential importance in P03999 - ALL signaling pathways .", "T cells redirected to EphA2 for the immunotherapy of glioblastoma . Outcomes for patients with glioblastoma ( GBM ) remain poor despite aggressive multimodal therapy . Immunotherapy with genetically modified T cells expressing chimeric antigen receptors ( CARs ) targeting interleukin ( IL ) - 13Rα2 , epidermal growth factor receptor variant III ( EGFRvIII ) , or human epidermal growth factor receptor 2 ( P04626 ) has shown promise for the treatment of gliomas in preclinical models and in a clinical study ( IL - 13Rα2 ) . However , targeting IL - 13Rα2 and EGFRvIII is associated with the development of antigen loss variants , and there are safety concerns with targeting P04626 . Erythropoietin - producing hepatocellular carcinoma A2 ( EphA2 ) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype . To generate EphA2 - specific T cells , we constructed an EphA2 - specific CAR with a P10747 - ζ endodomain . EphA2 - specific T cells recognized EphA2 - positive glioma cells as judged by interferon - γ ( IFN - γ ) and P60568 production and tumor cell killing . In addition , EphA2 - specific T cells had potent activity against human glioma - initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays . Adoptive transfer of EphA2 - specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency ( SCID ) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells . Thus , EphA2 - specific T - cell immunotherapy may be a promising approach for the treatment of EphA2 - positive GBM .", "Enhancement of device performance of organic solar cells by an interfacial perylene derivative layer . We report that device performance of organic solar cells consisting of zinc phthalocyanine and fullerene ( C ( 60 ) ) can be enhanced by insertion of a perylene derivative interfacial layer between fullerene and bathocuproine ( P03999 ) exciton blocking layer ( EBL ) . The morphology of the P03999 is influenced by the underlying N , N '- dihexyl - perylene - 3 , 4 , 9 , 10 - bis ( dicarboximide ) ( PTCDI - P13671 ) , which promotes migration of the cathode metal into the P03999 layer . Insertion of a PTCDI - P13671 layer between fullerene and P03999 layers enhances the power conversion efficiency to 2 . 5 % , an improvement of 32 % over devices without PTCDI - P13671 layer . The enhancement in device performance by insertion of PTCDI - P13671 is attributed to a reduction in series resistance due to promoted metal migration into P03999 and optimized optical interference effects in multilayered devices .", "T cells stimulated by P29965 positive leukemic blasts - pulsed dendritic cells meet optimal functional requirements for adoptive T - cell therapy . Adoptive T - cell immunotherapy may provide complementary therapy for childhood B - cell precursor acute lymphoblastic leukemia ( P03999 - ALL ) . In this study , we have analyzed the functional characteristics of anti - P03999 - ALL effector T cells generated by co - culturing T lymphocytes and dendritic cells ( DC ) from allogeneic human stem cell transplantation ( HSCT ) donors . After 21 - day co - culture with DC pulsed with P29965 + apoptotic P03999 - ALL blasts , T cells presented with both effector and central memory phenotype , and showed high and specific cytotoxic activity against leukemic cells ( average lysis = 77 % ) , mostly mediated by CD8 + T cells . Noticeably , growth of P01730 T cells was maintained ( 45 % of total cells ) , which actively produced Th1 cytokines ( P01579 , P01375 , P60568 ) , but not P05112 , P05113 and P22301 . Anti - P03999 - ALL T cells expressed CD49d and P61073 ( implicated in the recruitment to bone marrow ) , and CD62L and P32248 ( involved in the migration to lymphoid organs ) . In accordance with this profile , T cells significantly migrated in response to the chemokines P48061 and Q99731 . In conclusion , stimulation of T cells with P29965 + P03999 - ALL cells - loaded DC not only elicited the generation of potent and specific anti - leukemic cytotoxic effectors , but also the differentiation of specific and functional Th - 1 P01730 lymphocytes . These effectors are fully equipped to reach leukemia - infiltrated tissues and have characteristics to support and orchestrate the anti - tumor immune - response .", "Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK49___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK49___ is also being investigated as part of triplet drug regimens . ___MASK49___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .", "Lessons learned from the irinotecan metabolic pathway . ___MASK76___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK76___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK76___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .", "___MASK50___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK50___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .", "___MASK84___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK84___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK84___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK84___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .", "Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 , Q9UHF0 , P01282 , NOS1 ) and receptors ( P25103 , P21452 , P29371 , P10721 ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 , P29371 , P10721 , and NOS1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS1 , P25103 , P29371 , and P10721 genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 , which showed the highest association .", "P04818 genotype - directed chemotherapy for patients with gastric and gastroesophageal junction cancers . BACKGROUND : Retrospective studies indicate associations between TSER ( thymidylate synthase enhancer region ) genotypes and clinical outcomes in patients receiving ___MASK100___ based chemotherapy , but well - controlled prospective validation has been lacking . METHODS : In this phase II study ( NCT00515216 registered through ClinicalTrials . gov , http :// clinicaltrials . gov / show / NCT00515216 ) , patients with \" good risk \" TSER genotypes ( at least one TSER * 2 allele ) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates ( ORR ) in patients with gastric and gastroesophageal junction ( GEJ ) cancers , compared with historical outcomes in unselected patients ( estimated 43 % ) . RESULTS : The ORR in genotype - selected patients was Q04695 % ( 9 partial responses out of 23 evaluable patients , 95 % CI , 22 . 2 to 59 . 2 ) , not achieving the primary objective of improving ORR . An encouraging disease control rate ( DCR , consisting of partial responses and stable diseases ) of 95 . 7 % was noted and patients with homozygous TSER * 2 genotype showed better tumor response . CONCLUSIONS : In this first prospective , multi - institutional study in patients with gastric or GEJ cancers , selecting patients with at least one TSER * 2 allele did not improve the ORR but led to an encouraging DCR . Further studies are needed to investigate the utility of selecting patients homozygous for the TSER * 2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers . TRIAL REGISTRATION : ClinicalTrials . gov NCT00515216 .", "JNK is involved in signal integration during costimulation of T lymphocytes . T lymphocyte activation and interleukin - 2 ( P60568 ) production require at least two signals , generated by phorbol ester ( TPA ) and Ca2 + ionophore or costimulation of the T cell receptor ( TCR ) and the P10747 auxiliary receptor . We investigated how these stimuli affect mitogen activated protein ( Q96HU1 ) kinases . Q8N1N2 activation of the Q96HU1 kinases that phosphorylate the Jun activation domain , P45983 and P45984 , required costimulation of T cells with either TPA and Ca2 + ionophore or antibodies to TCR and P10747 . Alone , each stimulus resulted in little or no activation . Similar to its effect on P60568 induction , cyclosporin A ( DB00091 ) inhibited the synergistic activation of JNK , and a competitive inhibitor of Jun phosphorylation by JNK inhibited P60568 promoter activation . By contrast , the Q96HU1 kinases P27361 and P28482 were fully activated by TPA or TCR stimulation and were not affected by Ca2 + , P10747 , or DB00091 . Hence , integration of signals that lead to T cell activation occurs at the level of JNK activation .", "Effect of oncostatin M on uridine diphosphate - 5 '- glucuronosyltransferase 1A1 through cross talk with constitutive androstane receptor . Hyperbilirubinemia remains a common condition in neonates . The constitutive androstane receptor ( CAR ) is an orphan nuclear receptor that has been shown to participate in the activation of the uridine diphosphate - 5 '- glucuronosyltransferase 1A1 ( P22309 ) gene , which plays an important role in bilirubin clearance . Oncostatin M ( P13725 ) , a member of the P05231 family , is involved in the maturation of fetal hepatocytes . We have demonstrated that low P13725 levels are a potential indicator of neonatal jaundice and the need for phototherapy . In this study we examined the effects of P13725 on CAR - mediated signaling to investigate its potential role in neonatal jaundice via the CAR - P22309 pathway . We observed that P13725 positively augmented the CAR and P22309 expressions and CAR - mediated signaling in vivo and in vitro , through cross talk between the nuclear CAR receptor and the plasma membrane P13725 receptor , via the MAPK cascade . These data suggest that P13725 might play a role in bilirubin metabolism via the CAR - P22309 pathway .", "Hypoxic / normoxic preconditioning increases endothelial differentiation potential of human bone marrow CD133 + cells . CD133 + cells are hemangioblasts that have capacity to generate into both hematopoietic and endothelial cells ( ECs ) . Hypoxia / normoxia has shown to be the regulator of the balance between stemness and differentiation . In this study we performed Agilent ' s whole human genome oligo microarray analysis and examined the differentiation potential of the bone - marrow - derived CD133 + cells after hypoxic / normoxic preconditioning of CD133 + cells . Results showed that there was no significant increase in erythroid colony forming unit ( CFU - E ) and CFU - granulocyte , erythrocyte , monocyte , and megakaryocyte formation with cells treated under hypoxia / normoxia . However , a significant increment of EC forming unit at 24 h ( 143 . 2 +/- 8 . 0 % ) compared to 0 h ( 100 +/- 11 . 4 % ) was observed in CFU - EC analysis . Reverse transcription - polymerase chain reaction and immunostaining analysis showed that the differentiated cells diminished hematopoietic stem cell surface markers and acquired the gene markers and functional phenotype of ECs . The transcriptome profile revealed a cluster of 232 downregulated and 498 upregulated genes in cells treated for 24 h under hypoxia . The upregulated genes include angiogenic genes , angiogenic growth factor genes , angiogenic cytokine and chemokine genes , as well as angiogenic - positive regulatory genes , including Q14512 , PDGFB , Q16663 , P48061 , P80162 , P05231 , P21246 , O14944 , P04626 , O95136 , P11487 , Q92913 , Q99988 , P05412 , L1CAM , Q02297 , P08138 , and PDGFB . On the other hand , angiogenesis inhibitors and related genes , including P29459 , P98177 , Q9NY15 , and P16035 , are downregulated . Taken together , hypoxic / normoxic preconditioning may lead to the differentiation of CD133 + cells toward endothelial lineage , which may improve the current clinical trial studies .", "The superiority of blood over electrolyte cardioplegia in prevention of supraventricular arrhythmias and conduction disturbances following open heart surgery . A total of 111 patients underwent open heart surgery during which myocardial preservation was provided by systemic hypothermia , topical cardiac cooling and cardioplegic solution ( blood cardioplegia or electrolyte cardioplegia ) . The purpose of this study was to determine if the use of the different types of cardioplegia correlated with the occurrence of postoperative supraventricular arrhythmias and conduction disturbances . These patients were retrospectively divided into two groups according to the difference in the infused cardioplegic solutions . The group receiving blood cardioplegia ( P03999 ) comprised 69 patients and the group receiving electrolyte cardioplegia ( P12724 ) had 42 patients . There were a longer ischemic time and bypass time in the P03999 group as compared with those of the P12724 group ( 68 . 4 +/- 36 . 1 minutes v . s . 50 . 7 +/- 37 . 0 minutes , p less than 0 . 01 ; 93 . 7 +/- 48 . 9 minutes v . s . 65 . 5 +/- Q04695 minutes , p less than 0 . 005 ) . However , the result shows a significantly lower incidence of supraventricular arrhythmias and conduction disturbances in the P03999 group ( 5 . 8 % ) as compared with the P12724 group ( 21 . 4 % ; p = 0 . 013 ) . There was no significant difference in incidence of supraventricular arrhythmias and conduction disturbances between the two groups when the ischemic time was less than 60 minutes ( 6 . 7 % v . s . 17 . 2 % , p greater than 0 . 05 ) . On the other hand , there was a significant difference between the two groups when the ischemic time was a significant difference between the two groups when the ischemic time was longer than 60 minutes ( 5 . 1 % v . s . 30 . 8 % , p = 0 . 01 ) . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Acute lymphoblastic leukemia with the phenotype of a putative B - cell / T - cell bipotential precursor . Biphenotypic acute leukemias ( BALs ) are uncommon . Most are of myeloid - B - cell or myeloid - T - cell lineage . We report herein a 70 - year - old man with an unusual acute leukemia where the blasts expressed both B - and T - lymphoid markers . He presented to us with an enlarging cutaneous tumor . The presenting peripheral blood and bone marrow aspirate showed 40 % and 90 % blasts , respectively , which were negative for the usual cytochemical stains . The flow cytometric analysis revealed that the blasts were positive for P15391 , P11836 , P20273 , cytoplasmic ( Cyt ) CD79a , CD10 , Cyt CD3 , P06127 , P09564 , P01730 , HLA - DR , TdT , and were negative for myeloid markers . According to the scoring system from the European Group for the Immunological Characterization of Acute Leukaemias ( EGIL ) , this case was an unequivocal B - cell / T - cell BAL . Conventional cytogenetic analysis revealed 46XY [ t ( 4 ; 11 )( q31 ; q13 ) , add ( 8 )( q24 ) , der ( 9 ) del ( 9 )( P38936 ) del ( 9 )( q32q34 ) , - 13 , + mar ] in all 25 metaphases analyzed . Fluorescence in situ hybridization ( Q5TCZ1 ) and polymerase chain reaction ( PCR ) for 11q23 rearrangements as well as t ( 9 ; 22 ) were negative . PCR for both TCR - gamma and IgH gene analyses revealed polyclonal rearrangements . We postulate that this case of BAL might have arisen from the putative common lymphoid progenitor cell .", "New antibody conjugates in cancer therapy . Targeting of radiation , drugs , and protein toxins to cancers selectively with monoclonal antibodies ( MAbs ) has been a topic of considerable interest and an area of continued development . Radioimmunotherapy ( RAIT ) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti - P11836 MAbs , as illustrated with the near 100 % overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti - P20273 MAb , 90Y - epratuzumab . The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors . Importantly , the advantages of combining RAIT with radiation sensitizers , with immunotherapy , or a drug conjugate targeting a different antigen are being studied clinically and preclinically . The area of drug - conjugated antibodies is progressing with encouraging data published for the trastuzumab - DM1 conjugate in a phase I clinical trial in P04626 - positive breast cancer . The Dock - and - Lock platform technology has contributed to the design and the evaluation of complex antibody - cytokine and antibody - toxin conjugates . This review describes the advances made in these areas , with illustrations taken from advances made in the authors ' institutions .", "P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK25___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .", "Involvement of Rho - kinase in tumor necrosis factor - alpha - induced interleukin - 6 release from P13671 glioma cells . P01375 ( P01375 ) - alpha stimulated interleukin ( IL ) - 6 release and induced the phosphorylation of myosin phosphatase targeting subunit ( MYPT ) - 1 , a Rho - kinase substrate . The P05231 release was significantly suppressed by Y - 27632 and fasudil , Rho - kinase inhibitors . Although IkappaB inhibitor suppressed the P01375 - induced P05231 release , the Rho - kinase inhibitors did not affect the P01375 - induced IkappaB phosphorylation . P01375 induced the phosphorylation of p38 mitogen - activated protein ( Q96HU1 ) kinase , stress - activated protein kinase ( SAPK ) / c - Jun N - terminal kinase ( JNK ) , and Q8TCB0 / Q8NFH3 Q96HU1 kinase . The P01375 - induced P05231 release was suppressed by SB203580 , a p38 MAPK inhibitor , or SP600125 , a SAPK / JNK inhibitor , but not by PD98059 , a Q96HU1 kinase / extracellular signal - regulated kinase kinase inhibitor . The Rho - kinase inhibitors attenuated the P01375 - induced phosphorylation of both p38 Q96HU1 kinase and SAPK / JNK . Rho - kinase , which has been used for the clinical treatment of cerebral vasospasms , may be involved in other central nervous system ( CNS ) disorders such as traumatic injury , stroke , neurodegenerative disease and neuropathic pain . P01375 , a proinflammatory cytokine that affects the CNS through cytokines , such as P05231 , release from neurons , astrocytes and microglia . Therefore , we investigated the involvement of Rho - kinase in the P01375 - induced P05231 release from rat P13671 glioma cells . These results strongly suggest that Rho - kinase regulates the P01375 - induced P05231 release at a point upstream from p38 MAPK and SAPK / JNK in P13671 glioma cells . Therefore , Rho - kinase inhibitor may be considered to be a new clinical candidate for the treatment of CNS disorders in addition to cerebral vasospasms .", "Tissue - specific up - regulation of P33681 - 1 expression and function during the course of murine relapsing experimental autoimmune encephalomyelitis . P33681 / P10747 - mediated costimulation is a promising target for therapeutic intervention in autoimmune diseases . However , studies addressing the differential functional roles of P33681 - 1 and P33681 - 2 in several autoimmune models have resulted in conflicting data , perhaps due to the temporal dynamics of P33681 - 1 and P33681 - 2 surface expression on different cell types and / or at different sites during an autoimmune response . We examined the temporal expression of P33681 costimulatory molecules in the CNS and in various lymphoid organs during the course of murine relapsing - remitting experimental autoimmune encephalomyelitis ( R - EAE ) . Following immunization of SJL mice with the immunodominant proteolipid protein epitope , PLP139 - 151 , surface expression of P33681 - 1 was up - regulated on B cells , T cells , and macrophages , relative to P33681 - 2 , on CNS - infiltrating cells and on splenocytes . Similar enhancement in splenic P33681 - 1 expression could be induced in SJL mice by the adoptive transfer of PLP139 - 151 - specific cells or by immunization with O75347 alone . These changes were not observed on lymph node cells , including those isolated from lymph nodes draining the immunization site , which maintained the predominant P33681 - 2 expression pattern seen in naive mice . These phenotypic expression patterns correlated with the functional predominance of P33681 - 1 in costimulating T cell activation when employing APCs from the spleen or CNS of mice with ongoing R - EAE , while P33681 - 2 remained functionally predominant on lymph node APCs . Variation of phenotypic expression and functional dominance of costimulatory molecule expression in different lymphoid compartments during an active inflammatory autoimmune response has important implications in immune regulation , autoimmune pathogenesis , and therapeutic strategies .", "A secreted low - molecular - weight protein from Helicobacter pylori induces cell - cycle arrest of T cells . BACKGROUND & AIMS : Although Helicobacter pylori is recognized by the human immune system , the bacteria are not eliminated and lead to a chronic inflammation of the gastric mucosa . METHODS : We investigated the interaction of H . pylori with human lymphocytes . T and B lymphocytes were isolated from H . pylori - infected patients and stimulated with anti - CD3 / P10747 or interleukin - 6 . RESULTS : Proliferation of lymphocytes was abolished on co - incubation with different H . pylori strains ( 1 - 5 bacteria / cell ) or with protein extracts of culture supernatants . Inhibition of proliferation was independent of known virulence factors . The factor is a protein or protein complex with an apparent molecular weight between 30 and 60 kilodaltons , clearly distinct from VacA . Although antigen - specific activation of T cells ( as shown by nuclear factor of activated T cells [ NFAT ] - activation , interferon - gamma production , and CD25 or Q07108 up - regulation ) remained intact , cell - cycle analysis showed that S - phase entry of T cells was inhibited completely by H . pylori . Consequently , stimulated T cells arrested in the P55008 phase of the cell cycle . Western blot analysis showed markedly reduced phosphorylation of the retinoblastoma protein ( P06400 ) , suggesting inhibition of P55008 cyclin - dependent kinase activity . In line with this , activities of cyclin D3 and cyclin E were down - regulated , and levels of the cyclin - dependent kinase inhibitor P46527 were increased . Mouse embryonic fibroblasts deficient in p27 showed a decrease in H . pylori - induced inhibition of cell proliferation , suggesting a central role for p27 in mediating H . pylori - induced P55008 arrest . CONCLUSIONS : Induction of cell - cycle arrest in lymphocytes may be of major significance for the chronic persistence of bacteria in the human stomach .", "Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK73___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK73___ .", "DB03843 - or adjuvant - induced peripheral inflammation increases neurokinin - 1 receptor gene expression in the mouse . Substance P ( SP ) has been widely studied as a mediator of nociception . The release of SP from primary afferent neurons is increased during nociception , and SP activates neurokinin - 1 ( NK - 1 ) receptors in the spinal cord and periphery . Nociception - evoked alterations in P25103 gene expression have been studied in rat models of persistent pain but have not been characterized in any murine models of peripheral inflammation . This study assessed behavioral responses and P25103 mRNA gene expression in mice receiving formalin or Freund ' s complete adjuvant ( O75347 ) as an inflammatory stimulus . Mechanical withdrawal thresholds were measured before injection of formalin or O75347 and hind paw licking / biting timed during the late - phase of the formalin response . Two and 24 hours after formalin or O75347 injection , mechanical withdrawal thresholds were measured and the mice euthanized . Solution hybridization - nuclease protection assays were used to quantify P25103 mRNA levels . Results demonstrated that inflamed hind paws were edematous , and the withdrawal thresholds of the inflamed hind paws were significantly lower after formalin or O75347 injection . Neurokinin - 1 receptor mRNA levels in the ipsilateral dorsal spinal cords of mice were higher at 24 h after formalin injection or 4 days after O75347 injection . These results confirm that mice are hyperalgesic at late time points after formalin or adjuvant injection when P25103 gene expression is elevated in the dorsal spinal cord . This supports the hypothesis that increased P25103 gene expression contributes to the development and maintenance of a hyperalgesic state .", "The p16 ( INK4A )/ P06400 pathway and telomerase activity define a subgroup of Ph + adult Acute Lymphoblastic Leukemia associated with inferior outcome . Adult Acute Lymphoblastic Leukemia ( ALL ) therapies have been improved by pediatric - like approaches . However , treatment failures and relapses are common and new markers are needed to identify patients with poor prognosis in prospective trials . The p16 ( INK4A )/ P11802 - 6 / P06400 pathway and telomerase activity , which are implicated in cell activation and aging , were analyzed to identify new prognostic markers . Proteins of the p16 ( INK4A )/ P11802 - 6 / P06400 pathway and telomerase activity were analyzed in 123 adult B - cell precursor ( P03999 ) ALL cases included in the GRAALL / GRAAPH trials . We found a significantly increased expression of p16 ( INK4A ) in P03999 - ALLs with Q03164 rearrangement . Telomerase activity was significantly lower in Philadelphia chromosome - negative / Q13422 - deleted ( P11274 - P00519 (-)/ Q13422 ( del ) ) cases compared to Philadelphia chromosome - positive ( P11274 - P00519 + ) P03999 - ALLs . In P11274 - P00519 + ALLs , high P11802 expression , phosphorylated P06400 ( p - P06400 ) and telomerase activity were significantly associated with a shorter disease - free survival ( DFS ) and event - free survival ( O43281 ) . Enhanced p16 ( INK4A ) expression was only related to a significantly shorter DFS . In vitro analyses of normal stimulated lymphocytes after short - and long - term cultures demonstrated that the observed protein variations of poor prognosis in P11274 - P00519 + ALLs may be related to cell activation but not to cell aging . For these patients , our findings argue for the development of therapeutic strategies including the addition of new lymphocyte activation inhibitors to current treatments .", "A recombinant immunotoxin engineered for increased stability by adding a disulfide bond has decreased immunogenicity . Recombinant immunotoxins ( RITs ) are anti - cancer agents that combine the Fv of an antibody against cancer cells with a protein toxin from bacteria or plants . Since RITs contain a non - human protein , immunogenicity can be an obstacle in their development . In this study , we have explored the hypothesis that increasing stability can reduce the immunogenicity of a Q92963 using HA22 - LR , which is composed of an anti - P20273 Fv fused to domain III of Pseudomonas exotoxin A . We introduced a disulfide bond into domain III by identifying and mutating two structurally adjacent residues to cysteines at sites suggested by computer modeling . This Q92963 , HA22 - LR - DB , displays a remarkable increase in thermal stability and an enhanced resistance to trypsin degradation . In addition , HA22 - LR - DB retains cytotoxic and anti - tumor activity , while exhibiting significantly lower immunogenicity in mice . This study demonstrates that it is possible to design mutations in a protein molecule that will increase the stability of the protein and thereby reduce its immunogenicity .", "Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine - directed therapy . DB09052 is a P15391 / CD3 - bispecific T - cell receptor - engaging ( BiTE ) antibody with efficacy in refractory B - precursor acute lymphoblastic leukemia . Some patients treated with blinatumomab and other T cell - activating therapies develop cytokine release syndrome ( CRS ) . We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T - cell receptor - activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis ( HLH ) . We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH . He became ill 36 hours into the infusion with fever , respiratory failure , and circulatory collapse . He developed hyperferritinemia , cytopenias , hypofibrinogenemia , and a cytokine profile diagnostic for HLH . The HLH continued to progress after discontinuation of blinatumomab ; however , he had rapid improvement after P05231 receptor - directed therapy with tocilizumab . Patients treated with T cell - activating therapies , including blinatumomab , should be monitored for HLH , and cytokine - directed therapy may be considered in cases of life - threatening CRS . This trial was registered at www . clinicaltrials . gov as # NCT00103285 .", "Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 . In an attempt to treat cancer patients with P04626 overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) ___MASK49___ ( Herceptin ) . An optimized CAR vector containing P10747 , 4 - 1BB , and CD3zeta signaling moieties was assembled in a gamma - retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR (+) in CD3 (+) cells and these cells demonstrated high - specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10 ( 10 ) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X - ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon - gamma ( P01579 ) , granulocyte macrophage - colony stimulating factor ( GM - P04141 ) , tumor necrosis factor - alpha ( P01375 ) , interleukin - 6 ( P05231 ) , and P22301 , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 on lung epithelial cells .", "Chemotherapeutic drugs and human tumor cells cytokine network . The ability of human tumor cell lines to produce various cytokines , chemokines , angiogenic and growth factors was investigated using Luminex multiplex technology . Media conditioned by tumor cells protected tumor cells from drug - induced apoptosis and stimulated tumor cell proliferation . Antibodies neutralizing P05231 , P10145 , P13500 and P13501 blocked this stimulation . Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of P05231 , P10145 , P13500 , P13501 , BFGF , G - P04141 and P15692 . This stimulation was associated with drug - induced activation of NF - kappaB , AP - 1 , P05549 , CREB , Q9BYW2 , P35610 - 1 , P35610 - 3 , P35610 - 5 and P39905 - 2 transcription factors and upregulation of P05231 , P10145 , P09038 , P04141 - 3 and P13501 gene expression . Treatment of tumor cells with doxorubicin and antibodies neutralizing DB00099 , P13500 or P13501 had higher inhibitory effects than each modality used alone . These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug - mediated destruction . Clinical studies showed that antibodies neutralizing P15692 ( DB00112 / DB00112 ) or blocking P04626 / neu signaling ( Herceptin / ___MASK49___ ) could increase the efficacy of chemotherapy , although these beneficial effects have been limited . It is possible that drug - stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy . In addition , numerous growth factors and chemokines share angiogenic and growth - stimulating properties , and thus reduction of a single factor is insufficient to completely block tumor growth . Thus , a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy .", "Phenotype , ultrastructure , and function of CD1 + DR + epidermal cells that express P16671 ( OKM5 ) in cutaneous T - cell lymphoma . This study investigated the phenotype and function of different antigen - presenting cells ( P25054 ) present within the epidermis of patients with cutaneous T - cell lymphoma ( CTCL ) . Involved epidermis of CTCL compared with uninvolved was found to contain increased numbers of CD1 + DR + P25054 . This population was heterogeneous and comprised both leucocytes of a novel CD1 + DR + P16671 ( OKM5 )+ phenotype and CD1 + DR + P16671 - indeterminate / Langerhans cells . The CD1 + DR + P16671 + leucocytes did not express TcR - 1 , P06127 , CD15 , or P20273 , and only a minor population expressed CD11 , demonstrating that they were neither T nor B cells , and did not belong to the major CD11 + ( OKM1 + ) blood monocyte population . Electron microscopy of purified P16671 + lesional epidermal cells ( EC ) demonstrated that they lacked Birbeck granules found on CD1 (+)- selected Langerhans cells , and most cells exhibited features of indeterminate cells or macrophages . The capacity of EC from involved epidermis to present alloantigens was found to be increased relative to uninvolved epidermis in all patients tested , and this capacity was critically dependent upon the presence of P08575 + DR + bone marrow - derived cells but not on the presence of P08575 - DR + keratinocytes . Positive selection using MoAb against CD1 and P16671 demonstrated that both cell populations exhibited the capacity to stimulate T cells . The results indicate that a novel antigen - presenting cell population with a unique phenotype is present within involved skin of patients with mycosis fungoides . These cells express P16671 in addition to CD1 and have an ultrastructural appearance consistent with a dendritic antigen - presenting cell derivation .", "Peptide - specific intercellular transfer of MHC class II to P01730 + T cells directly from the immunological synapse upon cellular dissociation . The transfer of membrane proteins from P25054 to T cells was initially described in the 1970s , and subsequent work has described two mechanisms of transfer : P25054 - derived exosomes and direct transfer of small packets , while cells remain conjugated . Using fibroblast P25054 expressing a GFP - tagged I - E ( k ) molecule with covalently attached antigenic peptide , we observed a third mechanism in live cell imaging : T cells spontaneously dissociating from P25054 often capture MHC : peptide complexes directly from the immunological synapse . Using two I - E ( k )- restricted murine TCR transgenic T cells with different peptide specificity , we show in this study that the MHC transfer is peptide specific . Using blocking Abs , we found that MHC : peptide transfer in this system requires direct TCR - MHC : peptide interactions and is augmented by costimulation through P10747 - P33681 interactions . Capture of the GFP - tagged MHC : peptide complexes correlates with an activated phenotype of the T cell , elevated Q07108 with down - modulated TCR . The transferred MHC : peptide molecules transferred to the T cell are associated with molecules that imply continued TCR signaling ; p56 ( lck ) , phosphotyrosine , and polarization of the actin cytoskeleton .", "The interaction of thymidylate synthase expression with p53 - regulated signaling pathways in tumor cells . P04818 ( TS ) is a chemotherapeutic target for the fluoropyrimidine 5 - fluorouracil ( ___MASK100___ ) and antifolate tomudex ( TDX ) . Using the MCF - 7 breast cancer line , we have developed a cell line with inducible TS expression termed M7TS90 . Inducible TS expression in this line resulted in a moderate ( approximately 3 - fold ) increase in ___MASK100___ 50 % inhibitory concentration at 72 hours ( IC - 50 ( 72 h ) ) dose and a dramatic ( approximately 24 - fold ) increase in the IC - 50 ( 72 h ) dose of TDX , but did not affect chemosensitivity to cisplatin , oxaliplatin , irinotecan , and paclitaxel . In the absence of drug treatment , inducible TS expression had no effect on expression of the p53 tumor suppressor gene . However , TS induction abrogated p53 , P38936 , Fas , and Bak induction in response to TDX , but not ___MASK100___ . Similarly , downregulation of Bcl - 2 was reversed by inducible TS expression in TDX , but not ___MASK100___ - treated cells . Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX , but not ___MASK100___ .", "Beta - caryophyllene is a dietary cannabinoid . The psychoactive cannabinoids from Cannabis sativa L . and the arachidonic acid - derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 ( CB ( 1 ) ) and CB ( 2 ) receptors . Although the CB ( 1 ) receptor is responsible for the psychomodulatory effects , activation of the CB ( 2 ) receptor is a potential therapeutic strategy for the treatment of inflammation , pain , atherosclerosis , and osteoporosis . Here , we report that the widespread plant volatile ( E ) - beta - caryophyllene [ ( E ) - P03999 ] selectively binds to the CB ( 2 ) receptor ( K ( i ) = 155 +/- 4 nM ) and that it is a functional CB ( 2 ) agonist . Intriguingly , ( E ) - P03999 is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis . Molecular docking simulations have identified a putative binding site of ( E ) - P03999 in the CB ( 2 ) receptor , showing ligand pi - pi stacking interactions with residues F117 and W258 . Upon binding to the CB ( 2 ) receptor , ( E ) - P03999 inhibits adenylate cylcase , leads to intracellular calcium transients and weakly activates the mitogen - activated kinases Erk1 / 2 and p38 in primary human monocytes . ( E ) - P03999 ( 500 nM ) inhibits lipopolysaccharide ( LPS ) - induced proinflammatory cytokine expression in peripheral blood and attenuates LPS - stimulated Erk1 / 2 and P45983 / 2 phosphorylation in monocytes . Furthermore , peroral ( E ) - P03999 at 5 mg / kg strongly reduces the carrageenan - induced inflammatory response in wild - type mice but not in mice lacking CB ( 2 ) receptors , providing evidence that this natural product exerts cannabimimetic effects in vivo . These results identify ( E ) - P03999 as a functional nonpsychoactive CB ( 2 ) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis .", "Immune homeostasis requires several biologic factors including glucocorticoid hormones . Immunological tolerance can be achieved by several mechanisms including suppressor cells , soluble factors , and neurohormonal mediators . On the cellular level , we isolated a population of CD8 + P10747 - T cells capable of inhibiting anti - CD3 mAb - induced proliferation of autologous peripheral blood mononuclear cells in an HLA - I nonrestricted manner via production of P01579 and P05231 . Interestingly , CD8 + P10747 - T cells from systemic lupus erythematosus patients with active disease do not display this inhibitory activity and show a marked imbalance between inhibitory ( P05231 ) and stimulatory ( IL - 12 ) cytokines . For soluble factors , we studied soluble HLA molecules ( sHLAs ) and double - stranded DNA ( ds - DNA ) . Soluble HLA - I ( sHLA - I ) molecules induce soluble P48023 ( sFasL ) secretion and trigger apoptosis in phytohemagglutin ( PHA ) - activated Fas + T cells . Double - stranded DNA binds to HLA - II molecules and inhibits HLA - II - mediated antigen presentation . On the neurohormonal side , we focused our attention on the immunological activity of corticosteroids ( CTSs ) . CTSs inhibit recirculation of P01730 + T cells , suppress the proliferation and immunological function of activated T cells , and induce apoptosis of activated lymphocytes . Taken together , these data suggest the presence of a complex network of immunoregulatory mechanisms in which CTSs play a strong role supporting their recognized efficacy in the treatment of inflammatory and immunological diseases .", "Clinically localised prostate cancer is microsatellite stable . OBJECTIVES : To determine the frequency of microsatellite instability ( MSI ) change with mono - , di - and tetranucleotide markers in clinically localized prostate cancer , and to correlate those markers with clinical and pathological variables . MATERIALS AND METHODS : Two forms of MSI have been described in human cancer : MSI typical of hereditary nonpolyposis colon cancer , defined with mono - and dinucleotide repeat MS ; and a second variety of MSI is best seen at selective tetranucleotide repeats , i . e . elevated microsatellite alterations at select tetranucleotides ( EMAST ) . Prostate specimens were taken from 50 patients . The MS analysis used the Bethesda consensus panel ( P03999 ) and four tetranucleotide loci shown to detect the presence of EMAST . RESULTS : All but four tumours were stable for the 14 loci investigated . There were two ( 4 % ) cases with adenomatous polyposis coli ( P25054 ) instability among the P03999 markers and the same instability rate ( 4 % ) amongst the EMAST markers . These four tumours were all unstable at one locus of the 10 markers of the P03999 that classified them as MS stable . CONCLUSIONS : The MSI related to a mismatch repair deficiency or to the EMAST does not seem to be important in prostate cancer in the early stages of the disease .", "The biological features and prognosis of breast cancer diagnosed during pregnancy : a case - control study . BACKGROUND : Breast cancer during pregnancy ( P03999 ) is relatively rare and is associated with controversies about its biology and prognosis . Hence , we designed a case - control study to examine tumor features and outcome in a series of P03999 patients diagnosed and treated in a single institution . MATERIAL AND METHODS : We identified 65 patients diagnosed with P03999 and for each ; we selected two non - pregnant breast cancer patients , who were matched for age , year of surgery , stage , and neoadjuvant chemotherapy . We then compared the differences in pathology , immunohistochemical features ( ER , PR , P04626 and ki - 67 ) , disease - free ( DFS ) and overall survival ( OS ) . RESULTS : We did not find any significant differences in tumor characteristics between the two groups . However , at a median follow - up of four years , P03999 patients had an inferior DFS ( HR 2 . 3 ; 95 % CI 1 . 3 - 4 . 2 ) , after adjustment for possible confounding covariates . No difference in OS was observed . However , upon restricting the analysis to patients who did not receive neoadjuvant chemotherapy , patients with P03999 had inferior OS as well ( HR 2 . 6 ; 95 % CI 1 . 0 - 6 . 5 ) . No association between induction of abortion and prognosis was observed . CONCLUSIONS : While we did not observe any differences in tumor features , P03999 patients have poorer prognosis compared to age and stage - matched control . Further studies should try to elucidate reasons for such poor outcome .", "Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK73___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK73___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .", "Immunophenotypic characterization of normal peripheral blood B lymphocyte by flow cytometry : reference for diagnosis of chronic B cell leukemia / lymphoma . To establish reference values of various immunophenotypic markers in B lymphocyte population in healthy Chinese adults and build background information for accurate interpretation of B cell immunophenotyping data in clinical practice , peripheral blood from 41 healthy adults were collected separately into test tubes containing DB00974 - K ( 2 ) and stored in room temperature no more than 24 hours before analysis . Whole blood lysis technique and multiparameter flow cytometry were applied to immunophenotype B cells gated on P15391 / SSC dot - plot . The results showed that P20273 , P11836 , CD62L , P25942 , P25063 , CD79b , CD79a , and FMC - 7 were almost positive in the circulating B cell population , whereas CD11a , P33681 , CD103 , CD10 , P29965 , CD54 , P48023 , P42081 , and CD95 were almost negative in the peripheral blood B lymphocytes . P05107 , P16070 , CD23 , P06127 , CD11c and P16150 were positive in different B cell subpopulations . 78 % of B cells were IgD positive and ratio kappa / lambda was 1 . 26 . The significance of all these markers in the differential diagnosis of lymphoproliferative diseases was discussed . The conclusion is that it is necessary to consider the qualitative and quantitative levels of expression of various markers in normal B cell population in order to accurately interpret the pathological immunophenotypic data in clinical practice . It is also important to note the immunotypic differences of B cells between Chinese and Western populations .", "Modulation of Q8IVT5 activity in Caenorhabditis elegans by Zn ions , P25116 kinase and PP2A phosphatase . Vulval differentiation in Caenorhabditis elegans is controlled by a conserved signal transduction pathway mediated by Ras and a kinase cascade that includes Raf , Mek and MAPK . Activation of this cascade is positively regulated by a number of proteins such as Q8IVT5 ( kinase suppressor of Ras ) , Q09428 - 8 / Q5T124 - 2 , Q09428 - 6 / PP2A - B and P05231 - 1 . We describe the functional characterization of sur - 7 and several genes that regulate signaling downstream of ras . We identified sur - 7 by isolating a mutation that suppresses an activated ras allele , and showed that Q09428 - 7 is a divergent member of the cation diffusion facilitator family of heavy metal ion transporters that is probably localized to the endoplosmic recticulum membrane and regulates cellular Zn ( 2 +) concentrations . Genetic double mutant analyses suggest that the Q09428 - 7 - mediated effect is not a general toxic response . Instead , Zn ( 2 +) ions target a specific step of the pathway , probably regulation of the scaffolding protein Q8IVT5 . Biochemical analysis in mammalian cells indicates that high Zn ( 2 +) concentration causes a dramatic increase of Q8IVT5 phosphorylation . Genetic analysis also indicates that PP2A phosphatase and P25116 kinase act downstream of Raf to positively and negatively regulate Q8IVT5 activity , respectively .", "Elevated CD3 + and CD8 + tumor - infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level . We characterized GBM patients ' tumor and systemic immune contexture with aim to reveal the mechanisms of immunological escape , their impact on patient outcome , and identify targets for immunotherapy . Increased CD3 (+) T - cell infiltration was associated with prolonged survival independent of age , P16455 promoter methylation and post - operative treatment that implies potential for immunotherapy for GBM . Several mechanisms of escape were identified : within the tumor microenvironment : induced CD8 (+) P10747 (-) Foxp3 (+) Tregs that may tolerize antigen presenting cells , elevated CD73 and P49961 ectonucleotidases that suppress T - cell function , and at the systemic level : elevated P22301 levels in serum , diminished helper T - cell counts , and upregulated inhibitory P16410 .", "P28702 polymorphisms do not explain functional differences in vitamins D and A response in Antineutrophil cytoplasmic antibody associated vasculitis patients . It has been suggested that the retinoid X receptor beta ( P28702 ) gene is a risk factor for Wegener ' s granulomatosis . We addressed if there is a functional difference in the response to retinoic acid ( RA ) and vitamin D in Antineutrophil cytoplasmic antibody ( ANCA ) associated systemic vasculitis ( AASV ) patients and if this was associated with P28702 genotypes . TNFalpha and P22301 production were measured in whole blood assay from AASV patients ( n = 51 ) and healthy controls ( HC , n = 67 ) . One micromolar of 1 , 25 -( OH )( 2 ) D3 , 9 - cis RA ( 9c - RA ) or all - trans RA ( ___MASK73___ ) was added to the assay . Genotyping was performed for exons 7 and 2 of the P28702 gene and for a microsatellite in vicinity of the P28702 gene . Lipopolysaccharide ( LPS ) mediated TNFalpha production and P22301 were significantly lower in patients . Addition of 1 , 25 -( OH )( 2 ) D3 , ___MASK73___ or 9c - RA , blunted TNFalpha production , more pronounced in patients . Although all three compounds inhibited P22301 production significantly in HC , only 1 , 25 -( OH )( 2 ) D3 was found to be effective in patients . Allele distribution of the P28702 microsatellite differed significantly between patients and HC . This was not found for the SNP in exons 2 and 7 . Genotype of the latter correlated with the ability of 1 , 25 -( OH )( 2 ) D3 and ___MASK73___ to inhibit P22301 production . We provide immunological evidence for a functional difference in vitamins D and A responsiveness in AASV patients . Since the inhibition of TNFalpha was more effective in patients , vitamin D supplementation might be an additional therapeutical approach .", "DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin - dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .", "A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK84___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .", "SLP - 76 is recruited to P20273 and dephosphorylated by Q15466 - 1 , thereby regulating B cell receptor - induced c - Jun N - terminal kinase activation . Despite the important role in the development and activation of T cells , NK cells , mast cells , and macrophages , the expression and function of SLP - 76 in B cells have been largely unknown . Here we demonstrate that SLP - 76 is expressed in all mouse B cell lines tested and in normal splenic B cells , and serves as an Q15466 - 1 substrate . Dephosphorylation of SLP - 76 by Q15466 - 1 inhibits its association with Nck , down - regulating c - Jun N - terminal kinase ( JNK ) activation and exerting a positive effect on apoptosis . Knockdown of SLP - 76 in WEHI - 231 cells by small interfering RNA attenuated JNK activation , but showed little effects on extracellular signal - regulated kinase ( P29323 ) or p38 activation . Although WEHI - 231 does not express linker for activation of T cells ( O43561 ) , SLP - 76 localizes in membrane fraction , which increases following B cell receptor ( P11274 ) cross - linking . Further analyses revealed that SLP - 76 complexed with Gads is associated with tyrosine - phosphorylated P20273 through the SH2 domains of SLP - 76 and Gads . Given that Q15466 - 1 binds to P20273 upon P11274 ligation , our findings suggest that dephosphorylation of SLP - 76 recruited to P20273 by Q15466 - 1 inhibits P11274 - induced JNK activation , dictating apoptosis .", "Chemoimmunotherapy in acute lymphoblastic leukemia . ALL blast cells express a variety of specific antigens e . g . P15391 , P11836 , P20273 , P20138 , and P31358 , which serve as targets for Monoclonal Antibodies ( MoAbs ) . So far , the most experience is available for anti - P11836 ( rituximab ) , which has been combined with chemotherapy for treatment of mature B - ALL / Burkitt ' s lymphoma . Studies with rituximab have also been completed in B - precursor ALL . Another antigen , P15391 , is of great interest due to a very high rate of expression in ALL . It can be targeted by a bispecific monoclonal antibody , DB09052 , directed against P15391 and CD3 . Smaller studies or case reports are also available for the anti P31358 antibody ( DB00087 ) , for anti P20273 ( DB04958 ) or anti P20138 ( Gemtuzumab ) . Available data demonstrate that MoAb therapy in ALL is a highly promising targeted treatment . However , several details for an optimal treatment approach e . g . the required level of antigen expression , timing , schedule , dosage and stage of disease still need to be defined .", "Influence of octacalcium phosphate coating on osteoinductive properties of biomaterials . In this study , we investigated the influence of octacalcium phosphate ( OCP ) coating on osteoinductive behaviour of the biomaterials . Porous titanium alloy ( Ti6Al4V ) , hydroxyapatite ( HA ) , biphasic calcium phosphate ( P03999 ) and polyethylene glyco terephtalate / polybuthylene terephtalate ( PEGT - P10721 ) copolymer , all uncoated and coated with biomimetically produced OCP , were implanted in back muscles of 10 goats for 6 and 12 weeks . Uncoated Ti6Al4Vand HA did not show any bone formation after intramuscular implantation . All OCP coated implants , except PEGT - P10721 , did induce bone in the soft tissue . The reason for the non - inductive behaviour of the copolymer is probably its softness , that makes it impossible to maintain its porous shape after implantation . Both uncoated and OCP coated P03999 induced bone . However , the amount of animals in which the bone was induced was higher in the coated P03999 implants in comparison to the uncoated ones . Osteoinductive potential of biomaterials is influenced by various material characteristics , such as chemical composition , crystallinity , macro - and microstructure . OCP coating has a positive effect on osteoinductivity of the biomaterials . The combination of the advantages of biomimetic coating method above traditional methods , and a good osteoinductivity of OCP coating that is produced by using this method , opens new possibilities for designing more advanced orthopaedic implants .", "Sphingomyelin - ceramide turnover in P10747 costimulatory signaling . When the P10747 membrane glycoprotein of T cells binds to its ligand , a signal is transmitted that is required for T cell receptor - induced proliferation and cytokine secretion : T cells are not stimulated by the P10747 signal alone . Ligation of P10747 initiated sphingomyelin hydrolysis and generated ceramide . Treatment of T cells with either exogenous sphingomyelinase or a cell - permeable ceramide analogue . P13671 - ceramide , mimicked the P10747 signal by inducing T cell proliferation and interleukin - 2 gene transcription . Stabilization of interleukin - 2 mRNA was also observed in P13671 - ceramide - treated cells . Thus , the sphingomyelin - ceramide pathway is a candidate for mediating the costimulatory signal .", "The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .", "Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .", "Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK31___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK31___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK31___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK31___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK31___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .", "DB09052 induces autologous T - cell killing of chronic lymphocytic leukemia cells . Chronic lymphocytic leukemia is an incurable B - cell malignancy that is associated with tumor cell - mediated T - cell dysfunction . It therefore represents a challenging disease for T - cell immunotherapeutics . The P15391 / CD3 bi - specific antibody construct blinatumomab ( AMG103 or MT103 ) has been tested clinically in non - Hodgkin ' s lymphoma and acute lymphoblastic leukemia but has not been assessed in chronic lymphocytic leukemia . We investigated whether blinatumomab could overcome T - cell dysfunction in chronic lymphocytic leukemia in vitro . DB09052 was tested on peripheral blood mononuclear cells from 28 patients ( treatment naïve and previously treated ) . T - cell activation and function , as well as cytotoxicity against leukemic tumor cells were measured . DB09052 induced T - cell activation , proliferation , cytokine secretion and granzyme B release in a manner similar to that occurring with stimulation with anti - CD3 / anti - P10747 beads . However , only blinatumomab was able to induce tumor cell death and this was found to require blinatumomab - mediated conjugate formation between T cells and tumor cells . Cytotoxicity of tumor cells was observed at very low T - cell : tumor cell ratios . A three - dimensional model based on confocal microscopy suggested that up to 11 tumor cells could cluster round each T cell . Importantly , blinatumomab induced cytotoxicity against tumor cells in samples from both treatment - naïve and treated patients , and in the presence of co - culture pro - survival signals . The potent cytotoxic action of blinatumomab on tumor cells appears to involve conjugation of T cells with tumor cells at both the activation and effector stages . The efficacy of blinatumomab in vitro suggests that the bi - specific antibody approach may be a powerful immunotherapeutic strategy in chronic lymphocytic leukemia .", "Physiologically Based Pharmacokinetic Model to Assess the Influence of DB09052 - Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity . DB09052 is a P15391 / CD3 bispecific T - cell engager ( BiTE ® ) antibody construct for treatment of leukemia . Transient elevation of cytokines ( interleukin ( IL ) - 6 , P22301 , interferon - gamma ( IFN - γ ) ) has been observed within the first 48 hours of continuous intravenous blinatumomab infusion . In human hepatocytes , blinatumomab showed no effect on cytochrome P450 ( CYP450 ) activities , whereas a cytokine cocktail showed suppression of P08684 , P05177 , and P11712 activities . We developed a physiologically based pharmacokinetic ( PBPK ) model to evaluate the effect of transient elevation of cytokines , particularly P05231 , on CYP450 suppression . The predicted suppression of hepatic CYP450 activities was < 30 % , and P05231 - mediated changes in exposure to sensitive substrates of P08684 , P05177 , and P11712 were < twofold and lasted < 1 week . Model verification indicated that P05231 was the key cytokine suppressing CYP450 activities ; the duration of cytokine elevation was a major determinant of magnitude of suppression . This study shows the utility of PBPK modeling for risk assessment of cytokine - mediated drug interactions .", "Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways . White adipose tissue is intimately involved in the regulation of immunity and inflammation . We reported that human mesenteric preadipocytes express the DB05875 ( SP ) - mediated neurokinin - 1 receptor ( P25103 ) , which signals proinflammatory responses . Here we tested the hypothesis that SP promotes proliferation and survival of human mesenteric preadipocytes and investigated responsible mechanism ( s ) . Preadipocytes were isolated from mesenteric fat biopsies during gastric bypass surgery . Proliferative and antiapoptotic responses were delineated in 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 5 -( 3 - carboxymethoxyphenyl )- 2 -( 4 - sulfophenyl )- 2H - tetrazolium ( MTS ) , bromodeoxyuridine ( BrdU ) , caspase - 3 , and TUNEL assays , as well as Western immunoanalysis . SP ( 10 (- 7 ) M ) increased MTS and proliferation ( BrdU ) and time dependently ( 15 - 30 min ) induced Akt , P01133 receptor , IGF receptor , integrin alphaVbeta3 , phosphatidylinositol 3 - kinase , and PKC - theta phosphorylation . Furthermore , pharmacological antagonism of Akt and PKC - theta activation significantly attenuated SP - induced preadipocyte proliferation . Exposure of preadipocytes to the proapoptotic P48023 ( P48023 , 100 microM ) resulted in nuclear DNA fragmentation ( TUNEL assay ) , as well as increased cleaved poly ( ADP - ribose ) polymerase , cleaved caspase - 7 , and caspase - 3 expression . Cotreatment with SP almost completely abolished these responses in a P25103 - dependent fashion . SP ( 10 (- 7 ) M ) also time dependently stimulated expression 4E binding protein 1 and phosphorylation of P08133 S6 kinase , which increased protein translation efficiency . SP increases preadipocyte viability , reduces apoptosis , and stimulates proliferation , possibly via cell cycle upregulation and increased protein translation efficiency . SP - induced proliferative and antiapoptotic pathways in fat depots may contribute to development of the creeping fat and inflammation characteristic of Crohn ' s disease .", "___MASK84___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .", "Associations between single nucleotide polymorphisms in cellular viral receptors and attachment factor - related genes and humoral immunity to rubella vaccination . BACKGROUND : Viral attachment and cell entry host factors are important for viral replication , pathogenesis , and the generation and sustenance of immune responses after infection and / or vaccination , and are plausible genetic regulators of vaccine - induced immunity . METHODS : Using a tag - SNP approach in candidate gene study , we assessed the role of selected cell surface receptor genes , attachment factor - related genes , along with other immune genes in the genetic control of immune response variations after live rubella vaccination in two independent study cohorts . RESULTS : Our analysis revealed evidence for multiple associations between genetic variants in the P15151 , Q92692 , Q9NNX6 / Q9NNX6 , P10826 , Q16653 , P05231 and other immune function - related genes and rubella - specific neutralizing antibodies after vaccination ( meta p - value < 0 . 05 ) . CONCLUSION : Our results indicate that multiple SNPs from genes involved in cell adhesion , viral attachment , and viral entry , as well as others in genes involved in signaling and / or immune response regulation , play a role in modulating humoral immune responses following live rubella vaccination .", "Monoclonal antibodies in acute lymphoblastic leukemia . With modern intensive combination polychemotherapy , the complete response ( CR ) rate in adults with acute lymphoblastic leukemia ( ALL ) is 80 % to 90 % , and the cure rate is 40 % to 50 % . Hence , there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy . ALL leukemic cells express several surface antigens amenable to target therapies , including P11836 , P20273 , and P15391 . Monoclonal antibodies target these leukemic surface antigens selectively and minimize off - target toxicity . When added to frontline chemotherapy , rituximab , an antibody directed against P11836 , increases cure rates of adults with Burkitt leukemia from 40 % to 80 % and those with pre - B ALL from 35 % to 50 % . Inotuzumab ozogamicin , a P20273 monoclonal antibody bound to calicheamicin , has resulted in marrow CR rates of 55 % and a median survival of 6 to 7 months when given to patients with refractory - relapsed ALL . DB09052 , a biallelic T cell engaging the CD3 - P15391 monoclonal antibody , also resulted in overall response rates of 40 % to 50 % and a median survival of 6 . 5 months in a similar refractory - relapsed population . Other promising monoclonal antibodies targeting P11836 ( ofatumumab and obinutuzumab ) or P15391 or P11836 and bound to different cytotoxins or immunotoxins are under development . Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation .", "Effect of matrine on the expression of DB05875 receptor and inflammatory cytokines production in human skin keratinocytes and fibroblasts . Matrine is a kind of alkaloid found in certain Sophora plants , which has been extensively used in China for the treatment of viral hepatitis , cancer , cardiac diseases and skin diseases ( such as atopic dermatitis and eczema ) . It also has been confirmed that DB05875 ( SP ) and its receptor ( neurokinin - 1 receptor , P25103 ) are involved in the pathogenesis of inflammatory skin disorders . So the present study was designed to investigate the effect of matrine on the expression of P25103 and cytokines production induced by SP in HaCaT cells ( a human epidermal keratinocyte cell line ) and dermal fibroblasts . In addition , cell viability was also evaluated . The results showed that matrine inhibited the expression of P25103 in HaCaT cells and fibroblasts . SP induced the production of interleukin ( IL ) - 1beta , P10145 , interferon ( IFN ) - gamma , and monocyte chemotactic protein ( MCP ) - 1 in both cell types . Matrine 5 - 100 microg / mL had little effect on cell viability . It inhibited SP - induced IL - 1beta , P10145 and P13500 production in HaCaT cells and fibroblasts , while it increased the production of P01579 in HaCaT cells . Both SP and matrine had no effect on the secretion of P05231 . These findings suggest that matrine may have potential treatment function on SP related cutaneous inflammation by inhibition of the expression of DB05875 receptor and regulation of the production of inflammatory cytokines .", "Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK28___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .", "DB00563 reduces inflammatory cell numbers , expression of monokines and of adhesion molecules in synovial tissue of patients with rheumatoid arthritis . DB00563 ( MTX ) is one of the most widely prescribed drugs in the treatment of rheumatoid arthritis ( RA ) . The mechanism by which MTX exerts its anti - rheumatic effect has not yet been defined . The aim of the present study was to investigate the effect of MTX treatment ( 7 . 5 - 15 mg / week ) on synovial tissue in RA . For this purpose , synovial biopsies were taken from 11 RA patients before and 16 weeks after initiation of MTX therapy . Immunohistochemistry was performed using monoclonal antibodies ( MAb ) specific for CD3 , P01730 , CD8 , P20273 , CD25 , P28907 , P34810 , MAb67 , Ki67 , interferon gamma ( P01579 ) , interleukin ( IL ) - 1alpha , IL - 1beta , tumour necrosis factor alpha ( P01375 ) , P16581 , P05362 and P19320 . All parameters for disease activity improved during the period of treatment . Immunohistochemical analysis revealed a statistically significant decrease in scores for CD3 , CD8 , P28907 , P34810 , Ki67 , IL - 1beta , P01375 and the adhesion molecules P16581 and P19320 . The observed decrease in synovial scores for inflammatory cells , monokines and adhesion molecules suggests that the anti - inflammatory effect of MTX is , in part , dependent on a reduction in monokine - inducible vascular adhesion molecules and subsequent reduction of cell traffic into joints .", "Current status of antibody therapy in ALL . Despite the significant advances in modern chemotherapy , it remains challenging to treat adult patients with acute lymphoblastic leukaemia ( ALL ) . The relapse rate remains high , and the outcome at the time of relapse is dismal . Antibody - based therapies have demonstrated promising results in this patient group . Variable mechanisms have been applied to target surface antigens ( P11836 [ also termed P11836 ] , P20273 , P31358 and P15391 ) that are commonly expressed on malignant leukaemia cells . In this review , we will focus on the clinical application of such therapies in adult ALL , including the naked antibodies : DB00073 , Ofatumumab , DB04958 and DB00087 ; the immunotoxins : BL22 and Combotox ; the immunoconjugates : inotuzumab and SAR 3419 ; as well as the Bi - specific T cell engaging ( BiTE ) - specific antibody , DB09052 .", "P05181 epigenetic regulation in chronic , low - level toluene exposure : Relationship with oxidative stress and smoking habit . BACKGROUND : P05181 is a versatile phase I drug - metabolizing enzyme responsible for the biotransformation of most volatile organic compounds , including toluene . Human toluene exposure increases P05181 mRNA and modifies its activity in leucocytes ; however , epigenetic implications of this interaction have not been investigated . GOAL : To determine promoter methylation of P05181 and other genes known to be affected by toluene exposure . METHODS : We obtained venous blood from 24 tannery workers exposed to toluene ( mean levels : 10 . 86 +/- 7mg / m ( 3 ) ) and 24 administrative workers ( reference group , mean levels 0 . 21 +/- 0 . 02mg / m ( 3 ) ) all of them from the city of León , Guanajuato , México . After DNA extraction and bisulfite treatment , we performed PCR - pyrosequencing in order to measure methylation levels at promoter region of 13 genes . RESULTS : In exposed group we found significant correlations between toluene airborne levels and P05181 promoter methylation ( r =-. 36 , p < 0 . 05 ) , as well as for P05231 promoter methylation levels ( r =. 44 , p < 0 . 05 ) . Moreover , P05181 promoter methylation levels where higher in toluene - exposed smokers compared to nonsmokers ( p = 0 . 009 ) . We also observed significant correlations for P05181 promoter methylation with P09211 and P00441 promoter methylation levels ( r =-. 37 , p < 0 . 05 and r =-. 34 , p < 0 . 05 respectively ) . CONCLUSION : These results highlight the importance of considering P05181 epigenetic modifications , as well as its interactions with other genes , as key factors for unraveling the sub cellular mechanisms of toxicity exerted by oxidative stress , which can initiate disease process in chronic , low - level toluene exposure . People co - exposed to toluene and tobacco smoke are in higher risk due to a possible P05181 repression .", "Similar ameliorating effects of benzomorphans and 5 - HT2 antagonists on drug - induced impairment of passive avoidance response in mice : comparison with acetylcholinesterase inhibitors . Mice were trained to avoid electric shocks by means of step - down type passive avoidance learning tasks , and memory retention was measured 24 h after the training session . Memory impairment ( amnesia ) was produced by administering either p - chloroamphetamine ( DB11245 ) , a serotonin ( 5 - HT ) releaser or scopolamine ( O60346 ) , a muscarinic cholinoceptor antagonist , 30 min prior to the training session . Benzomorphans , 5 - HT2 antagonists and acetylcholinesterase ( P22303 ) inhibitors were administered immediately after the training session . DB11245 - but not O60346 - induced amnesia was attenuated by the post - training administration of two benzomorphans , (+) N - allylnormetazocine ( (+) SKF - 10 , 047 ) and ( +/- ) pentazocine ( ( +/- ) PTZ ) . Similarly , DB11245 - induced amnesia was reversed by the post - training administration of 5 - HT2 antagonists , ritanserin ( Q92963 ) and mianserin ( Q16674 ) , but O60346 - induced amnesia was not . However , the P22303 inhibitors , tetrahydroaminoacridine ( ___MASK31___ ) and physostigmine ( PHY ) attenuated both DB11245 - and O60346 - induced amnesia when administered immediately after the training session . These results indicated that benzomorphans and 5 - HT2 antagonists have antiamnestic effects in mice , as do P22303 inhibitors . In addition , it is interesting that the patterns of ameliorating effect of benzomorphans were similar to those of 5 - HT2 antagonists , which differ from those of P22303 inhibitors ." ]

[ "___MASK100___", "___MASK25___", "___MASK28___", "___MASK31___", "___MASK49___", "___MASK50___", "___MASK73___", "___MASK76___", "___MASK84___" ]

[ "Polyamines and membrane transporters . In recent years , our understanding of the importance of membrane transporters ( MTs ) in the disposition of and response to drugs has increased significantly . MTs are proteins that regulate the transport of endogenous molecules and xenobiotics across the cell membrane . In mammals , two super - families have been identified : DB00171 - binding cassette ( DB01048 ) and solute carrier ( O00585 ) transporters . There is evidence that MTs might mediate polyamines ( PA ) transport . PA are ubiquitous polycations which are found in all living cells . In mammalian cells , three major PA are synthesised : putrescine , spermidine and spermine ; whilst the decarboxylated arginine ( agmatine ) is not produced by mammals but is synthesised by plants and bacteria . In addition , research in the PA field suggests that PA are transported into cells via a specific transporter , the polyamine transport system ( s ) ( Q03393 ) . Although the Q03393 has not been fully defined , there is evidence that some of the known MTs might be involved in PA transport . In this mini review , eight O00585 transporters will be reviewed and their potential to mediate PA transport in human cells discussed . These transporters are O15245 , O15244 , O75751 , Q96FL8 , P30825 , P08195 , SLC12A8A , and Q86VW1 . Preliminary data from our laboratory have revealed that O15245 might be involved in the PA uptake ; in addition to one member of ABC superfamily ( P08183 protein ) might also mediate the efflux of polyamine like molecules .", "A genomic insight into diversity among tribal and nontribal population groups of Manipur , India . Twenty autosomal markers , including linked markers at two gene markers , are used to understand the genomic similarity and diversity among three tribal ( Paite , Thadou , and Kom ) and one nontribal communities of Manipur ( Northeast India ) . Two of the markers ( P01730 and HB9 ) are monomorphic in Paite and one ( the P01730 marker ) in Kom . Data suggest the Meitei ( nontribal groups ) stand apart from the three tribal groups with respect to higher heterozygosity ( 0 . 366 ) and presence of the highest ancestor haplotypes of P14416 markers ( 0 . 228 ) ; this is also supported by principal co - ordinate analysis . These populations are found to be genomically closer to the Chinese population than to other Indian populations .", "[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK75___ GITS , Diaprel MR ) . One daily dose of ___MASK75___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .", "Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .", "D2 - dopamine receptor and alpha2 - adrenoreceptor - mediated analgesic response of quercetin . DB04216 , a bioflavonoid ( 100 - 300 mg / kg ) produced dose dependent increase in tail - flick latency , the analgesic effect being sensitive to reversal by naloxone ( 1 mg / kg ) . Prior treatment with haloperidol ( 1 mg / kg ) , D1 / D2 receptor antagonist haloperidol , sulpiride ( 50 mg / kg ) , a selective D2 receptor antagonist , yohimbine ( 5 mg / kg ) , a alpha2 - adrenoreceptor antagonist but not by P35240 23390 a , selective D1 receptor antagonist blocked this response . DB00714 ( 1 mg / kg ) a mixed D1 / D2 dopamine receptor agonist , and quinpirole ( 0 . 5 mg / kg ) , a selective D2 receptor agonist also produced antinociception , that was reversed by haloperidol ( 1 mg / kg ) , sulpiride ( 50 mg / kg ) , but not by yohimbine ( 5 mg / kg ) . The antinociceptive action of quercetin ( 200 mg / kg ) was potentiated by D2 agonist quinpirole ( 0 . 2 mg / kg ) . P21728 agonist SKF38393 ( 10 and 15 mg / kg ) failed to alter the antinociceptive effect of quercetin ( 200 mg / kg ) . DB04216 ( 200 mg / kg ) reversed reserpine ( 2 mg / kg - 4 hr ) induced hyperalgesia , which was reversed by sulpiride but not by yohimbine . Thus , a role of dopamine D2 and alpha2 - adrenoreceptors is postulated in the antinociceptive action of quercetin .", "Penile erection and yawning induced by P28335 receptor agonists in male rats : relationship with dopaminergic and oxytocinergic transmission . 1 -( 3 - Chlorophenyl ) piperazine ( m - CPP ) ( 0 . 1 - 4 mg / kg s . c . ) and N -( 3 - trifluoromethylphenyl )- piperazine ( TFMPP ) ( 0 . 5 - 4 mg / kg s . c . ) , P28335 receptor agonists , but not 8 - hydroxy - dipropylamino - tetralin ( 8 - OH - DPAT ) ( 0 . 1 and 0 . 2 mg / kg s . c . ) , a P08908 receptor agonist , induced penile erection and yawning with a U - inverted dose - response curve in male rats . The maximal effect was found with 0 . 5 mg / kg s . c . of m - CPP and with 1 mg / kg s . c . of TFMPP . The m - CPP ( 0 . 5 mg / kg s . c . ) and TFMPP ( 1 mg / kg s . c . ) responses were prevented by mianserin ( 0 . 2 mg / kg s . c . ) and by ritanserin ( 1 mg / kg s . c . ) given 15 min before m - CPP and TFMPP . In contrast , m - CPP - or TFMPP - induced penile erection and yawning were not antagonized by haloperidol ( 0 . 1 mg / kg s . c . ) or by [ d ( CH2 ) 5Tyr ( Me ) 2 , Orn8 ] vasotocin ( 5 micrograms i . c . v . ) . DB00714 - and oxytocin - induced penile erection , but not yawning , was also antagonized by mianserin and less effectively by ritanserin . The results suggest that P28335 receptor agonist - induced penile erection and yawning are not mediated by increased dopaminergic and / or oxytocinergic transmission , and raise the possibility that a neuronal dopamine - oxytocin - 5 - HT link is involved in the control of penile erection and not necessarily of yawning in male rats .", "The expression of the solute carriers Q14973 and O75051 - 1 is regulated by cholesterol in HepG2 cells . Drug disposition and response are greatly determined by the activities of drug - metabolizing enzymes and transporters . While the knowledge in terms of CYP enzymes and efflux ABC transporters ( such as P08183 , P - glycoprotein ) is quite extensive , influx transporters are increasingly being unveiled as key contributors to the process of drug disposition . There is little information on the regulation of these proteins in human cells , especially as regards the effect of endogenous compounds . In this study , we analysed the expression of P08684 and three uptake transporters Q14973 ( Q14973 ) , P46721 / P46721 ( P46721 ) and O75051 - 1 ( O15245 ) in HepG2 cells following treatment with cholesterol . While P08684 and P46721 expression was unaffected , cholesterol treatment led to increased levels of Q14973 and O75051 - 1 mRNAs . Alterations in the functional characteristics and / or expression levels of drug transporters in the liver may conceivably contribute to the variability in drug oral bioavailability often observed in the clinical settings .", "Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells . Sorting nexin 5 ( Q9Y5X3 ) belongs to the P20073 family , which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins , receptors , and transporters . Q9Y5X3 is important in the resensitization of the dopamine D1 - like receptor ( D1R ) . D1R is uncoupled from its effector proteins in hypertension and diabetes , and treatment of diabetes restores D1R function and insulin receptor ( IR ) expression . We tested the hypothesis that the D1R and Q9Y5X3 regulate IR by studying the expression , distribution , dynamics , and functional consequences of their interaction in human renal proximal tubule cells ( hRPTCs ) . D1R , Q9Y5X3 , and IR were expressed and colocalized in the brush border of RPTs . P01308 promoted the colocalization of Q9Y5X3 and IR at the perinuclear area of hRPTCs . Unlike Q9Y5X3 , the D1R colocalized and coimmunoprecipitated with IR , and this interaction was enhanced by insulin . To evaluate the role of Q9Y5X3 and D1R on IR signaling , we silenced via RNA interference the endogenous expression of Q9Y5X3 or the D1R gene P21728 in hRPTCs . We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B , which are crucial components of the IR signal transduction pathway . Our data indicate that Q9Y5X3 and D1R are necessary for normal IR expression and activity . It is conceivable that D1R and Q9Y5X3 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling .", "Enhancement and inhibition of apomorphine - induced sensitization in rats exposed to immobilization stress : relationship with adaptation to stress . Stress increases vulnerability to addiction while drugs of abuse impair coping responses and pre - dispose to depression . Pre - clinical research shows that stress exposure augments locomotor sensitization effects of drugs of abuse and impairs behavioral tolerance to repeated stress . The present study investigates relationship between behavioral tolerance to repeated immobilization stress and apomorphine - induced sensitization . DB00714 was injected either before exposure or after the termination of immobilization , daily for 5 days , to monitor drug - induced behavioral sensitization and tolerance in immobilization stress - induced anorexia . We find that apomorphine - induced sensitization is enhanced and tolerance to repeated immobilization is impaired if the drug is administered before exposure to stress episode . Conversely , apomorphine - induced sensitization is inhibited and adaptation to stress is facilitated if the drug is administered after the termination of stress episode . It shows that apomorphine , if experienced during stress , produces greater sensitization and impairs stress tolerance . Conversely , sensitization effects of apomorphine are blocked and tolerance to stress is facilitated in animals receiving drug after the termination of stress episode . It is suggested that additive effects of stress and apomorphine on mesocorticolimbic dopamine neurotransmission and P08908 influences on dopamine neurotransmission may have a role in the modulation of apomorphine sensitization and tolerance to repeated immobilization stress . The results may help develop potential pharmacotherapies when substance abuse / dependence disorder and depression occur together .", "Arsenic decreases antinociceptive activity of paracetamol : possible involvement of serotonergic and endocannabinoid receptors . We assessed whether repeated arsenic exposure can decrease paracetamol - mediated antinociception by modulating serotonergic and endocannabinoid pathways . Rats were preexposed to elemental arsenic ( 4ppm ) as sodium arsenite through drinking water for 28 days . Next day paracetamol ' s ( 400mg / kg , oral ) antinociceptive activity was assessed through formalin - induced nociception . Serotonin content and gene expression of P08908 , 5 - Q13049 and P21554 receptors were evaluated in brainstem and frontal cortex . Arsenic decreased paracetamol - mediated analgesia . DB00316 , but not arsenic , increased serotonin content in these regions . Arsenic attenuated paracetamol - mediated increase in serotonin level . DB00316 did not alter P08908 expression , but caused down - regulation of 5 - Q13049 and up - regulation of P21554 receptors . Arsenic down - regulated these receptors . However , paracetamol - mediated down - regulation of 5 - Q13049 was more pronounced . Arsenic did not modify paracetamol ' s effect on P08908 expression , but reduced paracetamol - mediated down - regulation of 5 - Q13049 and reversed up - regulation of P21554 receptors . Results suggest arsenic reduced paracetamol - induced analgesia possibly by interfering with pronociceptive 5 - Q13049 and antinociceptive P21554 receptors .", "Methamphetamine enhances HIV infection of macrophages . Epidemiological studies have demonstrated that the use of methamphetamine ( meth ) , a sympathomimetic stimulant , is particularly common among patients infected with HIV . However , there is a lack of direct evidence that meth promotes HIV infection of target cells . This study examined whether meth is able to enhance HIV infection of macrophages , the primary target site for the virus . Meth treatment resulted in a significant and dose - dependent increase of HIV reverse transcriptase activity in human blood monocyte - derived macrophages . P21728 antagonists ( SCH23390 and SKF83566 ) blocked this meth - mediated increase in the HIV infectivity of macrophages . Investigation of the underlying mechanisms of meth action showed that meth up - regulated the expression of the HIV entry co - receptor P51681 on macrophages . Additionally , meth inhibited the expression of endogenous interferon - alpha and signal transducer and activator of transcription - 1 in macrophages . These findings provide direct in vitro evidence to support the possibility that meth may function as a cofactor in the immunopathogenesis of HIV infection and may lead to the future development of innate immunity - based intervention for meth users with HIV infection .", "Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .", "P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK45___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .", "Dopamine - related genes and their relationships to monoamine metabolites in P04141 . Monoamine metabolite ( MM ) levels in lumbar cerebrospinal fluid ( P04141 ) are extensively used as indirect estimates of monoamine turnover in the brain . In this study we investigated genotypes for DNA polymorphisms in the D2 ( P14416 ) , D3 ( P35462 ) , and D4 ( P21917 ) dopamine receptor and tyrosine hydroxylase ( TH ) genes and their relationships to P04141 MM in healthy volunteers ( n = 66 ) . Concentrations of homovanillic acid ( HVA ) , 3 - methoxy - 4 - hydroxyphenylglycol ( MHPG ) , and 5 - hydroxyindoleacetic acid ( 5 - HIAA ) were corrected for back length , a confounding variable . Corrected MM levels were not related to age , gender , height , weight heredity , season or atmospheric pressure at sampling . Individuals with specific P14416 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations . P35462 homo - and heterozygotic genotypes had significantly different P04141 5 - HIAA levels . P21917 genotypes were not related to MM concentrations . The results suggest that specific P14416 , P35462 , and TH genotypes participate in the regulation of monoamine turnover in the central nervous system . Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in P04141 . The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain .", "Pharmacological Q9BWK5 mapping of age - associated changes in basal ganglia circuitry of awake rhesus monkeys . While the pathophysiological changes induced by the loss of dopamine innervation in the basal ganglia by Parkinson ' s disease ( PD ) are well studied , little is known about functional changes in the neural circuitry of this area during normal aging . Here we report the first survey of age - associated changes in the basal ganglia of behaviorally characterized , awake rhesus monkeys , using pharmacological Q9BWK5 to map responses to dopaminergic stimulation . DB00714 , a mixed D ( 1 )/ P14416 agonist , evoked little change in the substantia nigra ( SN ) of aged animals while significantly reducing activation in young adult monkeys . Compared to young animals , both apomorphine and DB01576 ( which increases synaptic dopamine levels ) significantly increased activation of the aged rhesus globus pallidus externa ( GPe ) . In addition , the aged animals showed decreased activity in the putamen in response to DB01576 administration . Although the responses in the SN and putamen of the aged monkeys differed from those in animal models of PD , the apomorphine - evoked activation of their GPe corresponded with apomorphine - induced increases in neuronal activity seen in Parkinson ' s patients and animal models . Given the major role of the GPe in regulating motor behavior , the altered responses in the aged GPe may contribute significantly to the motor slowing and movement dysfunctions characterizing advanced age .", "LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self - identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi - square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0 . 01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0 . 05 ) , and increased energy ( P < 0 . 001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 - gamma2 , P42898 , 5 - Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0 . 42 , P = 0 . 045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA - directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .", "Integrative gene network analysis provides novel regulatory relationships , genetic contributions and susceptible targets in autism spectrum disorders . Autism spectrum disorders ( ASDs ) are a group of diseases exhibiting impairment in social drive , communication / language skills and stereotyped behaviors . Though an increased number of candidate genes and molecular interactions have been identified by various approaches , the pathogenesis remains elusive . Based on clinical observations , data from accessible GWAS and expression datasets we identified ASDs gene candidates . Integrative gene network and a novel CNV - centric Node Network ( CNN ) analysis method highlighted ASDs - associated key elements and biological processes . Functional analysis identified neurological functions including synaptic cholinergic receptor ( CHRNA ) families , dopamine receptor ( P14416 ) , and correlations between social behavior and oxytocin related pathways . CNN analysis of genome - wide genetic and expression data identified inheritance - related clusters related to P60484 / Q92574 / Q06787 and mTor / PI3K regulation . Integrative analysis identified potential regulators of networks , specifically P01375 and beta - estradiol , suggesting a potential central role in ASDs . Our data provide information on potential disease mechanisms , and key regulators that may generate novel postulations , and diagnostic molecular biomarkers .", "2 ( 3H )- benzoxazolone and bioisosters as \" privileged scaffold \" in the design of pharmacological probes . The 2 ( 3H )- benzoxazolone heterocycle and its bioisosteric surrogates ( such as 2 ( 3H )- benzothiazolinone , benzoxazinone , etc . ) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template . These heterocycles and pyrocatechol have indeed similar pKa ' s , electronic charge distribution , and chemical reactivity . Therapeutic applications of this template are very broad , and range from analgesic anti - inflammatory compounds ( including P37231 antagonists ) to antipsychotic and neuroprotective anticonvulsant compounds . High affinity ligands have been obtained also for dopaminergic ( D2 and D4 ) , serotoninergic ( P08908 and P28223 ) , sigma - 1 and sigma - 2 receptors . Owing to the high number of positive hits encountered with this heterocycle and its congeners , 2 ( 3H )- benzoxazolone template certainly deserves the title of \" privileged scaffold \" in medicinal chemistry .", "Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with ___MASK85___ , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20 - week - old Zucker obese and 16 - week - old ZDF rats were treated with ___MASK85___ ( 25 mg / kg / day ) or Enalapril ( 20 mg / kg / day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75 - 175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with ___MASK85___ or Enalapril .", "PDGF - B signaling is important for murine cardiac development : its role in developing atrioventricular valves , coronaries , and cardiac innervation . We hypothesized that PDGF - B / P09619 - signaling is important in the cardiac contribution of epicardium - derived cells and cardiac neural crest , cell lineages crucial for heart development . We analyzed hearts of different embryonic stages of both Pdgf - b -/- and Pdgfr - beta -/- mouse embryos for structural aberrations with an established causal relation to defective contribution of these cell lineages . Immunohistochemical staining for alphaSMA , periostin , ephrinB2 , EphB4 , P35968 , Dll1 , and P13591 was performed on wild - type and knockout embryos . We observed that knockout embryos showed perimembranous and muscular ventricular septal defects , maldevelopment of the atrioventricular cushions and valves , impaired coronary arteriogenesis , and hypoplasia of the myocardium and cardiac nerves . The abnormalities correspond with models in which epicardial development is impaired and with neuronal neural crest - related innervation deficits . This implies a role for PDGF - B / P09619 - signaling specifically in the contribution of these cell lineages to cardiac development .", "Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .", "Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK10___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .", "Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK91___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK91___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK91___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .", "Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .", "[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .", "Dysregulation of gene expression in primary neuron models of Huntington ' s disease shows that polyglutamine - related effects on the striatal transcriptome may not be dependent on brain circuitry . Gene expression changes are a hallmark of the neuropathology of Huntington ' s disease ( HD ) , but the exact molecular mechanisms of this effect remain uncertain . Here , we report that in vitro models of disease comprised of primary striatal neurons expressing N - terminal fragments of mutant huntingtin ( via lentiviral gene delivery ) faithfully reproduce the gene expression changes seen in human HD . Neither viral infection nor unrelated ( enhanced green fluorescent protein ) transgene expression had a major effect on resultant RNA profiles . Expression of a wild - type fragment of huntingtin [ htt171 - 18Q ] also caused only a small number of RNA changes . The disease - related signal in htt171 - 82Q versus htt171 - 18Q comparisons was far greater , resulting in the differential detection of 20 % of all mRNA probe sets . Transcriptomic effects of mutated htt171 are time - and polyglutamine - length dependent and occur in parallel with other manifestations of polyglutamine toxicity over 4 - 8 weeks . Specific RNA changes in htt171 - 82Q - expressing striatal cells accurately recapitulated those observed in human HD caudate and included decreases in P01210 ( proenkephalin ) , P49798 ( regulator of G - protein signaling 4 ) , dopamine D ( 1 ) receptor ( P21728 ) , P14416 , P21554 ( cannabinoid CB ( 1 ) receptor ) , and Q9UD71 ( dopamine - and DB02527 - regulated phosphoprotein - 32 ; also known as Q9UD71 ) mRNAs . HD - related transcriptomic changes were also observed in primary neurons expressing a longer fragment of mutant huntingtin ( htt853 - 82Q ) . The gene expression changes observed in cultured striatal neurons are not secondary to abnormalities of neuronal firing or glutamatergic , dopaminergic , or brain - derived neurotrophic factor signaling , thereby demonstrating that HD - induced dysregulation of the striatal transcriptome might be attributed to intrinsic effects of mutant huntingtin .", "Indispensable functions of P00519 and PDGF receptor kinases in epithelial adherence of attaching / effacing pathogens under physiological conditions . Enteropathogenic Escherichia coli ( EPEC ) and Citrobacter rodentium are attaching - and - effacing ( A / E ) pathogens that cause intestinal inflammation and diarrhea . The bacteria adhere to the intestinal epithelium , destroy microvilli , and induce actin - filled membranous pedestals but do not invade the mucosa . Adherence leads to activation of several host cell kinases , including P06241 , n - P12931 , P07947 , P00519 , and ARG , phosphorylation of the bacterial translocated intimin receptor , and actin polymerization and pedestal formation in cultured cells . However , marked functional redundancy appears to exist between kinases , and their physiological importance in A / E pathogen infections has remained unclear . To address this question , we employed a novel dynamic in vitro infection model that mimics transient and short - term interactions in the intestinal tract . Screening of a kinase inhibitor library and RNA interference experiments in vitro revealed that P00519 and platelet - derived growth factor ( PDGF ) receptor ( P09619 ) kinases , as well as p38 Q96HU1 kinase , have unique , indispensable roles in early attachment of EPEC to epithelial cells under dynamic infection conditions . Studies with mutant EPEC showed that the attachment functions of P00519 and P09619 were independent of the intimin receptor but required bacterial bundle - forming pili . Furthermore , inhibition of P00519 and P09619 with imatinib protected against infection of mice with modest loads of C . rodentium , whereas the kinases were dispensable for high inocula or late after infection . These results indicate that P00519 and P09619 have indispensable roles in early A / E pathogen attachment to intestinal epithelial cells and for in vivo infection with limiting inocula but are not required for late intimate bacterial attachment or high inoculum infections .", "Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK42___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK42___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .", "Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .", "Inhibition of c - kit receptor tyrosine kinase activity by ___MASK62___ , a selective tyrosine kinase inhibitor . ___MASK62___ ( formerly known as CGP 57148B ) is a known inhibitor of the c - abl , bcr - abl , and platelet - derived growth - factor receptor ( P09619 ) tyrosine kinases . This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia . We sought to extend the activity profile of ___MASK62___ by testing its ability to inhibit the tyrosine kinase activity of c - kit , a receptor structurally similar to P09619 . We treated a c - kit expressing a human myeloid leukemia cell line , M - 07e , with ___MASK62___ before stimulation with Steel factor ( SLF ) . ___MASK62___ inhibited c - kit autophosphorylation , activation of mitogen - activated protein ( Q96HU1 ) kinase , and activation of Akt without altering total protein levels of c - kit , Q96HU1 kinase , or Akt . The concentration that produced 50 % inhibition for these effects was approximately 100 nmol / L . ___MASK62___ also significantly decreased SLF - dependent growth of M - 07e cells in a dose - dependent manner and blocked the antiapoptotic activity of SLF . In contrast , the compound had no effect on Q96HU1 kinase activation or cellular proliferation in response to granulocyte - macrophage colony - stimulating factor . We also tested the activity of ___MASK62___ in a human mast cell leukemia cell line ( HMC - 1 ) , which has an activated mutant form of c - kit . ___MASK62___ had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand - dependent activation of the wild - type receptor . These findings show that ___MASK62___ selectively inhibits c - kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival . This compound may be useful in treating cancers associated with increased c - kit kinase activity .", "Influence of P14416 and Q8NFD2 genotypes on apomorphine - induced growth hormone ( GH ) response in alcohol - dependent patients . BACKGROUND : D ( 2 ) receptor function can be assessed by growth hormone ( GH ) response to apomorphine . Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol - dependent subjects yielded inconsistent results . In this pilot study , we tested polymorphisms from the P14416 region for GH response to apomorphine challenge in more detail . METHODS : DB00714 challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence ; patients were genotyped for 11 polymorphisms including P14416 , Q8NFD2 , P13591 and Q9H892 . RESULTS : Associations ( p < 0 . 05 ) were found for Q8NFD2 ( rs11604671 , rs1800497 ) and P14416 ( rs6276 , rs1076560 ) , which are located on adjacent chromosomal positions . Consistent with PET studies suggesting a reduced D ( 2 ) receptor availability in patients carrying the Q8NFD2 rs1800497 T polymorphism ( formerly known as P14416 TaqI A1 ) we found a reduced GH response to apomorphine in those subjects . CONCLUSION : This has been the first study showing significant associations between apomorphine - induced GH response and SNPs in P14416 and Q8NFD2 in alcohol - dependent patients . In this respect , our preliminary results are in line with other reports which suggested that P14416 and Q8NFD2 polymorphisms influence D ( 2 ) receptor availability and signal transduction in the dopaminergic pathways . Small sample size in our study limits the generalizability of our results .", "Human enteroendocrine cell responses to infection with Chlamydia trachomatis : a microarray study . BACKGROUND : Enteroendocrine cells ( EEC ) are highly specialized cells producing signalling molecules vital to the normal functions of the gut . Recently , we showed altered protein distribution in Chlamydia infected EEC in vitro . The aim of this study was to perform a microarray analysis of the response pattern of EEC from both large and small bowel to infection in vitro , using Chlamydia trachomatis infection as a model . METHODS : TWO HUMAN EEC LINES : LCC - 18 , derived from a neuroendocrine colonic tumour , and CNDT - 2 , derived from a small intestinal carcinoid , were infected using cultured C . trachomatis serovar LGV II strain 434 ( ATCC VR - 902B ) . DB01053 was used to induce persistent infection . We used microarray analysis ( Affymetrix GeneChip ® ) for studying changes in gene expression at different stages of infection . RESULTS : Twenty - four hours after active and persistent infection , 66 and 411 genes in LCC - 18 and 68 and 170 genes in CNDT - 2 cells , respectively showed mean expression ratios > 2 - fold compared to non - infected cells . These genes encoded factors regulating apoptosis , cell differentiation , transcription regulation , cytokine activity , amine biosynthesis and vesicular transport . We found significant differences in gene transcription levels between persistently infected and non - infected cells in 10 genes coding for different solute carrier transporters ( O00585 ) and in 5 genes related to endocrine function ( Q9H0R8 , GRIP1 , P14416 , O00445 and O43581 ) . CONCLUSIONS : Infected EEC cells exhibit cell - type specific patterns related to vesicular transport , secretion and neurotransmitters . EEC play a pivotal role in regulation of gut motility and an impairment of enteroendocrine function can contribute to motility disorders .", "Post - synaptic P08908 receptor involvement in yawning and penile erections induced by apomorphine , physostigmine and mCPP in rats . DB00714 and mCPP induced yawning associated with penile erections in rats , whereas physostigmine induced only yawns . DB00714 - induced yawning and penile erections were antagonized by low doses of raclopride , whereas physostigmine - induced yawning and mCPP - induced effects were only partly inhibited at high doses of raclopride . DB00747 as well as clozapine antagonized yawning and penile erections induced by apomorphine , mCPP and physostigmine . Similarly , the P08908 agonists 8 - OH - DPAT and S 14506 inhibited yawning and penile erections induced by apomorphine , mCPP and physostigmine , and at similar doses induced lower lip retraction and hyperreactivity to handling . The beta / P08908 antagonist tertatolol reversed the inhibitory effects of 8 - OH - DPAT and S 14506 on drug - induced yawning and penile erections and increased apomorphine - and physostigmine - induced yawn frequency but not penile erection frequency . Like tertatolol , propranolol increased apomorphine - and physostigmine - induced yawn frequency , whereas ICI 118551 increased only physostigmine - induced yawning . 8 - OH - DPAT - and S 14506 - induced lower lip retraction and hyperreactivity to handling were also significantly antagonized by tertatolol . Finally , p - chlorophenylalanine pretreatment produced about 95 % depletion in 5 - HT in hypothalamus , hippocampus , striatum and frontal cortex and modified neither the responses of the inducing drugs nor the inhibitory effects of 8 - OH - DPAT and S 14506 on drug - induced yawning and penile erections . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK3___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .", "Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .", "Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .", "[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK62___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK62___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .", "Mobilization of Ph chromosome - negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate - induced complete cytogenetic remission . Imatinib mesylate ( IM , ___MASK62___ , Glivec ) can induce a high rate of complete cytogenetic response ( CCR ) in chronic myeloid leukaemia ( CML ) patients , although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction ( RT - PCR ) . It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant ( APBSCT ) . We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony - stimulating factor [ rHu - DB00099 ; 10 micro g / kg / d subcutaneously ( s . c . ) for at least 4 d ] alone , while continuing IM treatment . The median d 5 ( peak ) P28906 + count was 11 . 5 / microl ( range 0 - 108 / microl ) , and 43 / 58 ( 74 % ) patients underwent a median of two ( range 1 - 3 ) apheresis procedures . A median dose of 2 . 1 x 10 ( 6 )/ kg P28906 + cells ( range 0 . 1 - 6 . 5 x 10 ( 6 )/ kg ) was collected . Some 84 % of 31 collections analysed were negative for the Philadelphia ( Ph ) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue ( P11274 - P00519 ) translocation by cytogenetics or fluorescent in situ hybridization respectively . No toxicity was reported with the regimen . Overall , the target P28906 + dose ( 2 x 10 ( 6 )/ kg P28906 + ) was attained in 23 / 58 ( 40 % ) patients who entered the study . In summary , we have demonstrated that successful mobilization of Ph - P28906 + cells from IM - treated patients in CCR is possible using rHu - G - P04141 alone .", "DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "Lack of allelic association of dopamine D1 and D2 ( TaqIA ) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism . Our study tested the hypothesis of whether the sensitivity of central dopamine receptors corresponds to the genotypic constitution of DNA - polymorphisms of the dopamine D1 and D2 receptor ( P21728 , P14416 ) genes and is associated with poor treatment outcome . Therefore , 97 alcohol - dependent patients were assessed according to their sensitivity of central dopamine receptors ( apomorphine - induced secretion of growth hormone ) , clinical outcome during a 6 - month observation period , and genotypic constitution of the TaqIA restriction fragment length polymorphism ( RFLP ) at the P14416 locus and of the Bsp1286I RFLP at the P21728 locus . On the 1st day of detoxification , dopamine receptor hyposensitivity was found in treatment nonresponders , but not in responders . DB00714 - induced growth hormone release did not differ significantly in alcoholics with different genotypes of the P21728 and P14416 RFLPs . Neither did we find a significant allelic association with treatment response . Thus , we did not find evidence for a genetic determination of dopamine receptor hyposensitivity in alcoholics with poor treatment outcome .", "Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy . A number of candidate genes for lithium prophylactic efficacy have been proposed , some of them being also associated with a predisposition to bipolar illness . The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder , in relation to the putative role of these genes in the pathogenesis of this disorder . Some association with lithium prophylactic efficacy was found for the polymorphisms of P31645 , P21728 , P21964 , P23560 and P06241 genes , but not for 5HT2A , 5HT2C , P14416 , P35462 , P21917 , GSK - 3 , Q16620 , Q13224 and P14780 . Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed .", "Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .", "Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .", "P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .", "Activation of P21554 cannabinoid receptors impairs memory consolidation and hippocampal polysialylated neural cell adhesion molecule expression in contextual fear conditioning . We investigated the role of P21554 receptors in hippocampal - dependent memory consolidation mediated by polysialylated neural cell adhesion molecule ( PSA - P13591 ) during contextual fear conditioning ( Q15814 ) . The P21554 receptor agonist 3 -( 1 , 1 - dimethylheptyl )-(-)- 11 - hydroxy - Delta ( 8 )- tetrahydrocannabinol ( HU - 210 ) ( 0 . 1 mg / kg ) was given immediately after training during the memory consolidation phase , and freezing behavior was measured 24 h after conditioning . Administration of HU - 210 attenuated freezing behavior measured in Q15814 . Western blot analysis showed that Q15814 induced a decrease in the expression of P13591 - 180 , but did not change the level of P13591 - 140 and increased PSA - P13591 expression measured 24 h after training in the rat hippocampus . HU - 210 ( 0 . 1 mg / kg ) injection did not affect the reduction in P13591 - 180 levels induced by Q15814 , but it blocked the increase in PSA - P13591 expression . Since the dentate gyrus ( DG ) of the hippocampus is known to be involved in memory consolidation and expresses a high level of PSA - P13591 protein , we measured the effects of Q15814 and HU - 210 administration on PSA - P13591 - immunoreactive ( IR ) cells in the DG . Q15814 caused an increase in the number of PSA - P13591 - IR cells in the DG , but not K ( i )- 67 - or doublecortin ( O43602 ) - IR cells . This increase in PSA - P13591 - IR cells was abolished by HU - 210 injection . Administration of the P21554 receptor antagonist N -( piperidin - 1 - yl )- 5 -( 4 - iodophenyl )- 1 -( 2 , 4 - dichlorophenyl )- 4 - methyl - 1H - pyrazole - 3 - carboxamide ( AM - 251 ) ( 3 mg / kg immediately before HU - 210 ) inhibited the effects of HU - 210 on freezing behavior and PSA - P13591 expression in the DG . These results indicate that activation of P21554 receptors disturbs consolidation of fear memory in Q15814 , likely by affecting PSA - P13591 expression in the DG , which plays an important role in synaptic rearrangement during the formation of memory traces .", "DB00714 - induced aggressiveness and [ 3H ] citalopram binding after antidepressant treatment in rats . The effects of acute and repeated administration of antidepressive drugs on apomorphine - induced aggressive behavior and [ 3H ] citalopram binding were studied . In acute behavioral experiments with apomorphine pretreated ( 1 . 0 mg / kg , once daily ) animals , desipramine ( 10 mg / kg ) and clomipramine ( 10 mg / kg ) enhanced , buspirone ( 2 . 5 and 5 . 0 mg / kg ) completely blocked , but fluoxetine , amitriptyline , imipramine ( 10 mg / kg ) , and citalopram ( 10 and 20 mg / kg ) had no effect on the intensity of aggressive behavior . Repeated concomitant apomorphine ( 1 . 0 mg / kg ) and citalopram ( 10 mg / kg ) administration reduced the affinity ( Kd ) of the 5 - HT transporter binding sites in three brain regions . This finding was confirmed by an additional experiment as the effect of citalopram treatment . Repeated apomorphine ( 1 . 0 mg / kg ) or apomorphine ( 1 . 0 mg / kg ) plus desipramine ( 10 mg / kg ) treatment had no unidirectional effect on Kd , the maximal number of apparent binding sties ( Bmax ) was unchanged in all experiments . Our study indicates that the 5 - HT reuptake blockade has no major influence on the apomorphine - induced aggressive behavior , but the P08908 receptor subtype may be involved in the mediation of the aggressive behavior in this paradigm .", "Inhibition of Akt / P31749 by a P35354 inhibitor induces apoptosis in gastric cancer cells . BACKGROUND / AIM : Inhibition of cyclooxygenase - 2 has been proposed to be a potential mechanism for the chemoprevention of gastrointestinal tumors by nonsteroidal anti - inflammatory drugs . This study investigates the mechanisms by which the cyclooxygenase - 2 inhibitor SC236 induces apoptosis of gastric cancer cell lines and its downstream signaling pathway . METHODS : Two gastric cancer cell lines , AGS and MKN28 , were treated with SC236 and assessed for cell growth and apoptosis . The involvement of mitogen - activated protein kinase and Akt kinase / protein kinase B ( Akt / P31749 ) pathways and their downstream signalings were studied in the AGS cell line . RESULTS : SC236 treatment induced apoptosis in gastric cancer cells and caused activation of p38 and stress - activated protein kinase / jun kinase , but down - regulated Akt / P31749 . The specific p38 inhibitor SB203580 and the dominant - negative stress - activated protein kinase / jun kinase both failed , while the constitutively active form of Akt / P31749 was able to block SC236 - induced apoptosis . SC236 - induced apoptosis was coupled with release of cytochrome c and activation of caspases . CONCLUSION : One of the pathways involved in SC - 236 - induced apoptosis in gastric cancer cells is through downregulation of Akt and then release of cytochrome c .", "___MASK85___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK85___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .", "Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .", "Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK21___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .", "Cytokine - mediated modulation of MMPs and TIMPs in multipotential neural precursor cells . Recent studies have implicated the inflammatory process during experimental allergic encephalomyelitis ( EAE ) in triggering migration and differentiation of transplanted neural precursors cells ( NPCs ) into the inflamed white matter . The pro - inflammatory cytokines tumor necrosis factor ( P01375 ) - alpha and interferon ( IFN ) - gamma are key factors in the pathogenesis of brain inflammation in EAE and were shown to enhance NPCs migration in vitro . As cell migration is dependent on extracellular matrix remodeling , involving proteolytic enzyme members of the matrix metalloproteinase ( MMPs ) family , we characterized the profile of expression of MMPs and their endogenous inhibitors ( TIMPs ) in rat NPCs , and evaluated the effects of P01375 , P01579 and IFN - beta , a clinically proven modulator of brain inflammation , on the expression of these molecules . Newborn rat striatal NPCs were expanded in spheres as nestin + , PSA - P13591 + and Q99942 (-) cells , which can differentiate into astrocytes , oligodendrocytes and neurons . NPCs ' gelatinase activities of P08253 and P14780 , as determined by zymography , were increased by P01375 , and to a lesser extent by P01579 . Semi - quantitative RT - PCR indicated that P01375 also upregulated P14780 mRNA levels . IFN - beta suppressed the P01375 - induced levels of secreted P14780 and P08253 , while enhancing the expression of P01033 and P16035 mRNA . These results suggest that MMPs activity is induced in NPCs by pro - inflammatory cytokines to mobilize them for promoting reparative processes . IFN - beta , on the other hand , appears to have an anti - proteolytic influence that may attenuate such NPC - mediated repair processes .", "Role of monoamine oxidases in the exaggerated 5 - hydroxytryptamine - induced tension development of human isolated preeclamptic umbilical artery . We investigated the role ( s ) of monoamine oxidases ( MAOs ) on the altered 5 - hydroxytryptamine ( 5 - HT , serotonin ) - induced tension development of the isolated umbilical artery of preeclamptic pregnancy of Chinese women . An enhanced 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy was observed when compared with that of normal pregnancy . The enhanced component of 5 - HT - induced tension development was eradicated by clorgyline ( a P21397 inhibitor ) . Blockade of P29474 ( endothelial isoform nitric oxide synthase ) ( N ( omega )- nitro - L - arginine methyl ester ) , 5 - HT transporter ( citalopram ) , 5 - HT receptor subtypes ( 5HT2B , SB 204741 ; P28335 , RS 102221 ; P34969 , SB 269970 ) , and endothelium denudation of the umbilical artery of normal pregnancy mimicked the enhanced 5 - HT - induced tension development as observed in the preeclamptic tissues . In contrast , no apparent changes in 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy were observed with the same pharmacological manipulations . A decreased protein expression levels of P21397 and P29474 ( no P35228 and P27338 expression was detected ) and no change in caveolin - 1 and 5 - HT transporter expression were demonstrated in the umbilical artery ( endothelium intact ) lysate of preeclamptic pregnancy , compared to that of the umbilical artery of normal pregnancy . Thus , in the umbilical artery of preeclamptic pregnancy , a decrease of P21397 and P29474 protein expression levels are probably associated with , or responsible for , the exaggerated 5 - HT - induced tension development .", "Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain . We previously demonstrated that chemokine receptors are expressed by neural progenitors grown as cultured neurospheres . To examine the significance of these findings for neural progenitor function in vivo , we investigated whether chemokine receptors were expressed by cells having the characteristics of neural progenitors in neurogenic regions of the postnatal brain . Using in situ hybridization we demonstrated the expression of P32246 , P41597 , P51681 , P49682 , and P61073 chemokine receptors by cells in the dentate gyrus ( DG ) , subventricular zone of the lateral ventricle , and olfactory bulb . The pattern of expression for all of these receptors was similar , including regions where neural progenitors normally reside . In addition , we attempted to colocalize chemokine receptors with markers for neural progenitors . In order to do this we used nestin - EGFP and TLX - LacZ transgenic mice , as well as labeling for Ki67 , a marker for dividing cells . In all three areas of the brain we demonstrated colocalization of chemokine receptors with these three markers in populations of cells . Expression of chemokine receptors by neural progenitors was further confirmed using P61073 - EGFP BAC transgenic mice . Expression of P61073 in the DG included cells that expressed nestin and P14136 as well as cells that appeared to be immature granule neurons expressing PSA - P13591 , calretinin , and Prox - 1 . P61073 - expressing cells in the DG were found in close proximity to immature granule neurons that expressed the chemokine P48061 / P48061 . Cells expressing P61073 frequently coexpressed P41597 receptors . These data support the hypothesis that chemokine receptors are important in regulating the migration of progenitor cells in postnatal brain .", "Presynaptic serotonergic inhibition of GABAergic synaptic transmission in mechanically dissociated rat basolateral amygdala neurons . 1 . The basolateral amygdala ( P00519 ) nuclei contribute to the process of anxiety . GABAergic transmission is critical in these nuclei and serotonergic inputs from dorsal raphe nuclei also significantly regulate GABA release . In mechanically dissociated rat P00519 neurons , spontaneous miniature inhibitory postsynaptic currents ( mIPSCs ) arising from attached GABAergic presynaptic nerve terminals were recorded with the nystatin - perforated patch method and pharmacological isolation . 2 . 5 - HT reversibly reduced the GABAergic mIPSC frequency without affecting the mean amplitude . The serotonergic effect was mimicked by the P08908 specific agonist 8 - OH DPAT ( 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ) and blocked by the P08908 antagonist spiperone . 3 . The GTP - binding protein inhibitor N - ethylmaleimide removed the serotonergic inhibition of mIPSC frequency . In either K +- free or Ca2 +- free external solution , 5 - HT could inhibit mIPSC frequency . 4 . High K + stimulation increased mIPSC frequency and 8 - OH DPAT inhibited this increase even in the presence of Cd2 + . 5 . DB02587 , an activator of adenylyl cyclase ( AC ) , significantly increased synaptic GABA release frequency . Pretreatment with forskolin prevented the serotonergic inhibition of mIPSC frequency in both the standard and high K + external solution . 6 . Ruthenium Red ( RR ) , an agent facilitating the secretory process in a Ca2 +- independent manner , increased synaptic GABA release . 5 - HT also suppressed RR - facilitated mIPSC frequency . 7 . We conclude that 5 - HT inhibits GABAergic mIPSCs by inactivating the AC - DB02527 signal transduction pathway via a G - protein - coupled P08908 receptor and this intracellular pathway directly acts on the GABA - releasing process independent of K + and Ca2 + channels in the presynaptic nerve terminals .", "Systematic meta - analyses and field synopsis of genetic association studies in schizophrenia : the SzGene database . In an effort to pinpoint potential genetic risk factors for schizophrenia , research groups worldwide have published over 1 , 000 genetic association studies with largely inconsistent results . To facilitate the interpretation of these findings , we have created a regularly updated online database of all published genetic association studies for schizophrenia ( ' SzGene ' ) . For all polymorphisms having genotype data available in at least four independent case - control samples , we systematically carried out random - effects meta - analyses using allelic contrasts . Across 118 meta - analyses , a total of 24 genetic variants in 16 different genes ( P02649 , P21964 , DAO , P21728 , P14416 , P21917 , Q96EV8 , P47870 , Q13224 , HP , P01584 , P42898 , O75051 , P31645 , P04637 and P17752 ) showed nominally significant effects with average summary odds ratios of approximately 1 . 23 . Seven of these variants had not been previously meta - analyzed . According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies , four of the significant results can be characterized as showing ' strong ' epidemiological credibility . Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia . As such , it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders ." ]

[ "___MASK10___", "___MASK21___", "___MASK3___", "___MASK42___", "___MASK45___", "___MASK62___", "___MASK75___", "___MASK85___", "___MASK91___" ]

[ "___MASK11___ . A preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia . ___MASK11___ is the first of a new class of cholesterol lowering drugs that competitively inhibit P04035 . This new drug decreases cholesterol synthesis and apolipoprotein B concentrations , and increases P01130 activity without adverse effects on other products in the cholesterol pathway . In patients with heterozygous familial or polygenic ( non - familial ) hypercholesterolaemia , oral lovastatin 20 to 40 mg twice daily reduces plasma total cholesterol and LDL - cholesterol concentrations by 25 to 40 % over a period of several weeks . ___MASK11___ also produces decreases in plasma triglyceride and VLDL - cholesterol concentrations , although to a lesser extent . In addition , small though significant increases in HDL - cholesterol concentrations have been observed . Combined administration of lovastatin with other lipid - lowering drugs results in further reductions in plasma total and LDL - cholesterol concentrations beyond those seen with either drug alone . From findings in short term studies , lovastatin appears to be well tolerated with a low incidence of side effects . However , liver function tests and eye examinations for possible lens opacities are advised , and further long term studies in larger groups of patients are necessary before the side effect profile of lovastatin will be clearly established . As would be expected at this relatively early stage of its clinical ' life , ' lovastatin has not yet been studied in a manner that would determine its effect on cardiovascular mortality during long term administration . Nevertheless , if the substantial improvements to patients ' lipid and lipoprotein profiles observed in short term studies are maintained during long term administration , then lovastatin will have an important role in the pharmacological management of hyperlipidaemia .", "Caenorhabditis elegans expressed sequence tags identify gene families and potential disease gene homologues . A database containing mapped partial cDNA sequences from Caenorhabditis elegans will provide a ready starting point for identifying nematode homologues of important human genes and determining their functions in C . elegans . A total of 720 expressed sequence tags ( ESTs ) have been generated from 585 clones randomly selected from a mixed - stage C . elegans cDNA library . Comparison of these ESTs with sequence databases identified 422 new C . elegans genes , of which 317 are not similar to any sequences in the database . Twenty - six new genes have been mapped by YAC clone hybridization . Members of several gene families , including cuticle collagens , GTP - binding proteins , and RNA helicases were discovered . Many of the new genes are similar to known or potential human disease genes , including P13569 and the P01130 .", "Molecular genetic studies in monogenic and polygenic human diseases . The main goal of this study was to determine and characterise the types of mutations in two monogenic human disorders : cystic fibrosis ( CF ) and Duchenne / Becker muscular dystrophy ( P11532 , BMD ) and the susceptibility allele frequency in a polygenic disease : type I insulin - dependent diabetes mellitus ( IDDM ) . After analysing 220 chromosomes for mutations in the CF ( Cystic Fibrosis Transmembrane Conductance Regulator = P13569 ) gene , delta F508 mutation was most abundant ( 41 % ) and out of the non - delta F508 CF mutations 5 % was identified as G542X , G551D , R553X , N1303K and W1282X . The CF haplotype analysis by using linked markers to the P13569 gene revealed that the CF \" B \" haplotype occurred in 66 . 7 % of patients , and this haplotype was 57 . 2 % in patients carrying the delta F508 mutation . Prenatal genetic diagnosis for CF was performed in 10 fetuses : 3 were affected , 6 were carriers , and 1 without any CF mutation . Fifty % of 66 patients with P28068 / BMD muscular dystrophy had one or more exon deletions in the dystrophin gene . Eighty - five % of the deletions occurred at the 3 ' and 15 % at the 5 ' end of the gene . Out of the three prenatal diagnosis in one case P11532 was substantiated . Thirty - six % of 50 patients with IDDM possessed four , 44 % three and 20 % two susceptibility markers in the HLA - DQA1 , - DQB1 region . The onset of the disease correlated with the number of susceptibility alleles .", "DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK69___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .", "The role of de novo ceramide synthesis in the mechanism of action of the tricyclic xanthate D609 . The cytotoxic effects of several chemotherapeutic drugs have been linked to elevated de novo ceramide biosynthesis . However , the relationship between the intracellular site ( s ) of ceramide accumulation and cytotoxicity is poorly understood . Here we examined the relationship between the site of ceramide deposition and inhibition of protein translation and induction of apoptosis by the antitumor / antiviral xanthate , D609 . In Chinese hamster ovary ( CHO ) - P04264 , P29320 - 293 , and NIH - 3T3 cells , D609 caused rapid ( 1 - 5 min ) and sustained eukaryotic initiation factor 2alpha ( eIF2alpha ) phosphorylation followed by apoptosis after 24 h . Concurrently , D609 stimulated de novo ceramide synthesis and increased ceramide mass 2 - fold by 2 h in CHO - P04264 cells . In D609 - treated CHO - P04264 cells , sphingomyelin synthesis was stimulated by brefeldin A , and P01031 - P28068 - ceramide transport to the Golgi apparatus was blocked , indicating ceramide accumulation in the endoplasmic reticulum ( ER ) . However , D609 - mediated eIF2alpha phosphorylation , inhibition of protein synthesis , and apoptosis in CHO - P04264 cells were not attenuated by fumonisin B1 or l - cycloserine . Interestingly , short - chain ceramide promoted eIF2alpha phosphorylation and inhibited protein synthesis in CHO - P04264 cells , indicating that the effectiveness of endogenous ceramide could be limited by access to signaling pathways . Thus , expansion of the ER ceramide pool by D609 was not implicated in early ( eIF2alpha phosphorylation ) or late ( apoptotic ) cytotoxic events .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "Gender disparity in LDL - induced cardiovascular damage and the protective role of estrogens against electronegative LDL . BACKGROUND : Increased levels of the most electronegative type of LDL , Q15004 , have been observed in the plasma of patients with metabolic syndrome ( MetS ) and ST - segment elevation myocardial infarction and can induce endothelial dysfunction . Because men have a higher predisposition to developing coronary artery disease than do premenopausal women , we hypothesized that LDL electronegativity is increased in men and promotes endothelial damage . METHODS : Q15004 levels were compared between middle - aged men and age - matched , premenopausal women with or without MetS . We further studied the effects of gender - influenced LDL electronegativity on aortic cellular senescence and DNA damage in leptin receptor - deficient ( db / db ) mice by using senescence - associated - β - galactosidase and γ P16104 staining , respectively . We also studied the protective effects of 17β - estradiol and genistein against electronegative LDL - induced senescence in cultured bovine aortic endothelial cells ( BAECs ) . RESULTS : Q15004 levels were higher in MetS patients than in healthy subjects ( P < 0 . 001 ) , particularly in men ( P = 0 . 001 ) . LDL isolated from male db / db mice was more electronegative than that from male or female wild - type mice . In addition , LDL from male db / db mice contained abundantly more apolipoprotein CIII and induced more BAEC senescence than did female db / db or wild - type LDL . In the aortas of db / db mice but not wild - type mice , we observed cellular senescence and DNA damage , and the effect was more significant in male than in female db / db mice . Pretreatment with 17β - estradiol or genistein inhibited BAEC senescence induced by male or female db / db LDL and downregulated the expression of lectin - like oxidized P01130 - 1 and tumor necrosis factor - alpha protein . CONCLUSION : The gender dichotomy of LDL - induced cardiovascular damage may underlie the increased propensity to coronary artery disease in men .", "aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK19___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .", "Determination of free N - acetylneuraminic acid in human body fluids by high - performance liquid chromatography with fluorimetric detection . Determinations of both the free and bound form of N - acetyl - neuraminic acid ( NANA ) in several human body fluids , such as serum , cerebrospinal fluid ( P04141 ) , saliva , urine , amniotic fluid , and milk were carried out by HPLC with fluorimetric detection . The method utilized 1 , 2 - diamino - 4 , 5 - methylenedioxybenzene dihydrochloride ( P28068 ) as a fluorimetric derivatizing reagent . Free - form NANA was obtained from the body fluids after ultrafiltration with Microcon 10 ( YM - 10 cellulose membrane , filtration limit M ( r ) = 10 , 000 , Amicon ) . The P28068 derivative of NANA was separated isocratically by a Nucleosil 5C18 column with a mixture of 0 . 1 M sodium phosphate buffer ( pH 2 . 0 ) - methanol ( 75 : 25 , v / v ) . A gradient elution system was used for urine analysis . Analysis times were 10 - 30 min . Recoveries of free NANA by ultrafiltration were satisfactory : 95 . 66 +/- 1 . 80 % for serum and 97 . 27 +/- 1 . 55 % for P04141 , respectively . The high sensitivity and specificity render this method applicable to all the body fluids tested . Although a physiological role for free NANA has not yet been elucidated , the method presented promises to contribute to the basic understanding of the NANA metabolism .", "Overproduced interleukin 6 decreases blood lipid levels via upregulation of very - low - density lipoprotein receptor . BACKGROUND : Interleukin 6 ( P05231 ) blockade raises blood lipid levels in patients with rheumatoid arthritis . OBJECTIVE : To examine the influence of P05231 on lipid metabolism . METHODS : Vascular smooth muscle cells ( VSMC ) were cultured in the presence of P05231 , soluble P05231 receptor ( sIL6R ) , P05231 + sIL6R or tumour necrosis factor alpha ( TNFalpha ) for 24 h . After culture , the expression of very - low - density lipoprotein receptor ( P98155 ) , low - density lipoprotein receptor ( P01130 ) and low - density lipoprotein - related protein - 1 ( Q07954 ) were measured by real - time PCR . Human P05231 was injected into mice twice a day for 2 weeks and then P98155 expression in several tissues and the change of total cholesterol ( TC ) and triglyceride ( TG ) levels were investigated . Finally , the effect of anti - P05231 receptor ( P08887 ) antibody injection on blood lipid levels was examined . RESULTS : P05231 + sIL6R significantly induced expression of P98155 mRNA in VSMC ( 8 . 6 - fold , p < 0 . 05 ) , but P05231 or sIL6R alone and TNFalpha did not do so . None of these cytokines induced P01130 and Q07954 mRNA expression . P05231 injection into mice increased the expression of P98155 in heart , adipose tissue and liver and decreased TC and TG levels . The injection of anti - P08887 antibody normalised the reduced levels of TC and TG caused by P05231 injection , whereas it had no influence on the levels of TC and TG in normal mice . CONCLUSIONS : Overproduced P05231 decreased blood lipid levels by increasing P98155 expression in several tissues . It is concluded that P05231 blockade normalises reduced lipid levels caused by P05231 , but does not affect normal lipid metabolism .", "Q9Y5Q5 mutations K317E and S472G from preeclamptic patients alter zymogen activation and cell surface targeting . [ Corrected ] . Q9Y5Q5 is a membrane - bound serine protease that acts as the atrial natriuretic peptide ( P01160 ) convertase in the heart . Recent studies show that corin also activates P01160 in the pregnant uterus to promote spiral artery remodeling and prevent pregnancy - induced hypertension . Two Q9Y5Q5 gene mutations , K317E and S472G , were identified in preeclamptic patients and shown to have reduced activity in vitro . In this study , we carried out molecular modeling and biochemical experiments to understand how these mutations impair corin function . By molecular modeling , the mutation K317E was predicted to alter corin P01130 - 2 module conformation . Western blot analysis of K317E mutant in HEK293 cells showed that the mutation did not block corin expression on the cell surface but inhibited corin zymogen activation . In contrast , the mutation S472G was predicted to abolish a β - sheet critical for corin frizzled - 2 module structure . In Western blot analysis and flow cytometry , S472G mutant was not detected on the cell surface in transfected HEK293 cells . By immunostaining , the S472G mutant was found in the ER , indicating that the mutation S472G disrupted the β - sheet , causing corin misfolding and ER retention . Thus , these results show that mutations in the Q9Y5Q5 gene may impair corin function by entirely different mechanisms . Together , our data provide important insights into the molecular basis underlying corin mutations that may contribute to preeclampsia in patients .", "___MASK11___ - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "[ The effect of type II diabetes and the metabolic syndrome on cardiac second window preconditioning ] . Preconditioning is the most powerful endogenous mechanism , to protect the heart against ischemic damage . Conflicting data are published whether preconditioning can be induced in case of diabetes and the metabolic syndrome , which are clinically very relevant conditions . If preconditioning could be induced consistently and chronically in this population , an important reduction of surgical morbidity and mortality could be reached . In this project we induced hypoxic preconditioning in mice and used cardiac pressure - conductance catheterisation and infarct size as outcome parameters . In the first part , we found that hypoxic preconditioning was capable to reduce infarct size with 40 % and preserve the load - independent parameters with 33 % after coronary occlusion . A DKO ( double knock - out : ob / ob ; P01130 -/- ) model for the metabolic syndrome developed a larger infarct size and had a reduced contractility . No preconditioning could be induced in this model . To detect the determing factor of the resistance to preconditioning , we used single knock - out models . A comparable preconditioning effect of wild type mice could be induced in the lipoprotein receptor deficient ( P01130 -/- ) model for dyslipidemia . The leptin deficient ( ob / ob ) model , characterized by insulin resistance and abdominal obesity had , identically to the DKO model , a larger infarct size . A second window of preconditioning could be induced , although it was less pronounced than the wild type and P01130 -/- model . P01308 resistance and abdominal obesity could be identified as the major factor in the resistance to preconditioning .", "Respective role of humoral factors and blood pressure in aortic remodeling of DOCA hypertensive rats . Hypertension results in increased thickness and stiffness of large artery walls . The goal of our study was to assess the respective roles of humoral factors such as Ang II , endothelin and blood pressure in these aortic modifications . For this purpose , uninephrectomized rats received DOCA and high salt diet , and when hypertension was installed , they were treated for 5 weeks with either a long - acting calcium antagonist , mibefradil ( 30 mg / kg / day ) , an P12821 inhibitor , enalapril ( 3 mg / kg / day ) , or a mixed P25101 and ETB endothelin receptor antagonist , ___MASK15___ ( 100 mg / kg / day ) . A group of hypertensive rats was left untreated and a sham - operated group of normotensive rats was used for control . At the end of treatment , aortic medial thickness and elastin as well as collagen were evaluated by quantitative morphometry . DOCA - salt hypertensive rats exhibited a marked increase in medial thickness associated with no change in absolute content in extracellular matrix . P15502 relative density decreased in DOCA rats . Enalapril had no effect on arterial pressure . ___MASK15___ decreased slightly ( by 12 mm Hg ) , but not significantly , blood pressure . None of these drugs had an effect on medial thickness suggesting that in DOCA hypertensive rats neither Ang II nor endothelin play a significant role in the remodeling of the aorta . In contrast , mibefradil almost normalized arterial pressure , prevented medial hypertrophy and increased elastin density . Further studies are required in order to assess if this effect is directly linked to the blood pressure decrease or to another mechanism related to the calcium antagonistic property of mibefradil .", "___MASK32___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .", "Impaired postprandial blood flow in adipose tissue may be an early marker of insulin resistance in type 2 diabetes . OBJECTIVE : We investigated the changes in subcutaneous adipose tissue blood flow ( ATBF ) after a meal in the various stages of type 2 diabetes . RESEARCH DESIGN AND METHODS : Five groups were examined : healthy control subjects , first - degree relatives of subjects with type 2 diabetes , subjects with impaired glucose tolerance ( IGT ) , subjects with type 2 diabetes and postprandial hyperglycemia but normal fasting plasma glucose levels ( diabetes group A [ P28067 ] ) , and subjects with type 2 diabetes with both postprandial and fasting hyperglycemia ( diabetes group B [ P28068 ] ) . ATBF was measured with ( 133 ) Xe . RESULTS : ATBF was higher in control subjects ( 1 , 507 +/- 103 ml / 100 cm ( 3 ) tissue x min ) versus relatives and IGT , P28067 , and P28068 subjects ( 845 +/- 123 , 679 +/- 69 , 765 +/- 60 , and 757 +/- 69 ml / 100 cm ( 3 ) tissue x min , respectively ; P < 0 . 001 ) . P01308 sensitivity index ( ISI ) in control subjects ( 82 +/- 3 mg x l ( 2 )/ mmol x mU x min ) was higher versus that for relatives and IGT , P28067 , and P28068 subjects ( 60 +/- 3 , 45 +/- 1 , 40 +/- 6 , and 29 +/- 4 mg x l ( 2 )/ mmol x mU x min , respectively ; P < 0 . 0001 ) . ISI was positively associated with peak - baseline ATBF ( beta coefficient 0 . 029 +/- 0 . 013 , P = 0 . 03 ) . CONCLUSIONS : After meal ingestion , insulin - stimulated ATBF was decreased in relatives and and IGT , P28067 , and P28068 subjects . This defect could be an early marker of insulin resistance that precedes the development of type 2 diabetes .", "P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK68___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .", "Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK69___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK69___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .", "Plasmodium falciparum exports the Golgi marker sphingomyelin synthase into a tubovesicular network in the cytoplasm of mature erythrocytes . This work describes two unusual features of membrane development in a eukaryotic cell . ( a ) The induction of an extensive network of tubovesicular membranes by the malaria parasite Plasmodium falciparum in the cytoplasm of the mature erythrocyte , and its visualization with two ceramide analogues P01031 - P28068 - ceramide and P13671 - NBD - ceramide . \" Sectioning \" of the infected erythrocytes using laser confocal microscopy has allowed the reconstruction of detailed three - dimensional images of this novel membrane network . ( b ) The stage - specific export of sphingomyelin synthase , a biosynthetic activity concentrated in the Golgi of mammalian cells , to this tubovesicular network . Evidence is presented that in the extracellular merozoite stage the parasite retains sphingomyelin synthase within its plasma membrane . However , intracellular ring - and trophozoite - stage parasites export a substantial fraction ( approximately 26 % ) of sphingomyelin synthase activity to membranes beyond their plasma membrane . Importantly we do not observe synthesis of new enzyme during these intracellular stages . Taken together these results strongly suggest that the export of this classic Golgi enzyme is developmentally regulated in Plasmodium . We discuss the significance of this export and the tubovesicular network with respect to membrane development and function in the erythrocyte cytosol .", "___MASK11___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .", "Activity , pharmacological inhibition and biological regulation of 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase in Trypanosoma brucei . Activity of hydroxymethylglutaryl - coenzyme A ( HMG - DB01992 ) reductase , the key enzyme in the biosynthesis of steroids and polyisoprenoids in mammalian cells , has been detected in both the bloodstream form and the culture - adapted procyclic form of Trypanosoma brucei ( 3 . 7 +/- 0 . 6 and 12 . 7 +/- 1 . 8 pmol mevalonate produced min - 1 ( mg cell protein ) - 1 , respectively ) . The enzyme activity is enriched 6 - fold in microsomal fractions . Several competitive inhibitors of mammalian P04035 , including synvinolin ( simvastatin ) , inhibit the multiplication of both forms of trypanosome in vitro ( IC50 , approx . 25 - 50 microM after 2 - 3 days ) . This growth inhibition is potentiated by agents interfering with the exogenous supply of cholesterol , such as antibodies blocking the low - density lipoprotein ( LDL ) receptor , or 5 microM chloroquine . Conversely , growth inhibition by synvinolin can be largely reverted either by 300 nM LDL or by products of the mevalonate pathway , such as 20 mM mevalonate and in procyclics by 100 microM squalene or cholesterol . In procyclics , low concentrations of synvinolin selectively inhibit the incorporation of [ 14C ] acetate into sterols , but not into fatty acids . These results argue for a critical role in trypanosomes of a mevalonate pathway , that is involved in the biosynthesis of sterol and probably of other metabolites . The P04035 activity is decreased 2 - fold in procyclics incubated with 4 mM mevalonate and increased 2 - fold in the presence of 2 . 5 microM synvinolin . DB00641 also upregulates LDL binding up to 4 - fold . These data suggest that P04035 and P01130 expression are regulated in T . brucei as in mammalian cells , to ensure sterol homeostasis .", "Effects of vasoactive intestinal peptide ( P01282 ) and somatostatin ( P61278 ) on lipoprotein receptor expression by A431 tumor cells . A variety of tumor cells have been shown to express lipoprotein receptors . Recent data suggest that lipoprotein receptors may play a regulatory role in the growth of certain tumor cells . We investigated the effects of vasoactive intestinal peptide ( P01282 ) and somatostatin - 14 ( P61278 - 14 ) on the binding of 111Indium - labeled lipoproteins [ ( 111 ) In - low density lipoprotein ( ( 111 ) In - LDL ) , ( 111 ) In - high density lipoprotein ( ( 111 ) In - HDL ) and ( 111 ) In - very low density lipoprotein ( ( 111 ) In - VLDL ) ] onto the epidermoid mammary carcinoma cell line A431 . Scatchard analyses of the binding data indicated one class of specific high affinity binding sites for LDL , HDL and VLDL expressed by A431 cells , respectively . P01282 increased significantly the binding capacity for ( 111 ) In - LDL on A431 cells . The P01282 - induced increase of ( 111 ) In - LDL binding sites was inhibited by P61278 - 14 . Furthermore , P61278 - 14 inhibited P01282 - induced 3H - thymidine incorporation and adenosine 3 '- 5 ' cyclic monophosphate ( DB02527 ) formation in A431 cells with IC50 values in the range of 5 - 7 nM . However , P61278 - 14 showed no effect on dibutyryl - DB02527 - induced increase of ( 111 ) In - LDL binding sites expressed on A431 cells . In contrast to ( 111 ) In - LDL binding , no effects of P01282 or P61278 - 14 on HDL or VLDL binding to A431 tumor cells were found . Our results suggest a direct effect of P01282 and P61278 - 14 on LDL - binding onto tumor cells . The complex interactions between P01282 and P61278 - 14 on P01130 expression of tumor cells may play a role in tumor cell lipid metabolism .", "Products of the unc - 52 gene in Caenorhabditis elegans are homologous to the core protein of the mammalian basement membrane heparan sulfate proteoglycan . Mutations in the unc - 52 gene of Caenorhabditis elegans affect attachment of the myofilament lattice to the muscle cell membrane . Here , we demonstrate that the unc - 52 gene encodes a nematode homolog of perlecan , the mammalian basement membrane heparan sulfate proteoglycan . The longest potential open reading frame of this gene encodes a 2482 - amino - acid protein with a signal peptide and four domains . The first domain is unique to the unc - 52 polypeptide , whereas the three remaining domains contain sequences found in the P01130 ( domain II ) laminin ( domain III ) and N - P62158 ( domain IV ) . We have identified three alternatively spliced transcripts that encode different carboxy - terminal sequences . The two larger transcripts encode proteins containing all or part of domain IV , whereas the smaller transcript encodes a shortened polypeptide that completely lacks domain IV . We have determined that the disorganized muscle phenotype observed in unc - 52 ( st196 ) animals is caused by the insertion of a Tc1 transposon into domain IV . Two monoclonal antibodies that recognize an extracellular component of all contractile tissues in C . elegans fail to stain embryos homozygous for a lethal unc - 52 allele . We have mapped the epitopes recognized by both monoclonal antibodies to a region of domain IV in the unc - 52 - encoded protein sequence .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK53___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "Effect of acetazolamide on aquaporin - 1 and fluid flow in cultured choroid plexus . ___MASK32___ ( AZA ) , used in treatment of early or infantile hydrocephalus , is effective in some cases , while its effect on the choroid plexus ( CP ) remains ill - defined . The drug reversibly inhibits aquaporin - 4 ( P55087 ) , the most ubiquitous \" water pore \" in the brain , and perhaps modulation of P29972 ( located apically on CP cells ) by AZA may reduce cerebrospinal fluid ( P04141 ) production . We sought to elucidate the effect of AZA on P29972 and fluid flow in CP cell cultures . CP tissue culture from 10 - day Sprague - Dawley rats and a TRCSF - B cell line were grown on Transwell permeable supports and treated with 100 μM AZA . Fluid assays to assess direction and extent of fluid flow , and P29972 expression patterns by immunoblot , Immuncytochemistry ( ICC ) , and quantitative reverse transcriptase polymerase chain reaction ( qRT - PCR ) were performed . Immunoblots and ICC analyses showed a decrease in P29972 protein shortly after AZA treatment ( lowest at 12 h ) , with transient P29972 reduction mediated by mRNA expression ( lowest at 6 h ) . Transwell fluid assays indicated a fluid shift at 2 h , before significant changes in P29972 mRNA or protein levels . Timing of AZA effect on P29972 suggests the drug alters protein transcription , while affecting fluid flow by a concomitant method . It is plausible that other mechanisms account for these phenomena , as the processes may occur independently .", "Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK30___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .", "Role of Q14116 in overt pain - like behaviour in mice . There are evidences that targeting Q14116 might be beneficial to inhibit inflammatory symptoms , including hypernociception ( decrease in nociceptive threshold ) . The mechanism of Q14116 mechanical hypernociception depends on endothelin in rats and mice . However , the role of Q14116 in overt pain - like behaviour remains undetermined . Therefore , we addressed the role of Q14116 in writhing response induced by intraperitoneal ( i . p . ) injection of phenyl - p - benzoquinone ( PBQ ) and acetic acid in mice . Firstly , it was detected that PBQ and acetic acid i . p . injection induced a dose - dependent number of writhes in Balb / c mice . Subsequently , it was observed that the PBQ - but not the acetic acid - induced writhes were diminished in Q14116 deficient ( ( -/- ) ) mice . Therefore , considering that P01579 , endothelin and prostanoids mediate Q14116 - induced mechanical hypernociception , we also investigated the role of these mediators in the same model of writhing response in which Q14116 participates . It was noticed that PBQ - induced writhes were diminished in P01579 (-/-) mice and by the treatment with ___MASK15___ ( mixed endothelin P25101 / ETB receptor antagonist ) , BQ 123 ( cyclo [ DTrp - DAsp - Pro - DVal - DB00149 ] , selective endothelin P25101 receptor antagonist ) , BQ 788 ( N - cys - 2 , 6 dimethylpiperidinocarbonyl - l - methylleucyl - d - 1 - methoxycarboyl - d - norleucine , selective endothelin ETB receptor antagonist ) or indomethacin ( cycloxigenase inhibitor ) . Thus , Q14116 , P01579 , endothelin acting on endothelin P25101 and ETB receptors , and prostanoids mediate PBQ - induced writhing response in mice . To conclude , these results further advance the understanding of the physiopathology of overt pain - like behaviour , and suggest for the first time a role for Q14116 in writhing response in mice .", "DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .", "Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK35___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .", "Development of a sensitive , accurate and robust liquid chromatography / mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice . Quantification of angiotensin ( Ang ) peptides in biological matrices is a challenge due to their low picomolar ( pM ) concentration and poor analytical performance of current methods . This work aimed to select an optimal strategy for liquid chromatography / mass spectrometry ( LC / MS ) quantification of major angiotensins in plasma of wild type and atherosclerotic mice . Optimal LC / MS set - up for Ang quantification was chosen , based on analytical performance , from : nanoflow / orbitrap , nanoflow / triple quadrupole and preconcentration nanoflow / triple quadrupole . The best LC / MS configuration ( preconcentration nanoflow / triple quadrupole ) was validated and used for measurement of angiotensins ( Ang I , II , III , IV and ( 1 - 7 ) ) in plasma of 6 - month - old atherosclerotic apolipoprotein E / P01130 double knock - outs ( ApoE / P01130 ( -- / -- ) ) and wild type C57BL / 6J ( WT ) mice . The method established for Ang quantification was selective , accurate and highly sensitive with LLOQ of 5pgmL (- 1 ) . The peak area intra - day precisions for Ang II and Ang -( 1 - 7 ) were in the range 3 . 0 - 5 . 1 and 3 . 5 - 5 . 8 , respectively , with corresponding accuracy of 95 . 4 - 103 . 5 % and 95 . 6 - 106 . 3 % . Plasma angiotensin profile was substantially modified in ApoE / P01130 knock - out mice with increase in concentration of Ang II from 37 . 6 ± 21 . 3pgmL (- 1 ) in WT to 200 . 2 ± 47 . 6pgmL (- 1 ) . Concentrations of Ang I , III and IV were also increased 3 - 10 fold in ApoE / P01130 ( -- / -- ) mice while that of Ang -( 1 - 7 ) was unchanged . We conclude that the method developed could be effectively used for accurate , comprehensive profiling of angiotensin peptides in mouse plasma . We identified substantial changes in renin - angiotensin system in a genetic mouse model of atherosclerosis consistent with the overactivation of angiotensin converting enzyme ( P12821 ) and the impairment of Q9BYF1 .", "Metabolic fate of 2 , 2 - dimethylbutyryl moiety of simvastatin in rats : identification of metabolites by gas chromatography / mass spectrometry . Metabolic pathways of simvastatin ( DB00641 ) , a lactone prodrug of an inhibitor of P04035 , were elucidated in male rats , using the [ 14C ] - labelled compound . Evidence has been obtained for hydrolysis of simvastatin and its metabolites at their 2 , 2 - dimethylbutyryl moieties . Metabolites identified in plasma were 2 , 2 - dimethylbutyric acid ( P28068 ) , 2 , 2 - dimethyl - 3 - hydroxybutyric acid ( DMHB ) and an open chain hydroxy acid of simvastatin : metabolites identified in urine were DMHB , a glucuronide and the glycine conjugate of P28068 . They were characterized by gas chromatography / electron impact and chemical ionization mass spectrometry as phenacyl or pertrimethylsilylated derivatives . The structures of the metabolites and the aglycone of the glucuronide were confirmed as phenacyl esters by comparison of their chromatographic data and mass spectra with those of the phenacyl derivatives of authentic compounds .", "Genetic influences on sarcoidosis . To investigate the genetic influences underlying the development of sarcoidosis , HLA class II genotyping was performed in Japanese patients with sarcoidosis and healthy controls using the PCR - RFLP method . The frequencies of both DR52 group antigen - associated alleles ( HLA - Q8IUH3 * 11 , - Q8IUH3 * 12 and - Q8IUH3 * 14 ) and Q8IUH3 * 08 alleles were higher in the patient group , suggesting that the common , specific amino acid residue on the Q8IUH3 molecule of these alleles may determine susceptibility to sarcoidosis . Alternatively , it is possible that another susceptibility gene , linked to these Q8IUH3 alleles , exists within the MHC region . We screened the P01375 , P01374 , P0DMV8 and Hum70t genes around the class III region , as well as the P28067 and - P28068 genes in the class II region , for genetic polymorphism in sarcoidosis . None of these genes suggested a susceptibility to sarcoidosis . These studies support the thesis that one of the major genetic factors controlling the development of sarcoidosis is located within the Q8IUH3 locus in the HLA class II region .", "Combinations of dominant - negative class II transactivator , p300 or P50750 proteins block the expression of MHC II genes . The class II transactivator ( P33076 ) regulates not only the transcription of HLA - DR , - DQ , - DP , but also invariant chain , P28067 and P28068 genes . A hybrid mutant P33076 protein , which contained residues from positions 302 to 1130 in P33076 fused to the enhanced green fluorescent protein ( EdCIITA ) , inhibited the function of the wild - type protein . EdCIITA extinguished the inducible and constitutive expression of MHC II genes in epithelial cells treated with P01579 and B lymphoblastoid cells respectively . Also , it blocked T cell activation by superantigen . This inhibition correlated with the localization of EdCIITA but not P33076 in the cytoplasm of cells . However , when EdCIITA was co - expressed with a dominant - negative form of the nucleoporin Nup214 / P35658 , it also accumulated in the nucleus . These data suggest that EdCIITA not only competes with the wild - type protein for the binding to MHC II promoters but sequesters a critical co - factor of P33076 in the cytoplasm . P33076 also recruits the histone acetyltransferase DB02527 responsive element binding protein ( CREB ) binding protein and positive transcription elongation factor b ( p - TEFb ) for the transcription of MHC II genes . Dominant - negative p300 ( DNp300 ) or P50750 ( DNCDK9 ) proteins inhibited the function of P33076 and of the P40879 promoter . Thus , combinations of EdCIITA and DNp300 and / or DNCDK9 proteins extinguished the transcription of MHC II genes . They might become useful for future genetic therapeutic approaches in organ transplantation and autoimmune diseases ." ]

[ "___MASK11___", "___MASK15___", "___MASK19___", "___MASK30___", "___MASK32___", "___MASK35___", "___MASK53___", "___MASK68___", "___MASK69___" ]

[ "Enhanced sensitivity to the P00533 / epidermal growth factor receptor tyrosine kinase inhibitor erlotinib hydrochloride in chemotherapy - resistant tumor cell lines . PURPOSE : Erlotinib ( Tarceva , DB00530 ) is a potent and specific inhibitor of the P00533 / epidermal growth factor receptor ( P00533 ) tyrosine kinase . In phase II clinical studies , oral erlotinib monotherapy has shown antitumor activity in patients with advanced non - small cell lung cancer , head and neck cancer , and ovarian cancer after the failure of standard chemotherapy . We hypothesized that some tumors treated with multiple cytotoxic therapies may become more dependent on the P00533 / P00533 signaling pathways for survival . EXPERIMENTAL DESIGN : The growth - inhibitory effect of erlotinib was tested on 10 pairs of chemosensitive , parental , and chemoresistant tumor cell lines . RESULTS : Enhanced sensitivity to erlotinib was observed in the doxorubicin - resistant human breast cancer cell line MCF - 7 , paclitaxel - resistant human ovarian carcinoma cell line A2780 , and cisplatin - resistant human cervical carcinoma cell line ME180 . The IC ( 50 ) values of erlotinib in the resistant cell lines were 2 - to 20 - fold lower than those in the corresponding parental cell lines . This enhanced sensitivity to erlotinib correlated with higher P00533 / P00533 and phospho - P00533 / P00533 expression when compared with the corresponding parental cell lines . Acquired resistance to cytotoxic agents was not associated with cross - resistance to erlotinib . AE - ME180 / DB00515 - resistant xenografts showed greater sensitivity to erlotinib than parental ME180 xenografts did . CONCLUSIONS : Our findings suggest that acquired resistance to cytotoxic therapy in some tumors is associated with enhanced sensitivity to P00533 / P00533 inhibitors , which correlates with increased P00533 / P00533 expression . These data may explain some of the observed clinical activity of P00533 / P00533 inhibitors in patients previously treated with multiple therapies . P00533 / P00533 tyrosine kinase inhibitors may be more effective as second - or third - line treatment for certain patients with tumors that were previously treated with multiple chemotherapy regimens .", "Rationale and clinical validation of epidermal growth factor receptor as a target in the treatment of head and neck cancer . Recurrent / metastatic head and neck cancer is an area of high , unmet treatment need . There is a strong rationale for targeting the epidermal growth factor receptor ( P00533 ) in head and neck cancer as most of these tumors express high levels of P00533 relative to normal tissue , with high expression correlating with poor patient outcome . This rationale has been validated in extensive preclinical studies . Two small molecules with P00533 inhibitory activity , gefitinib ( ' DB00317 ' , ZD1839 ) and erlotinib ( ' Tarceva ' , DB00530 ) , and a humanized monoclonal antibody against the P00533 extracellular domain , cetuximab ( ' Erbitux ' , C225 ) , are in clinical trials for advanced head and neck cancer . The initial results of these trials are promising . Gefitinib and erlotinib show activity as monotherapy in patients with recurrent or metastatic head and neck cancer , and have an acceptable safety profile compared with conventional chemotherapy . Gefitinib , which can be given at doses below the maximum tolerated dose , is associated with slightly lower rates of adverse events than erlotinib , which is dosed at the maximum tolerated dose . Combinations of cetuximab with radiotherapy or platinum - based chemotherapy have also shown activity in phase I / II studies . Both gefitinib and cetuximab have entered phase III studies . The results of these trials , which will mature over the next few years , will help determine the optimal use of P00533 agents in head and neck cancers .", "Purine receptor Q15077 mediates cellular response to γ - ray - induced DNA damage . We previously showed that nucleotide P2 receptor agonists such as DB00171 and UTP amplify γ - ray - induced focus formation of phosphorylated histone H2A variant P16104 ( γ P16104 ) , which is considered to be an indicator of DNA damage so far , by activating purine Q15077 and Q9H244 receptors . Therefore , we hypothesized that these P2 receptors play a role in inducing the repair response to γ - ray - induced DNA damage . In the present study , we tested this idea by using human lung cancer A549 cells . First , reverse - transcription polymerase chain reaction ( RT - PCR ) showed that Q15077 receptor is highly expressed in A549 cells , but Q9H244 receptor is only weakly expressed . Next , colony formation assay revealed that Q15077 receptor antagonist MRS2578 markedly reduced the survival rate of γ - ray - exposed A549 cells . The survival rate was also significantly reduced in Q15077 - knock - down cells , compared with scramble siRNA - transfected cells . Since it has reported that phosphorylation of P27361 / 2 after activation of P00533 via Q15077 and Q9H244 receptors is involved in the repair response to γ - ray - induced DNA damage , we next examined whether γ - ray - induced phosphorylation of P27361 / 2 was also inhibited by MRS2578 in A549 cells . We found that it was . Taken together , these findings indicate that purinergic signaling through Q15077 receptor , followed by P27361 / 2 activation , promotes the cellular repair response to γ - ray - induced DNA damage .", "Tamoxifen enhances erlotinib - induced cytotoxicity through down - regulating AKT - mediated thymidine phosphorylase expression in human non - small - cell lung cancer cells . Tamoxifen is a triphenylethylene nonsteroidal estrogen receptor ( ER ) antagonist used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer . However , the molecular mechanism of tamoxifen - induced cytotoxicity in non - small cell lung cancer ( NSCLC ) cells has not been identified . P19971 ( TP ) is an enzyme of the pyrimidine salvage pathway which is upregulated in cancers . In this study , tamoxifen treatment inhibited cell survival in two NSCLC cells , H520 and H1975 . Treatment with tamoxifen decreased TP mRNA and protein levels through AKT inactivation . Furthermore , expression of constitutively active AKT ( AKT - CA ) vectors significantly rescued the decreased TP protein and mRNA levels in tamoxifen - treated NSCLC cells . In contrast , combination treatment with PI3K inhibitors ( LY294002 or wortmannin ) and tamoxifen further decreased the TP expression and cell viability of NSCLC cells . Knocking down TP expression by transfection with small interfering RNA of TP enhanced the cytotoxicity and cell growth inhibition of tamoxifen . Erlotinib ( Tarceva , DB00530 ) , an orally available small molecular inhibitor of epidermal growth factor receptor ( P00533 ) tyrosine kinase , is approved for clinical treatment of NSCLC . Compared to a single agent alone , tamoxifen combined with erlotinib resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells , accompanied with reduced activation of phospho - AKT and phospho - P27361 / 2 , and reduced TP protein levels . These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and erlotinib for the treatment of NSCLC .", "P00533 inhibitors , gefitinib and erlotinib ( Tarceva , DB00530 ) , in the treatment of bronchioloalveolar carcinoma .", "A phase II study of erlotinib ( DB00530 ) given in combination with carboplatin in patients with recurrent epithelial ovarian cancer ( NCIC CTG IND . 149 ) . OBJECTIVES : Approximately 50 % of ovarian cancers have elevated levels of epidermal growth factor receptor ( P00533 ) which correlates with a poor prognosis . Preclinical evidence suggests that P00533 tyrosine kinase inhibitors ( TKIs ) , such as erlotinib ( DB00530 ) , may potentiate the anti - tumour effects of cytotoxic agents , including carboplatin . Blocking P00533 could thus potentially reverse drug resistance . The primary objective of the study was to assess the response rate to the addition of erlotinib in patients with recurrent ovarian cancer who were receiving carboplatin . METHODS : Patients enrolled on this study had either local or advanced recurrent ovarian cancer with measurable disease . They may have had up to 2 prior chemotherapy regimens , one of which must have contained platinum , and they must have responded to prior platinum therapy . Patients were stratified by platinum sensitivity and were treated with erlotinib 150 mg daily on a continuous dosing schedule , and carboplatin at an AUC of 5 every 21 days . RESULTS : Fifty patients with recurrent ovarian cancer entered the study , 33 in the platinum - sensitive arm and 17 in the platinum - resistant arm . Of patients evaluable for response , there were 14 partial responses ( PR ) of 30 evaluable for response ( 57 % objective response rate ( ORR ) ) in the platinum - sensitive arm , and 1 PR of 14 evaluable for response ( 7 % ORR ) in the platinum - resistant arm . CONCLUSIONS : The combination of erlotinib and carboplatin was active in patients with platinum - sensitive disease , but not in platinum - resistant disease . The toxicities seen were those expected with carboplatin and erlotinib .", "Efficacy and safety of erlotinib HCl , an epidermal growth factor receptor ( P00533 / P00533 ) tyrosine kinase inhibitor , in patients with advanced ovarian carcinoma : results from a phase II multicenter study . The aim of this single - arm , phase II study was to estimate the tumor response rate and safety profile of erlotinib HCl ( erlotinib , Tarceva , DB00530 ) monotherapy in patients with refractory , recurrent , P00533 / P00533 - positive epithelial ovarian tumors , who had failed prior taxane and / or platinum - based chemotherapy . Thirty - four patients received 150 mg erlotinib orally once daily for up to 48 weeks or until disease progression or dose - limiting toxicity . Two patients had partial responses , lasting 8 + and 17 weeks , giving an objective response rate of 6 % ( 95 % confidence interval [ CI ] , 0 . 7 - 19 . 7 % ) . Fifteen patients ( 44 % ) had stable disease , and 17 patients ( 50 % ) had progressive disease . Median overall survival was 8 months ( 95 % CI , 5 . 7 - 12 . 7 months ) , with a 1 - year survival rate of 35 . 3 % ( 95 % CI , 19 . 8 - 53 . 5 % ) . Patients with rash survived significantly longer than those without ( P = 0 . 009 ) , correlating with rash grade . Erlotinib was generally well tolerated . The most frequent erlotinib - related adverse events were rash ( 68 % ) and diarrhea ( 38 % ) . Erlotinib had marginal activity but was generally well tolerated . The safety profile appears more favorable than typically experienced with standard chemotherapeutic agents , which is encouraging in these heavily pretreated patients . Combination of erlotinib with chemotherapy or other targeted agents should be considered .", "5 - Q13049 receptor induces P29323 phosphorylation and proliferation through ADAM - 17 tumor necrosis factor - alpha - converting enzyme ( P78536 ) activation and heparin - bound epidermal growth factor - like growth factor ( HB - P01133 ) shedding in mesangial cells . In this study , we present multiple lines of evidence to support a critical role for heparin - bound P01133 ( epidermal growth factor ) - like growth factor ( HB - P01133 ) and tumor necrosis factor - alpha - converting enzyme ( P78536 ) ( P78536 ) in the transactivation of P01133 receptor ( P00533 ) , P29323 phosphorylation , and cellular proliferation induced by the 5 - HT ( 2A ) receptor in renal mesangial cells . 5 - hydroxy - tryptamine ( 5 - HT ) resulted in rapid activation of P78536 , HB - P01133 shedding , P00533 activation , P29323 phosphorylation , and longer term increases in DNA content in mesangial cells . P29323 phosphorylation was attenuated by 1 ) neutralizing P00533 antibodies and the P00533 kinase inhibitor , AG1478 , 2 ) neutralizing HB - P01133 , but not amphiregulin , antibodies , heparin , or CM197 , and 3 ) pharmacological inhibitors of matrix - degrading metalloproteinases or P78536 small interfering RNA . Exogenously administered HB - P01133 stimulated P29323 phosphorylation . Additionally , P78536 was co - immunoprecipitated with HB - P01133 . Small interfering RNA against P78536 also blocked 5 - HT - induced increases in P29323 phosphorylation , HB - P01133 shedding , and DNA content . In aggregate , this work supports a pathway map that can be depicted as follows : 5 - HT --> 5 - HT ( 2A ) receptor --> P78536 --> HB - P01133 shedding --> P00533 --> P29323 --> increased DNA content . To our knowledge , this is the first time that P78536 has been implicated in 5 - HT - induced P00533 transactivation or in proliferation induced by a G protein - coupled receptor in native cells in culture .", "Overview of tyrosine kinase inhibitors in clinical breast cancer . Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti - oestrogen therapy , and to tamoxifen in particular , have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors , notably the epidermal growth factor receptor ( P00533 ) and P04626 . Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor ( ER ) signalling . Inhibition of receptor tyrosine kinase activity involved in the P00533 signalling cascade forms the basis for the use of P00533 specific tyrosine kinase inhibitors exemplified by gefitinib ( ZD1839 , DB00317 ) and erlotinib ( DB00530 , Tarceva ) . Such agents have proved promising in pre - clinical studies and are currently in clinical trials in breast cancer , where gefitinib has been studied more extensively to date . Here , we present an overview of the current development of gefitinib in clinical breast cancer . This includes results from our clinical breast cancer trial 1839IL / 0057 that demonstrate the efficacy of gefitinib within ER - positive , tamoxifen - resistant patients with locally advanced / metastatic disease , where parallel decreases in P00533 signal transduction and the Ki67 ( Q86YT6 ) proliferation marker can be detected as predicted from model system studies . We also consider trials examining combination treatment with gefitinib and anti - hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay / prevent onset of anti - hormone resistance .", "Extracellular signal - regulated kinase / mitogen - activated protein kinases block internalization of delta - opioid receptors . Translocation of G protein - coupled receptors ( GPCRs ) from the cell membrane to cytosol depends on the kind of ligand activating the receptor . This principle is clearly demonstrated for opioid receptors , because diverse opiate agonists rapidly induce receptor internalization , whereas morphine almost fails . We report here the impact of mitogen - activated protein ( Q96HU1 ) kinase isoforms extracellular signal - regulated kinase ( P29323 ) 1 / 2 on the internalization of delta - opioid receptors ( DORs ) expressed in human embryonic kidney ( P29320 ) 293 cells . Receptor activation by etorphine turned out to transiently phosphorylate P29323 / Q96HU1 kinases and bring about Q8IXH6 internalization within 20 min . In contrast , prolonged exposure of HEK293 cells to morphine excited persistent phosphorylation of P29323 / Q96HU1 kinases , and those cells failed to internalize the opioid receptor . When P29323 / Q96HU1 kinase phosphorylation was blocked by 2 '- Amino - 3 '- methoxyflavone ( PD98059 ) , morphine gained the ability to strongly induce Q8IXH6 endocytosis . The importance of activated Q96HU1 kinases for Q8IXH6 internalization is further demonstrated by glutamate and paclitaxel because these substances induce phosphorylation of P27361 / 2 and concomitantly prevent Q8IXH6 sequestration by etorphine . In addition , receptor internalization by morphine was facilitated by inhibition of protein kinase C and opioid - mediated transactivation of epidermal growth factor receptor ( P00533 ) , both activating P29323 / Q96HU1 kinases by opioids . The mechanism affording Q8IXH6 internalization by PD98059 may relate to arrestin , which uncouples GPCRs and thus triggers receptor internalization . Arrestin considerably translocates toward the cell membrane upon Q8IXH6 activation by morphine in presence of the Q96HU1 kinase blocker , but it fails in the absence of PD98059 . We conclude that P29323 / Q96HU1 kinase activity prevents opioid receptor desensitization and sequestration by blocking arrestin 2 interaction with activated DORs .", "Somatic mutations of the epidermal growth factor receptor and non - small - cell lung cancer . Frequent overexpression of epidermal growth factor receptor ( P00533 ) in non - small - cell lung cancer ( NSCLC ) makes P00533 a new therapeutic target . Two specific P00533 tyrosine kinase inhibitors , gefitinib ( ZD1839 , DB00317 ) and erlotinib ( DB00530 , Tarceva ) , have been developed and approved by the US Food and Drug Administration for second - line and third - line treatment of advanced NSCLC . Clinical trials have shown considerable variability in the response rate between different patients with NSCLC , which led to the discovery of somatic P00533 - activating mutations . This brief review summarises the discovery and functional consequences of the mutations , their clinicopathological features and significant implications in the treatment and prognosis of NSCLC .", "Label - free electrochemical measurement of protein tyrosine kinase activity and inhibition based on electro - catalyzed tyrosine signaling . A novel label - free electrochemical method for measuring the activity of protein tyrosine kinases ( PTK ) has been developed . P00533 ( P00533 ) , a typical PTK associated with a large percentage of all solid tumors , was used as the model kinase . Poly ( glu , tyr ) ( 4 : 1 ) peptide , as a substrate of P00533 , was covalently immobilized on the surface of indium tin oxide ( ITO ) electrode by silane chemistry . The tyrosine ( DB00135 ) residue in the polypeptide served as an electrochemical signal reporter . Its voltammetric current was catalyzed by a dissolved electron mediator Os ( bpy )( 3 )( 2 +) ( bpy = 2 , 2 '- bipyridine ) for increased sensitivity . Phosphorylation of the DB00135 led to a loss of its electrochemical current , thus providing a sensing mechanism for PTK activity . Experimental conditions for the silanization of ITO surface and immobilization of polypeptide were investigated in details to facilitate the generation of DB00135 electrochemical signal . The proposed biosensor exhibited high sensitivity and excellent stability . The limit of detection for P00533 was 1 UmL (- 1 ) . Furthermore , this biosensor can also be used for quantitative analysis of kinase inhibition . On the basis of the inhibitor concentration dependent electrochemical signal , the half - maximal inhibition value IC ( 50 ) of three P00533 inhibitors , PD - 153035 , DB00530 and ZD - 1839 , and their corresponding inhibition constants K ( i ) were estimated , which were in agreement with those obtained from the conventional kinase assay . This electrochemical biosensor can be implemented in an array format for the high throughput assay of in vitro PTK activity and PTK inhibitors screening for practical diagnostic application and drug discovery .", "A novel approach in the treatment of cancer : targeting the epidermal growth factor receptor . The epidermal growth factor receptor ( P00533 ) autocrine pathway contributes to a number of processes important to cancer development and progression , including cell proliferation , apoptosis , angiogenesis , and metastatic spread . The critical role the P00533 plays in cancer has led to an extensive search for selective inhibitors of the P00533 signaling pathway . The results of a large body of preclinical studies and the early clinical trials thus far conducted suggest that targeting the P00533 could represent a significant contribution to cancer therapy . A variety of different approaches are currently being used to target the P00533 . The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling . At least five blocking monoclonal antibodies have been developed against the P00533 . Among these , IMC - 225 is a chimeric human - mouse monoclonal IgG1 antibody that has been the first anti - P00533 targeted therapy to enter clinical evaluation in cancer patients in Phase II and III studies , alone or in combination with conventional therapies , such as radiotherapy and chemotherapy . A number of small molecule inhibitors of the P00533 tyrosine kinase enzymatic activity is also in development . DB00530 and ZD1839 ( DB00317 ) are currently in Phase II and III development , respectively . ZD1839 , a p . o . active , selective quinazoline derivative has demonstrated promising in vitro and in vivo antitumor activity . Preliminary results from Phase I and II trials in patients with advanced disease demonstrate that ZD1839 and DB00530 have an acceptable tolerability profile and promising clinical efficacy in patients with a variety of tumor types . This mini - review describes the P00533 inhibitors in clinical development .", "Erlotinib ( DB00530 ) - induced inhibition of transitional cell carcinoma of bladder cell line growth is enhanced by interferon - alpha . OBJECTIVE : To examine whether erlotinib gives similar results to gefitinib , a small molecule epidermal growth factor receptor ( P00533 / P00533 ) tyrosine kinase ( TK ) inhibitor that inhibits the growth of human bladder cancer cell lines in vitro , and given that interferon - alpha ( IFNalpha ) promotes an antiproliferative effect of P00533 / P00533 inhibitors on colon cancer cell lines , to also determine the effects of erlotinib alone or together with INFalpha on bladder cancer cell lines , and whether sensitivity is influenced by P00533 / P00533 mutation status . MATERIALS AND METHODS : Seven bladder cancer cell lines were characterized for P00533 / P00533 expression , then treated with erlotinib alone , IFNalpha alone , or IFNalpha plus erlotinib . Cell growth inhibition was assessed by crystal - violet staining and P00533 / P00533 expression by flow cytometry . Synergy was evaluated using the combination index of Chou and Talalay . DNA from these cell lines in the linear growth phase and from 14 bladder cancer tissue samples were tested for P00533 / EGFRTK mutations . RESULTS : Cell - surface P00533 / P00533 expression was present in all seven bladder cancer cell lines . Both erlotinib and IFNalpha independently were significantly antiproliferative , and combined treatment synergistically enhanced the sensitivity in six of the seven cell lines . No bladder cancer cell lines or tissues tested expressed P00533 / EGFRTK mutations . CONCLUSION : Erlotinib inhibits the growth of human bladder cancer cell lines . Enhanced inhibition in the presence of IFNalpha is not determined by the presence of P00533 / EGFRTK mutations . This study might have clinical implications for improving the treatment of bladder cancer .", "Rationale for investigation of epidermal growth factor receptor inhibitors in definitive treatment of locally advanced non - small cell lung cancer and head and neck cancer . Designing targeted therapies has become an important field in cancer therapeutics . The epidermal growth factor receptor ( P00533 ) is a molecular target that has gained immense attention as preclinical and clinical studies have supported its potential role for therapy of a variety of cancers , including non - small cell lung cancer ( NSCLC ) and head and neck ( HN ) cancer . Several compounds that specifically inhibit P00533 have been developed , including ZD1839 , C225 , and DB00530 . Interestingly , studies suggesting a potential role for P00533 inhibitors as an adjunct to the current combined - modality approach for therapy of NSCLC and HN cancer have been performed in the preclinical and clinical setting . Therefore , determining the potential of P00533 inhibitors to improve the efficacy of standard combined - modality regimens ( chemotherapy / radiation therapy +/- surgery ) for NSCLC and HN cancer patients is of the utmost importance . An overview of the rationale and the ongoing / proposed studies aimed at determining the role for P00533 inhibitors in combination with radiation therapy for NSCLC and HN cancer patients will be presented .", "Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK81___ and Tissue P00747 Activator in Occluded Arteries .", "A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3 - hydroxy - 3 - methylglutaryl - coenzyme - A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading to depletion of farnesyl diphosphate ( FPP ) and disruption of protein prenylation . P37268 ( P37268 ) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis . Herein , we have identified novel bisphosphonates as potent and specific inhibitors of P37268 , including the tetrasodium salt of 9 - biphenyl - 4 , 8 - dimethyl - nona - 3 , 7 - dienyl - 1 , 1 - bisphosphonic acid ( compound 5 ) . Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells . At high concentrations , lovastatin and zoledronate impaired protein prenylation and decreased cell viability , which limits their potential use for cholesterol depletion . When combined with lovastatin , compound 5 prevented lovastatin - induced FPP depletion and impairment of protein farnesylation . Compound 5 in combination with the NBP zoledronate completely prevented zoledronate - induced impairment of both protein farnesylation and geranylgeranylation . Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone . The combination of an P37268 inhibitor with an P04035 or P14324 inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion .", "Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK51___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .", "Interferon - alpha promotes the anti - proliferative effect of Erlotinib ( DB00530 ) on human colon cancer cell lines . Interferon - alpha ( IFNalpha ) treatment is associated with up - regulation of epidermal growth factor receptor ( P00533 / P00533 ) expression and marked growth inhibition while maintaining the sensitivity of the target colon cancer cells to epidermal growth factor ( Gut 2004 ; 53 : 123 ) . We aimed to determine the effect of combining IFNalpha and Erlotinib ( an P00533 / P00533 inhibitor ) on colon cancer cell line growth . Crystal - violet staining and flow cytometry were used to assess cell proliferation and expression of P00533 / P00533 . IFNalpha pre - treatment followed by a combination of IFNalpha plus Erlotinib significantly enhanced the sensitivity of 7 / 9 of colon cancer cell lines by 7 - 43 % . This approach may have clinical implications for improving treatment based on targeting of P00533 / P00533 .", "Development of the epidermal growth factor receptor inhibitor Tarceva ( DB00530 ) . The epidermal growth factor receptor ( P00533 ) is a transmembrane receptor involved in the regulation of a complex array of essential biological processes such as cell proliferation and survival . Dysregulation of P00533 signaling network has been frequently reported in multiple human cancers and has been associated with the processes of tumor development , growth , proliferation , metastasis and angiogenesis . Inhibition of the P00533 was associated with antitumor effects in preclinical models . On the bases of these data , therapeutics targeting the P00533 were explore in clinical trials . Tarceva ( DB00530 , OSI Pharmaceuticals , Uniondale , NY ) is a small molecule selective inhibitor of the P00533 tyrosine kinase ( TK ) . In preclinical studies , Tarceva inhibited the phosphorylation of the P00533 in a dose and concentration dependent manner resulting in cell cycle arrest and induction of apoptosis . In in vivo studies , the agent caused tumor growth inhibition and shoved synergistic effects when combined with conventional chemotherapy . Subsequent single agent phase I studies and phase I studies in combination with chemotherapy demonstrated that the agent has a good safety profile and induced tumor growth inhibition in a substantial number of patients with a variety of different solid tumor . Preliminary report from phase II studies confirmed the excellent tolerability of Tarceva as well as showed encouraging preliminary activity . Phase III studies have either been completed or are ongoing in several tumor types such as lung cancer and pancreatic cancer . In summary , Tarceva is a novel inhibitor of the P00533 TK which has shown promising activity in initial studies and is currently undergoing full development as an anticancer drug .", "P30532 gene D398N polymorphism in Japanese lung adenocarcinoma . BACKGROUND : Recently , to identify genetic factors that modify lung cancer risk , P30532 non - synonymous variant amino acid position 398 ( D398N ) was identified . The site was a highly conserved in the second cellular loop of the nicotinic acetylcholine receptor subunit protein . MATERIALS AND METHODS : We have investigated P30532 gene polymorphism status in 302 surgically treated lung adenocarcinoma cases from Nagoya City University Hospital . The presence or absence of P30532 polymorphism was analyzed by direct sequences . P00533 mutations status was already investigated and reported . RESULTS : We detected nine cases ( 2 . 98 % ) of P30532 polymorphism ( D398N ) in our cohort . Total P00533 mutations were present in 129 patients ( 42 . 7 % ) . The polymorphism statuses were not correlated with gender ( women ; 2 . 1 % versus men ; 3 . 7 % , P = 0 . 5119 ) , smoking status ( never smoker ; 2 . 0 % versus smoker ; 4 . 0 % , P = 0 . 3339 ) , pathological stages ( stage I ; 2 . 6 % versus stage II - IV ; 3 . 8 % , P = 0 . 7246 ) , and P00533 mutation status of the lung adenocarcinomas ( mutation ; 2 . 3 % versus wild type ; 3 . 7 % , P = 0 . 7373 ) . In this analysis , P30532 polymorphism ( D398N ) patients had significantly worse prognosis ( 5 / 9 were dead ; mean survival = 27 . 1 mo ) than the patients with P30532 wild type ( 74 / 293 were dead ; mean survival = 113 . 9 mo ) ( log - rank test ; P = 0 . 0146 ) . CONCLUSION : Although P30532 polymorphism is rare from Japanese lung cancer , polymorphism status might be correlated with shorter survival .", "Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .", "P04626 up - regulates P26447 and several other prometastatic genes in medulloblastoma . Medulloblastoma is frequently disseminated throughout the central nervous system by the time of diagnosis . Conventional therapeutic approaches have not reduced the high mortality associated with metastatic medulloblastoma and little is known regarding the molecular mechanisms that promote tumor invasion . Previously , we reported that overexpression of P04626 in medulloblastoma is associated with poor prognosis and metastasis . Here , we demonstrate that P04626 overexpression increases the migration of medulloblastoma cells across basement membranes in vitro . Furthermore , using microarray expression profiling , we show that P04626 up - regulates the expression of prometastatic genes in medulloblastoma cells . These include P26447 , which was previously shown to promote metastasis of breast cancer . We demonstrate that P26447 is a direct target of P04626 signaling in medulloblastoma cells via a pathway involving phosphatidylinositol 3 - kinase , P31749 , and extracellular signal - regulated kinase 1 / 2 and that levels of P04626 and P26447 are tightly correlated in samples of primary medulloblastoma . Finally , we show that P04626 - dependent medulloblastoma cell invasion in vitro and prometastatic gene expression in vivo can be blocked using the P00533 tyrosine kinase inhibitor DB00530 . These data identify an P04626 driven prometastatic pathway that may provide a novel target for therapeutic intervention in metastatic medulloblastoma .", "Targeting epidermal growth factor receptor : novel therapeutics in the management of cancer . Overexpression of epidermal growth factor receptor ( P00533 ) in epithelial tumors , including head and neck , lung , breast , colon and other solid tumors , has frequently been correlated with poor prognosis , thus stimulating efforts to develop new cancer therapies that target P00533 . Monoclonal antibodies and tyrosine kinase inhibitors specifically targeting P00533 are the most well - studied and hold substantial promise of success . Several compounds of monoclonal antibodies and tyrosine kinase inhibitors targeting P00533 have been studied and clinical trials are now underway to test the safety and efficacy of these targeting strategies in several human tumors . This review will address each of these agents alone or in combination with radiation or chemotherapy and highlight some of these promising developments . Cetuximab ( Erbitux ) is being evaluated in combination with radiation or chemotherapy in Phase III trials . Other compounds such as h - R3 , DB01269 , P50402 - 55900 and ICR - 62 have proved to be effective in targeting malignant cells alone or in combination with traditional therapies . Tyrosine kinase inhibitors targeting the intracellular domain of P00533 , including ZD - 1839 ( gefitinib , DB00317 ) , DB00530 ( Erlotinib / Tarceva ) , PD - 153053 , PD - 168393 and DB05424 , have been studied in clinical setting alone or in combination with radiation or chemotherapy . ZD - 1839 is being studied in a Phase III trial in patients with advanced non - small cell lung cancer . P00533 targeted treatment by monoclonal antibodies and tyrosine kinase inhibitors have been proven to sensitize tumor cells to the effects of chemotherapy and radiation therapy . The synergistic activities and nonoverlapping toxicities of these compounds allow concomitant administration with cytotoxic therapy . Challenges of evaluating P00533 targeted agents exist in selecting the optimal dosages and determining long - term toxicity .", "P00747 / plasmin regulates c - fos and egr - 1 expression via the MEK / P29323 pathway . In this study , we showed that plasminogen ( Plg ) and plasmin ( Pla ) bind to lysine - binding sites on cell surface and trigger a signaling pathway that activates the mitogen - activated protein kinase ( MAPK ) MEK and P27361 / 2 , which in turn leads to the expression of the primary response genes c - fos and early growth response gene egr - 1 . Our data show that the Plg / Pla - stimulated steady - state mRNA levels of both genes reached a maximum by 30 min and then returned to basal levels by 1h . The gene induction was sensitive to both pharmacological and genetic inhibition of MEK . Leupeptin , a serine protease inhibitor , suppressed Pla but not Plg - induced c - fos and egr - 1 expression , emphasizing the role played by the serine protease activity associated with Pla . Pre - incubation with cholera toxin completely blocked the Plg / Pla - induced gene expression , suggesting that another signaling pathway , which recruits G protein - coupled receptors , may also be involved . Furthermore , Plg / Pla also stimulated AP - 1 and P18146 DNA - binding activities , which were abrogated by pharmacological inhibition of MEK . Altogether , these results suggest that Plg / Pla stimulates c - fos and egr - 1 expression via activation of the MEK / P29323 pathway .", "A field synopsis and meta - analysis of genetic association studies in peripheral arterial disease : The CUMAGAS - PAD database . In an electronic search of the literature , the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease ( PAD ) . They created a comprehensive database of all eligible studies , collecting detailed genetic and bioinformatics data on each polymorphism . Data from eligible studies were synthesized using meta - analysis techniques . Gene variants were classified into distinct pathophysiologic pathways , and their potential involvement in PAD pathogenesis was determined . Forty - one publications that examined 44 gene polymorphisms were included . For 37 polymorphisms , the variant form had a functional effect . Twenty - three polymorphisms in 22 potential PAD candidate genes ( F2 , P02675 , P42898 , P05106 , P12821 , AGT , P05231 , P13500 , P05362 , P16581 , P14780 , P37231 , P03956 , P35611 , Q9H244 , P11150 , Q13093 , Q8WTV0 , P08254 , P55157 , P08519 , P32297 ) showed a significant association in individual studies . Eighty - eight percent of the studies had statistical power of less than 50 % , and in 15 studies the genotype distribution in the control group did not conform to Hardy - Weinberg equilibrium . Data on 12 polymorphisms ( P12259 1691 G / A , P42898 677C / T , F2 20210 G / A , P05106 1565 T / C , P12821 I / D , AGT 704C / T , AGT - 6G / A , AGT 733C / T , P05231 - 174 G / C , P14780 - 1562C / T , P05362 1462A / G , P32297 831C / T ) were synthesized , and a positive association was found for 3 ( P05231 - 174 G / C , P05362 1462A / G , P32297 831C / T ) .", "Erlotinib ( Tarceva , DB00530 ) antagonizes DB00171 - binding cassette subfamily B member 1 and DB00171 - binding cassette subfamily G member 2 - mediated drug resistance . It has been reported that gefitinib , an epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor ( TKI ) , has the ability to modulate the function of certain DB00171 - binding cassette ( DB01048 ) transporters and to reverse ABC subfamily B member 1 ( P08183 ; P - glycoprotein ) - and ABC subfamily G member 2 ( Q9UNQ0 ; breast cancer resistance protein / mitoxantrone resistance protein ) - mediated multidrug resistance ( MDR ) in cancer cells . However , it is unknown whether other P00533 TKIs have effects similar to that of gefitinib . In the present study , we have investigated the interaction of another P00533 TKI , erlotinib , with selected ABC drug transporters . Our findings show that erlotinib significantly potentiated the sensitivity of established P08183 or Q9UNQ0 substrates and increased the accumulation of paclitaxel or mitoxantrone in P08183 - or Q9UNQ0 - overexpressing cells . Furthermore , erlotinib did not significantly alter the sensitivity of non - P08183 or non - Q9UNQ0 substrates in all cells and was unable to reverse MRP1 - mediated MDR and had no effect on the parental cells . However , erlotinib remarkably inhibited the transport of E ( 2 ) 17 beta G and methotrexate by Q9UNQ0 . In addition , the results of ATPase assays show that erlotinib stimulated the ATPase activity of both P08183 and Q9UNQ0 . Interestingly , erlotinib slightly inhibited the photolabeling of P08183 with [( 125 ) I ] iodoarylazidoprazosin ( IAAP ) at high concentration , but it did not inhibit the photolabeling of Q9UNQ0 with IAAP . Overall , we conclude that erlotinib reverses P08183 - and Q9UNQ0 - mediated MDR in cancer cells through direct inhibition of the drug efflux function of P08183 and Q9UNQ0 . These findings may be useful for cancer combinational therapy with erlotinib in the clinic .", "DB00530 OSI Pharmaceuticals . DB00530 ( formerly CP - 358774 ) , a quinazoline derivative , is an orally active epidermal growth factor receptor ( P00533 ) inhibitor which was originally under joint development by Pfizer and OSI Pharmaceuticals ( formerly Oncogene Science ) for the potential treatment of cancer ( eg , ovarian , non - small cell lung cancer ( NSCLC ) and head and neck ) . It is being evaluated in phase II trials [ 304305 ] , [ 372201 ] . On 8 January 2001 , OSI announced that it had signed an agreement with Roche and Genentech for the global co - development and marketing of DB00530 . The agreement with Genentech covers the United States , that with Roche the rest of the world [ 395371 ] , [ 395526 ] . In June 2000 , OSI gained all development and marketing rights for DB00530 following Pfizer ' s merger with Warner - Lambert [ 371439 ] . In September 2000 , Pfizer transferred the IND dossierfor DB00530 to OSI ahead of the timeline agreed in the June 2000 development and marketing rights agreement [ 383786 ] . The phase II trials will assess DB00530 both as a single agent and in combination with existing chemotherapy regimens [ 347783 ] . Phase III trials are expected to be initiated in 2001 [ 347783 ] . In October 2000 , Lehman Brothers predicted that DB00530 would move into pivotal trials in thefirst half of 2001 and that the drug would be launched in 2003 . The analysts also estimated worldwide sales of US $ 66 million , $ 285 million and $ 461 million in 2003 , 2004 and 2005 , respectively , and peak sales in excess of US $ 500 million [ 395189 ] .", "Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK6___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .", "DB09280 - ___MASK69___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .", "Endogenous concentrations of ouabain act as a cofactor to stimulate fluid secretion and cyst growth of in vitro ADPKD models via DB02527 and P00533 - Src - MEK pathways . In autosomal - dominant polycystic kidney disease ( ADPKD ) , renal cysts develop by aberrant epithelial cell proliferation and transepithelial fluid secretion . We previously showed that ouabain increases proliferation of cultured human ADPKD cells via stimulation of the P01133 receptor ( P00533 ) - Src - MEK / P29323 signaling pathway . We examined whether ouabain affects fluid secretion and in vitro cyst growth of human ADPKD cell monolayers , ADPKD cell microcysts cultured in a three - dimensional collagen matrix , and metanephric organ cultures from Pkd1 ( m1Bei ) mice . Physiological concentrations of ouabain alone did not affect net transepithelial basal - to - apical fluid transport in ADPKD monolayers or growth of cultured ADPKD microcysts . In contrast , in the presence of forskolin or 8 - bromo - DB02527 , ouabain significantly enhanced ADPKD fluid secretion and microcyst expansion . Ouabain exerted this effect by enhancing DB02527 - dependent Cl (-) secretion via the P13569 . Similarly , ouabain accelerated DB02527 - dependent cyst enlargement in Pkd1 ( m1Bei ) mice metanephroi , with a more prominent response in homozygous than heterozygous mice . Ouabain had no effect on fluid secretion and cystogenesis of normal human kidney cells and caused only slight cystic dilations in wild - type mouse kidneys . The effects of ouabain in ADPKD cells and Pkd1 ( m1Bei ) metanephroi were prevented by inhibitors of P00533 ( AG1478 ) , Src ( Q99463 ) , and MEK ( U0126 ) . Together , our results show that ouabain , used in physiological concentrations , has synergistic effects on DB02527 - mediated fluid secretion and cyst growth , via activation of the P00533 - Src - MEK pathway . These data provide important evidence for the role of ouabain as an endogenous hormone that exacerbates ADPKD cyst progression .", "Targeting epidermal growth factor receptor in lung cancer . Among the most promising agents in clinical development to treat non - small - cell lung cancer ( NSCLC ) are the epidermal growth factor receptor ( P00533 ) targeting agents . A series of recent studies have demonstrated the activity of anti - P00533 targeted therapies for NSCLC . In advanced NSCLC that is refractory to chemotherapy , antitumor responses have been reported with P00533 tyrosine kinase inhibitors ( ZD1839 and DB00530 ) . The role of ZD1839 and DB00530 as possible additions to standard chemotherapy in the first - line setting has also been evaluated , and the studies conducted to date should respond to the question of whether these compounds could provide a survival benefit . Other areas of research involve looking at the role of P00533 tyrosine kinase inhibitors in the neoadjuvant treatment of stage III NSCLC and the planning of chemoprevention studies . These exciting results and plans are further complemented by an emerging number of compounds in clinical development , including both monoclonal antibodies ( ie , IMC - C225 ) and other tyrosine kinase inhibitors , directed at the P00533 .", "Why the epidermal growth factor receptor ? The rationale for cancer therapy . There is a need for new , selective anticancer agents that differentiate between malignant and nonmalignant cells . The benefits of such agents would include a higher therapeutic index and lower toxicity than conventional therapies . Although expressed in nonmalignant cells , the epidermal growth factor receptor ( P00533 ) is highly expressed in a variety of tumors , and its expression correlates with poor response to treatment , disease progression , and poor survival . Evidence for a role for the P00533 in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor . Activation of the P00533 signaling pathway in cancer cells has been linked with increased cell proliferation , angiogenesis , and metastasis , and decreased apoptosis . Preclinical data show that anti - P00533 therapies can inhibit these effects in vitro and in vivo . In addition , preclinical data confirm that many such agents have the potential to increase the effectiveness of current cytotoxic agents . Following accelerated drug development programs , phase III trials are now under way for a number of P00533 - targeted therapies , including the monoclonal antibody IMC - C225 and the P00533 - tyrosine kinase inhibitors ZD1839 ( DB00317 ) and DB00530 . Thus , the rationale for P00533 - targeted approaches to cancer treatment is apparent and now well established , and there is increasing evidence that they may represent a significant contribution to cancer therapy .", "Compensatory increases in Her - 2 / neu activation in response to P00533 tyrosine kinase inhibition in colon cancer cell lines . BACKGROUND : Tyrosine kinase receptors of the ErbB family have become promising targets for anti - neoplastic drugs , but mechanisms of resistance are incompletely understood . To investigate such pathways , we applied a small - molecule , selective P00533 inhibitor , DB00530 , to three well - characterized colon cancer cell lines and studied the alterations of expression and activation of receptors in the erbB family . METHODS : MTT assays were performed to determine the IC ( 50 ) s of GEO , FET , and HCT 116 human colorectal cancer cell lines treated with DB00530 . Plated cells were then exposed to either DB01093 control or 7 microm of DB00530 for treatment durations of 1 , 3 , 5 , 7 , 10 , 14 , 28 , and 56 days . Cell lysates were evaluated by Western blotting , evaluating both total and phosphorylated levels of P00533 , Her - 2 / neu , and erbB - 3 . RESULTS : IC ( 50 ) values for GEO , FET , and HCT 116 cell lines exposed to DB00530 were 12 . 0 , 16 . 0 , and greater than 100 microm , respectively . In all treated cell lines , DB00530 diminished P00533 activation but did not affect total expression compared with controls . In contrast , Her - 2 / neu activation was increased in all cell lines . These changes in P00533 and Her - 2 / neu were identified within 24 h but peaked later in the treatment cycle . ErbB - 3 expression and activation did not follow a consistent pattern between cell lines . CONCLUSIONS : Inhibition of P00533 led to increased activation of Her - 2 / neu . This result suggests a possible mechanism by which cells might escape the proapoptotic signals resulting from P00533 blockade . Our findings suggest concurrent inhibition of multiple members of the erbB family may yield stronger apoptotic responses than single receptor blockade alone .", "P00533 tyrosine kinase inhibitors : application in non - small cell lung cancer . Despite treatment advances over the past decade , long - term survival for patients with non - small cell lung cancer ( NSCLC ) remains poor , and treatment options available after second - line therapy are limited . Increased understanding of cancer biology has led to the identification of several potential targets for treatment . The epidermal growth factor receptor ( P00533 ) belongs to a family of plasma membrane receptor tyrosine kinases that controls many important cellular functions , from growth and proliferation to cell death . This receptor is a particularly promising therapeutic target because it often is overexpressed in patients with NSCLC and has been implicated in the pathogenesis as well as the proliferation , invasion , and metastasis of lung cancer and other malignancies . New agents developed to inhibit P00533 function include small - molecule tyrosine kinase inhibitors , monoclonal antibodies to P00533 , and pan - P00533 inhibitors . Completed and ongoing clinical trials have shown that P00533 inhibitors have remarkable efficacy for patients with relapsed NSCLC . Among these , two phase 2 trials have shown that ZD1839 is effective when used as monotherapy . The response rates are comparable with those for docetaxel given in the second - line setting . Another phase 2 trial has shown that DB00530 is effective in the same setting . Data from phase 3 trials indicate that adding an P00533 tyrosine kinase inhibitor to chemotherapy does not provide an additional survival benefit , as compared with standard chemotherapy alone for first - line treatment of NSCLC . It appears that P00533 tyrosine kinase inhibitors are safe and well tolerated by patients with cancer . Further studies will elucidate how these new agents can best be used for NSCLC and other tumor types .", "Potential role for epidermal growth factor receptor inhibitors in combined - modality therapy for non - small - cell lung cancer . There has been a surge of interest in the translation of discoveries in molecular biology into clinically relevant therapies in the field of hematology / oncology . The epidermal growth factor receptor ( P00533 ) has been a molecular target of significant interest and investigation , and preclinical and clinical studies support a role for targeted therapy in a variety of cancers , including non - small - cell lung cancer ( NSCLC ) via compounds that specifically inhibit P00533 . ZD1839 , IMC - C225 , and DB00530 are the most clinically developed of these compounds . Interestingly , preclinical studies have demonstrated that P00533 inhibitors may have radiation - sensitizing properties , as well as increased cytotoxic activity in combination with chemotherapeutic agents , suggesting a potential role for P00533 inhibitors as an adjunct to the current combined - modality approach for therapy of Stage III NSCLC . Therefore , clinical trials have been proposed and initiated to address the issue of determining the impact of the addition of P00533 inhibitors to the standard combined - modality regimen ( chemotherapy / radiation therapy +/- surgery ) for Stage III NSCLC . This article reviews preclinical and clinical data supporting the role for P00533 inhibitors alone or in combination with chemotherapy / radiation therapy for locally advanced NSCLC . Also , it will provide an overview of ongoing and proposed clinical studies investigating the potential role for P00533 inhibitors in Stage III NSCLC .", "P00533 tyrosine kinase inhibitors in late stage clinical trials . The epidermal growth factor receptor ( P00533 ) is a cell membrane receptor that plays a key role in cancer development and progression . Ligand - activated P00533 - dependent signalling is involved in cell proliferation , apoptosis , angiogenesis and metastatic spread . Targeting the P00533 , therefore , represents a promising molecular approach in cancer treatment . Several anti - P00533 agents are in clinical development . Three drugs are currently in Phase II and III development as single agents , or in combination with other anticancer modalities : IMC - 225 ( cetuximab / Erbitux ; ImClone ) , a chimaeric human - mouse monoclonal IgG ( 1 ) antibody , which blocks ligand binding and functional activation of the P00533 ; DB00530 ( erlotinib / Tarceva ; Genentech / OSI / Roch ) and ZD1839 ( gefitinib / DB00317 ; AstraZeneca ) , two small molecule P00533 - selective inhibitors of tyrosine kinase enzymatic activity , which prevent P00533 autophosphorylation and activation . DB00317 is the first P00533 - targeting agent to be registered as an anticancer drug in Japan , in Australia and in the US for the third - line treatment of chemoresistant non - small cell lung cancer ( NSCLC ) patients . This review will focus on the preclinical background and on the results from the first series of clinical trials with these drugs . Furthermore , continuing clinical trials and a series of open clinical issues for the development of optimal strategies of using P00533 - targeting agents will be discussed .", "[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK72___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .", "Mutant epidermal growth factor receptor up - regulates molecular effectors of tumor invasion . The gene most commonly altered in human glioblastomas is the epidermalgrowth factor receptor ( P00533 ) . We profiled transcripts induced by mutantEGFR to better understand its role in tumor progression . The pattern found suggested enhanced tumor invasion . The highly induced genes included extracellular matrix components , metalloproteases , and a serine protease . We confirmed that mutant P00533 did make glioblastoma cells both more motile and invasive using in vitro assays . Furthermore , inhibitors of P00533 ( DB00530 and Tyrphostin AG1478 ) selectively down - regulated these molecular effectors in glioblastoma cells , eliminating enhanced invasion .", "Inhibition of proliferation , migration , and matrix metalloprotease production in malignant mesothelioma cells by tyrosine kinase inhibitors . The epidermal growth factor receptor ( P00533 ) is expressed in a variety of human solid tumors , including malignant mesothelioma . P00533 has been implicated in regulation of cell proliferation , survival , angiogenesis , and metastasis , making it an ideal target for drug development . ZD1839 ( gefitinib ) and DB00530 ( erlotinib ) are new , low - molecular - weight , P00533 - selective tyrosine kinase ( TK ) inhibitors , whereas DB05424 is a pan - P00533 family TK inhibitor . In the present study , we used ZD1839 , DB00530 , and DB05424 and investigated the effect of these drugs on proliferation , migration , and matrix metalloprotease ( MMP ) production in three malignant mesothelioma cell lines ( M14K , ZL34 , and SPC212 ) . Using [ 3H ] thymidine incorporation , DNA synthesis assay , we found that all three drugs inhibited transforming growth factor - alpha ( TGF - alpha ) - induced cellular proliferation in a dose - dependent manner . In addition , all three drugs induced apoptosis in ZL34 cells as determined by flow cytometry using annexin - V staining . Furthermore , all three drugs inhibited TGF - alpha - induced cell migration ( chemotaxis ) in a dose - dependent manner as determined by Boyden chamber assay . TGF - alpha - induced P14780 production was also inhibited in a dose - dependent manner as determined by gelatin zymography in three cell lines tested . In conclusion , our study demonstrates inhibitory effectiveness of P00533 - TK inhibitors in malignant mesothelioma cells and suggests that these drugs may be an effective treatment strategy for malignant mesothelioma .", "___MASK77___ block of cloned human T - type voltage - gated calcium channels . ___MASK77___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .", "Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER - 3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity . Signaling through the receptor for epidermal growth factor receptor ( P00533 ) is frequently deregulated in solid tumors . Erlotinib ( Tarceva , DB00530 , OSI Pharmaceuticals , Inc . , Melville , NY ) is a low molecular weight , orally bioavailable inhibitor of the P00533 that has been approved for both non - small cell lung cancer and pancreatic cancers . Previous studies have indicated that sensitivity to P00533 antagonists correlated with HER - 3 signaling for non - small cell lung cancer . Herein , we have sought to understand the signaling pathways that mediate erlotinib sensitivity for pancreatic and colorectal cancers . In a panel of 12 pancreatic tumor cell lines , we find that P00533 is coexpressed with HER - 3 in all cell lines sensitive to erlotinib but not in insensitive cell lines . Erlotinib can block HER - 3 phosphorylation in these sensitive cell lines , suggesting that HER - 3 is transactivated by P00533 . Knockdown of HER - 3 in BxPC3 , an erlotinib - sensitive pancreatic tumor cell line , results in inhibition of the phosphorylation for both Akt and S6 and is associated with a decrease in cell proliferation and reduced sensitivity to erlotinib . Therefore , P00533 transactivation of HER - 3 mediates Akt signaling and can contribute to erlotinib sensitivity for pancreatic tumors . We extended our analysis to a panel of 13 colorectal tumor cell lines and find that , like pancreatic , HER - 3 is coexpressed with P00533 in the most erlotinib - sensitive cell lines but not in erlotinib - insensitive cell lines . These studies suggest that HER - 3 could be used as a biomarker to select patients who are most likely to respond to erlotinib therapy .", "Phase II study of carboplatin and erlotinib ( Tarceva , DB00530 ) in patients with recurrent glioblastoma . Targeting the epidermal growth factor receptor ( P00533 ) may be effective in a subset of glioblastoma patients . This phase II study assessed the clinical activity of erlotinib plus carboplatin and to determine molecular predictors of response . The primary endpoint was progression free survival ( PFS ) . Patients with recurrent glioblastoma with no more than two prior relapses received carboplatin intravenously on day 1 of every 28 - day cycle ( target AUC of 6 mg x ml / min ) . Daily erlotinib at 150 mg / day was dose escalated to 200 mg / day , as tolerated . Clinical and Q9BWK5 assessments were made every 4 and 8 weeks , respectively . Tumor tissue was evaluated for P00533 , AKT and phosphatase and tensin homolog ( P60484 ) status . One partial response ( PR ) was observed out of 43 assessable patients . Twenty patients ( 47 % ) had stable disease ( SD ) for an average of 12 weeks . Median PFS was 9 weeks . The 6 - month PFS rate was 14 % . Median overall survival ( OS ) was 30 weeks . This regimen was well tolerated with grade 3 / 4 toxicities of fatigue , leukopenia , thrombocytopenia and rash requiring dose reductions . A recursive partitioning analysis ( RPA ) predicted that patients with KPS > or = 90 treated with more than 1 prior regimen had the highest OS . No correlation was observed between P00533 , Akt or P60484 expression and either PFS or OS . Carboplatin plus erlotinib is well tolerated but has modest activity in unselected patients . Future trials should be stratified based on optimal molecular or clinical characteristics .", "Erlotinib : success of a molecularly targeted agent for the treatment of advanced pancreatic cancer . P00533 ( P00533 ) is overexpressed by several solid tumors , including pancreatic cancer , and has become an important target for novel anticancer pharmacotherapy . Erlotinib ( Tarceva , DB00530 ) is an orally available small - molecule inhibitor of the P00533 tyrosine kinase . The addition of erlotinib to gemcitabine has been shown to prolong survival of patients treated for advanced pancreatic cancer in the National Cancer Institute of Canada PA . 3 trial . This survival advantage is small yet noteworthy , in that numerous gemcitabine - containing combinations have failed to show a statistically significant survival advantage over gemcitabine alone . The most frequent toxicities associated with the addition of erlotinib are diarrhea and rash . Erlotinib - induced rash appears to be predictive of outcome . Further clinical studies of erlotinib in the treatment of pancreatic cancer are ongoing .", "Erlotinib in non - small cell lung cancer : a review . Erlotinib ( Tarceva , DB00530 ; Pfizer , Inc . ) is an orally - active , targeted inhibitor of the epidermal growth factor receptor ( P00533 / P00533 ) , which is part of a key regulatory pathway in cancer . Patients with advanced , incurable non - small cell lung cancer ( NSCLC ) may derive a clinical benefit from first - and second - line chemotherapy , but third - line treatment with available cytotoxic agents is not effective . Remarkably , P00533 / P00533 antagonists have demonstrated activity as second - and even third - line treatment for this disease . Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival , progression free survival and time to disease related symptoms ( cough , pain , shortness of breath ) compared with treatment with best supportive care in patients who have failed standard first - or second - line chemotherapy . This paper reviews the pharmacology , preclinical and clinical data to support the use of erlotinib in NSCLC .", "Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK18___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK18___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .", "Genome - wide analysis of DNA copy number alterations and gene expression in gastric cancer . Genomic copy number aberrations ( CNAs ) are believed to play a major role in the development and progression of human cancers . Although many CNAs have been reported in gastric cancer , their genome - wide transcriptional consequences are poorly understood . In this study , to reveal the impact of CNAs on genome - wide expression in gastric cancer , we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization ( array CGH ) and 24 of these 30 cases for their expression profiles by oligonucleotide - expression microarray . We found that with the application of laser microdissection , most CNAs were detected at higher frequency than in previous studies . Notably , gain at 20q13 was detected in almost all cases ( 97 % ) , suggesting that this may play an important role in the pathogenesis of gastric cancer . By comparing the array CGH data with expression profiles of the same samples , we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions . Furthermore , we identified 125 candidate genes , consisting of 114 up - regulated genes located in recurrent regions ( > 10 % ) of amplification and 11 down - regulated genes located in recurrent regions of deletion . Up - regulation of several candidate genes , such as Q99741 , P60059 , Q9BTT0 , Q13895 and P37268 , was confirmed by immunohistochemistry . Interestingly , some candidate genes were localized at genomic loci adjacent to well - known genes such as P00533 , P04626 and Q13485 , and concordantly deregulated by genomic alterations . Based on these results , we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer .", "The emerging role of epidermal growth factor receptor inhibitors in ovarian cancer . P00533 ( P00533 ) inhibitors are a new biologically targeted therapy , which may offer new hope in the treatment of patients with advanced or recurrent ovarian cancers . In this review , we summarize and discuss the results of research to date on P00533 inhibitors with particular emphasis on ovarian cancer . We reviewed data identified by searches of MEDLINE , PubMed , and abstracts from the proceedings of the American Society of Clinical Oncology meetings from 1998 to 2006 , with the search terms \" Ovarian Cancer , \" \" P00533 , \" \" gefitinib , ZD1839 , DB00317 , \" \" erlotinib , DB00530 , Tarceva , \" \" DB05424 , \" \" DB01259 , lapatinib , \" \" PKI - 166 , \" \" Q9Y259 569 , \" \" anti - P00533 antibodies , \" \" trastuzumab , Herceptin , \" \" cetuximab , Erbitux , IMC - C225 , \" \" matuzumab , P50402 72000 , \" \" panitumamab , DB01269 , \" \" pertuzumab , \" and \" vandetanib , rINN , DB05294 , DB05294 . \" Phase II trials of both small molecule inhibitors of P00533 - and antibody - based inhibitors are currently ongoing in ovarian cancer and emerging data suggest that their activity in unselected women with advanced or recurrent ovarian cancer is modest , when utilized as a single agent . It is possible that these agents will be highly effective in smaller subsets of patients whose tumors are dependent on P00533 signaling , perhaps through activating mutations in P00533 or its downstream pathway . Targeted therapy with P00533 inhibitors is an untapped potential resource in the treatment of advanced or recurrent ovarian cancer . Ongoing trials will elucidate the most effective strategies to use these agents individually or in combination with traditional chemotherapeutic agents .", "Targeted therapy in non - small - cell lung cancer . Although treatment of advanced non - small - cell lung cancer has been improved with the availability of such new agents as the taxanes , topoisomerase inhibitors , vinorelbine ( Navelbine ) , and gemcitabine ( Gemzar ) , platinum - based combination therapy has appeared to reach a threshold of therapeutic effectiveness . A paradigm shift in approach to non - small - cell lung cancer and other tumors may be heralded by the development of agents targeting specific biologic pathways in tumor development . Such new agents include antibody epithelial growth factor receptor ( P00533 ) inhibitors ( eg , the monoclonal antibodies trastuzumab [ Herceptin ] and cetuximab [ IMC - C225 , Erbitux ] ) and P00533 tyrosine kinase inhibitors ( eg , ZD1839 [ DB00317 ] and DB00530 ) , angiogenesis inhibitors ( eg , matrix metalloproteinase inhibitors ) , vascular endothelial growth factor ( P15692 ) inhibitors ( eg , monoclonal antibody to P15692 ligand and small - molecule tyrosine kinase ) , and signal transduction inhibitors ( eg , ISIS - 3521 , an antisense oligonucleotide to protein kinase C - alpha ) . A number of these agents have entered advanced - phase clinical investigation . It is likely that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment , including maintenance therapy . It is even possible that these new biologic therapies will be used together as rational combinations ( based on pathologic diagnosis ) for advanced non - small - cell lung cancer .", "Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib ( DB00530 ) in non - small - cell lung cancer . Erlotinib ( DB00530 ; Tarceva ) is an orally available , highly specific epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor . The results of 3 phase II studies with erlotinib in non - small - cell lung cancer ( NSCLC ) are reviewed herein : ( 1 ) in patients with chemotherapy - resistant , P00533 / P00533 - expressing NSCLC of all histologies , ( 2 ) in patients with bronchoalveolar carcinoma previously untreated or treated with chemotherapy , and ( 3 ) as first - line therapy in elderly patients with NSCLC of all histologies . These studies have evaluated tumor response , survival , and symptom improvement . Erlotinib was given as an oral , continuous daily dose of 150 mg . The drug was well tolerated ; drug - related cutaneous rash and diarrhea were observed in approximately two thirds of patients . Withdrawals caused by toxicity were rare . The response rates were 12 . 3 % , 25 % , and 13 . 3 % , respectively . Mature survival data are available for the first trial . The median survival was 8 . 4 months , and the 1 - year survival rate was 40 % . All responding patients in the first and second trials presented skin rash . In addition , survival correlated with the occurrence and severity of rash in the first trial . No data on the correlation between rash and survival are available for the second and third trials . Erlotinib is active and well tolerated in patients with NSCLC as first - and second - line therapy . Cutaneous rash appears to be a surrogate marker of clinical benefit , but this finding needs to be confirmed in ongoing and future studies .", "Development of the epidermal growth factor receptor inhibitor DB00530 . The epidermal growth factor receptor ( P00533 ) is a transmembrane receptor involved in the regulation of a complex array of essential biological processes such as cell proliferation and survival . Dysregulation of the P00533 signaling network has been frequently reported in multiple human cancers and has been associated with the processes of tumor development , growth , proliferation , metastasis , and angiogenesis . Inhibition of the P00533 was associated with antitumor effects in preclinical models . On the basis of these data , therapeutics targeting the P00533 were explored in clinical trials . DB00530 is a small - molecule selective inhibitor of the P00533 tyrosine kinase . In preclinical studies , DB00530 inhibited the phosphorylation of the P00533 in a dose - dependent and concentration - dependent manner resulting in cell cycle arrest and induction of apoptosis . In in vivo studies , this agent caused tumor growth inhibition and showed synergistic effects when combined with conventional chemotherapy . Subsequent single - agent phase I studies and phase I studies in combination with chemotherapy showed that the agent has a good safety profile and induced tumor growth inhibition in a substantial number of patients with a variety of different solid tumors . Preliminary reports from phase II studies confirmed the excellent tolerability of DB00530 and showed encouraging preliminary activity . Phase III studies have either been completed or are ongoing in several tumor types such as lung cancer and pancreatic cancer . In summary , DB00530 is a novel inhibitor of the P00533 tyrosine kinase that has shown promising activity in initial studies and is currently undergoing full development as an anticancer drug .", "Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .", "___MASK82___ binding to human and rat dopamine and 5 - HT receptors . ___MASK82___ ( ___MASK82___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK82___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK82___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK82___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .", "Epithelial growth factor receptor interacting agents . The data reviewed here have further established the promise of anti - P00533 - targeted therapies . This statement is supported by the evidence of antitumor activity of the TK inhibitors ZD1839 and DB00530 against several tumor types and by the ability of the monoclonal antibody IMC - C225 to reverse clinical chemotherapy resistance . These results are further supported by an emerging number of compounds , monoclonal antibodies , and TK inhibitors directed at the P00533 that are in clinical development ( see Fig . 2 , Table 1 ) . Among the TK inhibitors , these compounds can be further categorized by their receptor specificity and reversibility of binding . In the case of anti - P00533 monoclonal antibodies , compounds in clinical development include chimeric , humanized , and bispecific antibodies . The fundamental observation is that these compounds have shown activity in several tumor types , including NSCL cancer , prostate carcinoma , colorectal carcinoma , ovarian carcinoma , renal cell carcinoma , and head and neck cancers . These findings observed with different agents and in different tumor types validate P00533 as a target for cancer therapy . The results of ongoing studies with these agents in diverse indications and tumor types may establish the role of these promising therapies to our current cancer treatments .", "Phase II study of erlotinib ( DB00530 ) in patients with metastatic colorectal cancer . Erlotinib ( Tarceva , DB00530 ) , a potent epidermal growth factor receptor tyrosine kinase inhibitor ( P00533 ) , was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer . In all , 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg . Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8 . Of 31 evaluable patients , 19 ( 61 % ) had progressive disease and 12 ( 39 % ) had stable disease ( s . d . ) . The median time to progression for those patients having s . d . was 123 days ( range 108 - 329 days ) . The most common adverse events were rash in 34 patients and diarrhoea in 23 patients . Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling . Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre - and on therapy , and showed a statistically significant decrease in the median intensity of both pEGFR ( P = 0 . 008 ) and phospho - extracellular signal - regulated kinase ( P29323 ) ( P = 0 . 008 ) a week after commencement of treatment . No other statistically significant change in tumour markers was observed . Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea . More than one - third of evaluable patients had s . d . for a minimum of 8 weeks . Correlative studies showed a reduction in phosphorylated P00533 and P29323 in tumour tissue post - treatment .", "Protein kinase Cdelta and calmodulin regulate epidermal growth factor receptor recycling from early endosomes through Arp2 / 3 complex and cortactin . The intracellular trafficking of the epidermal growth factor receptor ( P00533 ) is regulated by a cross - talk between calmodulin ( P62158 ) and protein kinase Cdelta ( PKCdelta ) . On inhibition of P62158 , PKCdelta promotes the formation of enlarged early endosomes and blocks P00533 recycling and degradation . Here , we show that PKCdelta impairs P00533 trafficking due to the formation of an F - actin coat surrounding early endosomes . The PKCdelta - induced polymerization of actin is orchestrated by the Arp2 / 3 complex and requires the interaction of cortactin with PKCdelta . Accordingly , inhibition of actin polymerization by using cytochalasin D or by overexpression of active cofilin , restored the normal morphology of the organelle and the recycling of P00533 . Similar results were obtained after down - regulation of cortactin and the sequestration of the Arp2 / 3 complex . Furthermore we demonstrate an interaction of cortactin with P62158 and PKCdelta , the latter being dependent on P62158 inhibition . In summary , this study provides the first evidence that P62158 and PKCdelta organize actin dynamics in the early endosomal compartment , thereby regulating the intracellular trafficking of P00533 .", "Targeted therapy using novel agents in the treatment of non - small - cell lung cancer . Patients with advanced non - small - cell lung cancer ( NSCLC ) have a poor prognosis and high mortality . The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau . The main categories of targeted therapeutics applicable for NSCLC include receptor - targeted therapy , signal transduction or cell - cycle inhibition , angiogenesis inhibitors , gene therapy , and vaccines . Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC . The anti - epidermal growth factor receptor ( P00533 ) group contains trastuzumab and IMC - C225 , monoclonal antibodies against EGFRs that are overexpressed in many cancers . DB00530 and ZD1839 are inhibitors of P00533 tyrosine kinase , a key enzyme of the signaling pathway . Farnesyl transferase inhibitors , such as SCH66336 , and protein kinase C inhibitors , such as ISIS 3521 , have also shown antitumor activity . Antiangiogenesis agents that have shown promise include TNP - 470 , recombinant endostatin , and angiostatin . Antibodies to vascular endothelial growth factor ( P15692 ) also seem to control tumor progression and may prolong survival . LY317615 , an inhibitor of protein kinase Cb , augmented the tumor growth delay produced by cytotoxic drugs . All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs . These new agents are more target specific , less toxic , easier to administer , and may lead to enhanced safety and survival for patients with advanced NSCLC .", "Growth factors and their receptors : new targets for prostate cancer therapy . Stimulation of the signal transduction pathway of the epidermal growth - factor receptor ( P00533 ) tyrosine kinase family of receptors in tumor cells enhances cellular proliferation , prevents apoptosis , and promotes tumor - cell mobility , adhesion , and invasion . Therapeutic approaches used to target the P00533 and its signal transduction cascade include ( 1 ) monoclonal antibodies ( eg , cetuximab [ IMC - C225 ] ) directed against the extracellular binding domain of the receptor ; and ( 2 ) trastuzumab , a monoclonal antibody binding to the P04626 receptor ; immunotoxin conjugates use an antibody directed against P00533 joined to a cell toxin . All are in clinical trials for a number of cancers , including prostate cancer . Antisense strategies are in preclinical development . Low - molecular - weight inhibitors of the P00533 tyrosine kinase also in clinical development include DB00530 , PD182905 , PKI - 166 , DB05424 , and ZD1839 . ZD1839 has shown encouraging results in patients with prostate cancer in phase 1 trials . mn", "New targeted therapies in gastrointestinal cancers . Despite surgical , radiotherapeutic , and chemotherapeutic advances , a large proportion of gastrointestinal ( GI ) cancers remain incurable . An improved understanding of the molecular pathogenesis of cancer has promulgated the development of novel agents designed to target critical pathways involved in cancer development and progression . The crucial role of the epidermal growth factor receptor ( P00533 ) in tumor proliferation and the overexpression of P00533 in several GI cancers provides the rationale for targeting and interrupting this key signaling network . P00533 blockade through monoclonal antibodies ( C225 and DB01269 ) and tyrosine kinase inhibitors ( ZD1839 and DB00530 ) has translated into promising evidence of clinical benefit . Ras - mediated signal transduction has been targeted using inhibitors of farnesyl transferase ( R115777 and SCH66336 ) to block the post - translation modification of Ras . Inhibitors of vascular growth factor receptor ( bevacizumab and PTK787 ) and matrix metalloproteinase target the effects of the host environment . P35354 inhibitors in colorectal cancer and STI571 in GI stromal tumors represent novel therapies of interest for these specific GI cancers . Evidence suggests that novel agents can be administered alone or in combination with standard therapies with little additional toxicity . The results of ongoing and future research efforts will clarify the optimal use and survival benefit of targeted therapies for patients with GI malignancies .", "TGF - β1 → SMAD / p53 / Q15853 → P05121 transcriptional axis in ureteral obstruction - induced renal fibrosis . Chronic kidney disease constitutes an increasing medical burden affecting 26 million people in the United States alone . Diabetes , hypertension , ischemia , acute injury , and urological obstruction contribute to renal fibrosis , a common pathological hallmark of chronic kidney disease . Regardless of etiology , elevated TGF - β1 levels are causatively linked to the activation of profibrotic signaling pathways initiated by angiotensin , glucose , and oxidative stress . Unilateral ureteral obstruction ( UUO ) is a useful and accessible model to identify mechanisms underlying the progression of renal fibrosis . P00747 activator inhibitor - 1 ( P05121 ) , a major effector and downstream target of TGF - β1 in the progression of several clinically important fibrotic disorders , is highly up - regulated in UUO and causatively linked to disease severity . SMAD and non - SMAD pathways ( pp60 ( c - src ) , epidermal growth factor receptor [ P00533 ] , mitogen - activated protein kinase , p53 ) are required for P05121 induction by TGF - β1 . Q15796 / 3 , pp60 ( c - src ) , P00533 , and p53 activation are each increased in the obstructed kidney . This review summarizes the molecular basis and translational significance of TGF - β1 - stimulated P05121 expression in the progression of kidney disease induced by ureteral obstruction . Mechanisms discussed here appear to be operative in other renal fibrotic disorders and are relevant to the global issue of tissue fibrosis , regardless of organ site .", "___MASK39___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake ." ]

[ "___MASK18___", "___MASK39___", "___MASK51___", "___MASK69___", "___MASK6___", "___MASK72___", "___MASK77___", "___MASK81___", "___MASK82___" ]

[ "Persistence of Sulfadoxine - DB00205 Resistance Despite Reduction of Drug Pressure in Malawi . BACKGROUND : In 2007 , Malawi replaced sulfadoxine - pyrimethamine ( SP ) with an artemisinin - based combination therapy as the first - line treatment for uncomplicated Plasmodium falciparum malaria in response to failing SP efficacy . Here we estimate the effect of reduced SP pressure on the prevalence of SP - resistant parasites and the characteristics of the associated selective sweeps flanking the resistance loci . METHODS : Samples obtained from individuals with clinical malaria during a period of high SP use ( 1999 - 2001 ) , a transitional period ( 2007 - 2008 ) , and a period of low SP use ( 2012 ) were genotyped for resistance markers at pfdhfr - ts codons 51 , 59 , and 108 and pfdhps codons 437 , 540 , and 581 . Expected heterozygosity was estimated to evaluate the genetic diversity flanking pfdhfr - ts and pfdhps . RESULTS : An increase in the prevalence of the resistance haplotypes P00374 51I / 59R / 108N and P49366 437G / 540E occurred under sustained drug pressure , with no change in haplotype prevalence 5 years after reduction in SP pressure . The P49366 437G / 540E / 581G haplotype was observed in 2007 and increased in prevalence during a period of reduced SP pressure . Changes to the sweep characteristics flanking pfdhfr - ts and pfdhps were minimal . CONCLUSIONS : In contrast to the rapid and complete return of chloroquine - susceptible falciparum malaria after chloroquine was withdrawn from Malawi , a reemergence of SP efficacy is unlikely in the near future .", "Telomerase - immortalized human fibroblasts retain UV - induced mutagenesis and p53 - mediated DNA damage responses . Immortalized cells frequently have disruptions of p53 activity and lack p53 - dependent nucleotide excision repair ( P55055 ) . We hypothesized that telomerase immortalization would not alter p53 - mediated ultraviolet light ( UV ) - induced DNA damage responses . DNA repair proficient primary diploid human fibroblasts ( GM00024 ) were immortalized by transduction with a telomerase expressing retrovirus . Empty retrovirus transduced cells senesced after a few doublings . Telomerase transduced GM00024 cells ( tGM24 ) were cultured continuously for 6 months ( > 60 doublings ) . Colony forming ability after UV irradiation was dose - dependent between 0 and 20J / m2 UVC ( LD50 = 5 . 6J / m2 ). p53 accumulation was UV dose - and time - dependent as was induction of p48 ( XPE / Q92466 ) , P38936 ( CIP1 / P38936 ) , and phosphorylation on p53 - S15 . UV dose - dependent apoptosis was measured by nuclear condensation . UV exposure induced UV - damaged DNA binding as monitored by electrophoretic mobility shift assays using UV irradiated radiolabeled DNA probe was inhibited by p53 - specific siRNA transfection . p53 - Specific siRNA transfection also prevented UV induction of p48 and improved UV survival measured by colony forming ability . Strand - specific P55055 of cyclobutane pyrimidine dimers ( O75976 ) within P00374 was identical in tGM24 and GM00024 cells . O75976 removal from the transcribed strand was nearly complete in 6h and from the non - transcribed strand was 73 % complete in 24h . UV - induced P00492 mutagenesis in tGM24 was indistinguishable from primary human fibroblasts . These wide - ranging findings indicate that the UV - induced DNA damage response remains intact in telomerase - immortalized cells . Furthermore , telomerase immortalization provides permanent cell lines for testing the immediate impact on P55055 and mutagenesis of selective genetic manipulation without propagation to establish mutant lines .", "Prevalence of the dihydrofolate reductase DB00174 - 108 mutation as the basis for pyrimethamine - resistant falciparum malaria in the Brazilian Amazon . DB00205 resistance in cultivated laboratory isolates of Plasmodium falciparum is linked to the dihydrofolate reductase mutation DB00174 - 108 , a mutation that acts by interrupting drug binding within the active site of the enzyme . To determine the prevalence of this mutation in endemic regions harboring pyrimethamine - resistant malaria , we used a mutation - specific polymerase chain reaction assay to survey P . falciparum strains from a wide section of the Brazilian Amazon . Mutations were identified directly from blood samples without intervening steps of in vitro cultivation . Of 42 samples collected from four states in Brazil , 38 ( 90 % ) contained the DB00174 - 108 codon AAC that confers pyrimethamine resistance , four samples contained only the wild - type DB00133 - 108 codon AGC , and none contained the DB00156 - 108 codon ACC found in cycloguanil - resistant pyrimethamine - sensitive strains . These findings indicate that a very high incidence of the DB00174 - 108 P00374 mutation is responsible for pyrimethamine resistance in the Amazon , and they are consistent with recent failure rates reported for Fansidar ( pyrimethamine - sulfadoxine ) . We suggest that limited use of proguanil be evaluated as an alternative to pyrimethamine .", "Identification of a potent inverse agonist at a constitutively active mutant of human Q9H244 receptor . Human platelets express two P2Y receptors : G ( q )- coupled P2Y ( 1 ) , and G ( i )- coupled P2Y ( 12 ) . Both P2Y ( 1 ) and P2Y ( 12 ) are ADP receptors on human platelets and are essential for ADP - induced platelet aggregation that plays pivotal roles in thrombosis and hemostasis . Numerous constitutively active G protein - coupled receptors have been described in natural or recombinant systems , but in the P2Y receptors , to date , no constitutive activity has been reported . In our effort to identify G protein coupling domains of the human platelet ADP receptor , we constructed a chimeric hemagglutinin - tagged human P2Y ( 12 ) receptor with its C terminus replaced by the corresponding part of human P2Y ( 1 ) receptor and stably expressed it in Chinese hamster ovary - P04264 cells . It is interesting that the chimeric P2Y ( 12 ) mutant exhibited a high level of constitutive activity , as evidenced by decreased DB02527 levels in the absence of agonists . The constitutive activation of the chimeric P2Y ( 12 ) mutant was dramatically inhibited by pertussis toxin , a G ( i ) inhibitor . The constitutively active P2Y ( 12 ) mutant retained normal responses to 2 - methylthio - ADP , with an EC ( 50 ) of 0 . 15 +/- 0 . 04 nM . The constitutively active P2Y ( 12 ) mutant caused Akt phosphorylation that was abolished by the addition of pertussis toxin . Pharmacological evaluation of several P2Y ( 12 ) antagonists revealed ( E ) - N -[ 1 -[ 7 -( hexylamino )- 5 -( propylthio )- 3H - 1 , 2 , 3 - triazolo -[ 4 , 5 - d ]- pyrimidin - 3 - yl ]- 1 , 5 , 6 - trideoxy - beta - d - ribo - hept - 5 - enofuranuronoyl ]- l - aspartic acid ( AR - C78511 ) as a potent P2Y ( 12 ) inverse agonist and 5 '- adenylic acid , N -[ 2 -( methylthio ) ethyl ]- 2 -[( 3 , 3 , 3 - trifluoropropyl ) thio ]- , monoanhydride with ( dichloromethylene ) bis [ phosphonic acid ] ( AR - C69931MX ) as a neutral antagonist . In conclusion , this is the first report of a cell line stably expressing a constitutively active mutant of human platelet P2Y ( 12 ) receptor and the identification of potent inverse agonist .", "[ Genetic and clinical and pathological characteristics of breast cancer in premenopausal and postmenopausal women ] . This study involved 525 breast cancer ( BC ) patients of P24752 - 4N0 - 2M0 stages at the age of 35 years and older . Significant differences in clinical and pathological characteristics between premenopausal and postmenopausal BC patients were found . Mostly marked differences were shown for positive lymph node correlation with distant metastasis , multicentric growth and local recurrence depending on menopause status . The prevalence of various morphological structures in primary tumors was appeared to be associated with different forms of tumor progression in pre - and postmenopausal women . We have studied polymorphisms in 15 genes involved in major cancer related pathways ( apoptosis , interleukins , folate metabolism enzymes genes ) . We found that variant genotypes of P42898 and P00374 genes were associated with an increased BC risk among premenopausal women while polymorphism in Q14116 , p53 genes were associated with BC among postmenopausal women . These results demonstrate novel biological information , which points the different mechanisms contributed to breast cancer progression in premenopausal and postmenopausal women .", "Characterization of duck leucocytes by monoclonal antibodies . cDNAs encoding CD3epsilon , P01730 and the alpha - chain of CD8 of ducks were cloned . Monoclonal antibodies against Pekin duck P01730 and CD8alpha revealed that the antigens were expressed by the majority of thymocytes and by subpopulations of CD3 + cells in peripheral tissues . CD8alpha cell surface expression was also found on 90 % of bursal cells . The B cell specificity of a newly developed mab to the immunoglobulin light - chain ( L - chain ) was confirmed by double labelling studies with the chicken B - cell cytokine Q9Y275 . Using these tools and a mab reacting with the cytoplasmic domain of CD3epsilon , we demonstrated that the CD8alpha molecule is expressed to high levels in CD3 - positive T cells and at lower levels in CD3 - negative bursal and peripheral B cells . Mab 2 - 4 , which recognizes the chicken P10747 molecule , was found to react with P01730 - positive duck lymphocytes and with CD8 - positive duck T cells but not with CD8 - positive B cells . Mab P04264 , which recognizes a common antigen on chicken thrombocytes and monocytes / macrophages , was found to react with duck thrombocytes and macrophages . Thus , a range of mabs is now available which will allow to phenotype the major leucocyte populations in ducks , a surrogate infection model for hepatitis B virus .", "DB00205 resistant Plasmodium falciparum : overproduction of dihydrofolate reductase by a gene duplication . The accumulation of [ 3H ] pyrimethamine by pyrimethamine - resistant ( Pyrr ) mutants of the Plasmodium falciparum strain FCR3 was examined by measuring the accumulation of drug in infected red blood cells . [ 3H ] DB00205 was stage specifically accumulated in trophozoites and schizont infected red blood cells . The mutant parasites accumulated drug as efficiently as FCR3 . DB00205 was associated with a high molecular weight protein that eluted from a Sephadex G200 column exactly as [ 3H ] fluorodeoxyuridinemonophosphate ( FdUMP ) labeled parasite dihydrofolate reductase - thymidylate synthetase ( P00374 - TS ) enzyme . These results suggested that the pyrimethamine resistance was not associated with decreased drug permeability of the membrane . P00374 - TS -[ 3H ] FdUMP enzyme complex of all the Pyrr mutants and FCR3 had a monomer of 70 kDa as measured by sodium dodecyl sulfate - polyacrylamide gel electrophoresis . One highly resistant mutant , FCR3 - D7 , exhibited a 5 - 10 fold higher uptake of pyrimethamine and a proportionately higher amount of P00374 - TS protein than FCR3 but only a normal level of P00374 activity . The genomic DNA of FCR3 - D7 was shown to contain at least twice as much P00374 - TS specific DNA than either FCR3 - P41226 , another Pyrr mutant , or FCR3 . Preliminary results suggested some of the P00374 - TS genetic material in FCR3 - D7 is associated with a gene duplication .", "In - vitro activity of atovaquone , sulphamethoxazole and dapsone alone and combined with inhibitors of dihydrofolate reductase and macrolides against Pneumocystis carinii . The anti - Pneumocystis carinii activity of atovaquone , dapsone and sulphamethoxazole alone and combined with dihydrofolate reductase ( P00374 ) inhibitors and macrolides was investigated against five clinical isolates of P . carinii . The susceptibility tests were performed by inoculation of the organisms on to cell monolayer and parasite count after 72 h incubation at 37 degrees C . Culture plates were added to Dulbecco ' s modified Eagle ' s medium containing serial dilutions of atovaquone , dapsone and sulphamethoxazole alone or in combination with diaveridine , pyrimethamine , trimethoprim , azithromycin , clarithromycin and roxithromycin . DB01117 , dapsone and sulphamethoxazole were found to be effective at levels well below the concentrations that could be achieved clinically , while P00374 inhibitors were shown to combine effectively with dapsone and sulphamethoxazole . No synergy could be demonstrated between atovaquone and P00374 inhibitors or macrolides . A mild synergic effect was noted when macrolides were combined with dapsone and sulphamethoxazole . DB00205 ( 0 . 5 mg / L ) combined with dapsone and trimethoprim ( 0 . 5 mg / L ) combined with sulphamethoxazole exerted the strongest inhibitory effect .", "Crystal structure of dihydrofolate reductase from Plasmodium vivax : pyrimethamine displacement linked with mutation - induced resistance . DB00205 ( Pyr ) targets dihydrofolate reductase of Plasmodium vivax ( PvDHFR ) as well as other malarial parasites , but its use as antimalarial is hampered by the widespread high resistance . Comparison of the crystal structures of PvDHFR from wild - type and the Pyr - resistant ( SP21 , DB00133 - 58 --> DB00125 + DB00133 - 117 --> DB00174 ) strain as complexes with NADPH and Pyr or its analog lacking p - Cl ( Pyr20 ) clearly shows that the steric conflict arising from the side chain of DB00174 - 117 in the mutant enzyme , accompanied by the loss of binding to DB00133 - 120 , is mainly responsible for the reduction in binding of Pyr . Pyr20 still effectively inhibits both the wild - type and SP21 proteins , and the x - ray structures of these complexes show how Pyr20 fits into both active sites without steric strain . These structural insights suggest a general approach for developing new generations of antimalarial P00374 inhibitors that , by only occupying substrate space of the active site , would retain binding affinity with the mutant enzymes .", "Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women . Drug resistance in Plasmodium falciparum affects prevention of malaria in pregnancy . In a cross - sectional study of 530 pregnant Ghanaian women , P . falciparum dihydrofolate reductase ( P00374 ) gene mutations linked with pyrimethamine resistance were assessed and associations with pyrimethamine intake were analyzed . P . falciparum infected 69 % of women without pyrimethamine use , 59 % of those who had a history of pyrimethamine consumption but a negative urine test , and 53 % of individuals with a positive urine test . Eighty - one percent , 43 % , and 74 % of the isolates contained the mutations DB00174 - 108 , DB00167 - 51 , and DB00125 - 59 , respectively . DB00156 - 108 occurred in 8 % . DB00205 use was associated with increased frequencies of DB00174 - 108 and DB00125 - 59 but not of DB00167 - 51 or DB00156 - 108 . In women with prophylaxis , wild - type parasites were absent and anemia tended to be more common with an increasing number of P00374 gene mutations . DB00205 appears to be not adequately effective in this part of Ghana , most likely due to the predominance of resistant parasites . Selection for resistance following insufficient prophylaxis could possibly affect the efficacy of future intermittent sulfadoxine - pyrimethamine treatment .", "Changes in enzyme activity and expression of P00374 of Toxoplasma gondii by antifolates . The responses to antifolates of Toxoplasma gondii were investigated by measuring the dihydrofolate reductase ( P00374 ) activity , quantity of P00374 mRNA , and single - strand conformational polymorphism ( SSCP ) pattern . DB00205 ( Q9BRP8 ) and methotrexate ( MTX ) were tested as antifolates . When T . gondii was treated with Q9BRP8 , the viability was decreased by the increasing concentration of Q9BRP8 , P00374 activity tended to increase as the passage proceeded , and the quantity of mRNA expressed was also increased according to passages . The viability of T . gondii was decreased by the increasing concentration of MTX , but it was maintained over 40 % up to 100 microM MTX . P00374 activity was 77 . 4 % in the 1st passage ( 1 microM ) . 82 . 2 % in the 4th passage ( 10 microM ) , and 141 . 3 % in the 7th passage ( 100 microM ) . But no changes were detected in SSCP pattern of T . gondii exposed to Q9BRP8 and MTX , both . These results suggested that the response of T . gondii to Q9BRP8 was regulated by transcriptional level and that , in MTX , the viability of T . gondii was derived from increasing P00374 activity .", "Ovarian steroid - regulated synthesis and secretion of complement P01024 and factor B in mouse endometrium during the natural estrous cycle and pregnancy period . We demonstrate the presence of complement factor B ( Bf ) and complement P01024 in uterine luminal fluid collected from estrogen - stimulated immature and adult female mice . We examined the synthesis and secretion of these two proteins in mouse endometrium at various stages of the natural estrous cycle and during the pregnancy period . The mRNA levels of these two proteins increased markedly in proestrus and estrus and declined sharply in metestrus to an undetectable level . The Bf mRNA remained undetectable , whereas a readily detectable P01024 mRNA level reappeared , in diestrus . Meanwhile , these two proteins were immunolocalized to the apical cytoplasm of glandular and luminal epithelial cells of the endometrium during the estrous cycle . Administration of an estrogenic steroid to immature or ovariectomized adult mice markedly stimulated the expression of Bf , P01024 , and their RNA messages in the endometrium , whereas injection of progesterone alone to ovariectomized animals did not stimulate their expression . Expression of P01024 was remarkably enhanced , whereas that of Bf changed only slightly , after injection of combined estrogen and progesterone to ovariectomized animals . In pregnant mice ( Day [ D ] 1 = day of vaginal plug ) , Bf mRNA was at a high level on D1 and D2 , dropped to an almost undetectable level from D3 to P41226 , and then increased to a low level thereafter until delivery . The P01024 mRNA was at a high level on D1 , dropped on D2 to an almost undetectable level from D3 to D9 , increased to a very high level from D10 to D18 , and then declined sharply before delivery . Immunohistochemical patterns of both proteins in the endometrium during preimplantation were positively correlated with changes in their mRNA levels .", "Feature - map vectors : a new class of informative descriptors for computational drug discovery . In order to develop robust machine - learning or statistical models for predicting biological activity , descriptors that capture the essence of the protein - ligand interaction are required . In the absence of structural information from X - ray or NMR experiments , deriving informative descriptors can be difficult . We have developed feature - map vectors ( FMVs ) , a new class of descriptors based on chemical features , to address this challenge . FMVs , which are derived from the conformational models of a few actives , are low dimensional , problem specific , and highly interpretable . By using shape - based alignments and scoring with chemical features , FMVs can combine information about a molecule ' s shape and the pharmacophores it can match . In five validation studies , bag classifiers built using FMVs have shown high enrichments for identifying actives for five diverse targets : P24941 , 5 - HT ( 3 ) , P00374 , thrombin , and P12821 . The interpretability of these descriptors has been demonstrated for P24941 and 5 - HT ( 3 ) , where the method automatically discovers the standard literature pharmacophore .", "[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK67___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .", "In vitro susceptibility of various genotypic strains of Toxoplasma gondii to pyrimethamine , sulfadiazine , and atovaquone . Sulfadiazine , pyrimethamine , and atovaquone are widely used for the treatment of severe toxoplasmosis . Their in vitro activities have been almost exclusively demonstrated on laboratory strains belonging to genotype I . We determined the in vitro activities of these drugs against 17 strains of Toxoplasma gondii belonging to various genotypes and examined the correlations among 50 % inhibitory concentrations ( IC50s ) , growth kinetics , strain genotypes , and mutations on drug target genes . Growth kinetics were determined in THP - 1 cell cultures using real - time PCR . IC50s were determined in MRC - 5 cell cultures using a T . gondii - specific enzyme - linked immunosorbent assay performed on cultures . Mutations in dihydrofolate reductase ( P00374 ) , dihydropteroate synthase ( P49366 ) , and cytochrome b genes were determined by sequencing . DB00205 IC50s ranged between 0 . 07 and 0 . 39 mg / liter , with no correlation with the strain genotype but a significant correlation with growth kinetics . Several mutations found on the P00374 gene were not linked to lower susceptibility . DB01117 IC50s were in a narrow range of concentrations ( mean , 0 . 06 +/- 0 . 02 mg / liter ) ; no mutation was found on the cytochrome b gene . IC50s for sulfadiazine ranged between 3 and 18 . 9 mg / liter for 13 strains and were > 50 mg / liter for three strains . High IC50s were not correlated to strain genotypes or growth kinetics . A new mutation of the P49366 gene was demonstrated in one of these strains . In conclusion , we found variability in the susceptibilities of T . gondii strains to pyrimethamine and atovaquone , with no evidence of drug resistance . A higher variability was found for sulfadiazine , with a possible resistance of three strains . No relationship was found between drug susceptibility and strain genotype .", "Connexin36 knockout mice display increased sensitivity to pentylenetetrazol - induced seizure - like behaviors . OBJECTIVE : Large - scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions . To explore roles for connexin36 ( Q9UKL4 ) gap junctions in seizures , we examined the seizure threshold of connexin36 knockout ( Cx36KO ) mice using a pentylenetetrazol ( PTZ ) model . METHODS : Mice ( 2 - 3months old ) with Q9UKL4 wildtype ( WT ) or Cx36KO genotype were treated with vehicle or 10 - 40mg / kg of the convulsant PTZ by intraperitoneal injection . Seizure and seizure - like behaviors were scored by examination of video collected for 20min . Quantitative real - time PCR ( QPCR ) was performed to measure potential compensatory neuronal connexin ( Q8NFK1 , P35212 , P17302 and P36383 ) , pannexin ( Q96RD7 and Q96RD6 ) and gamma - aminobutyric acid type A ( GABA ( A ) ) receptor α1 subunit gene expression . RESULTS : Cx36KO animals exhibited considerably more severe seizures ; 40mg / kg of PTZ caused severe generalized ( ≥ grade III ) seizures in 78 % of KO , but just 5 % of WT mice . A lower dose of PTZ ( 20mg / kg ) induced grade II seizure - like behaviors in 40 % KO vs . 0 % of WT animals . There was no significant difference in either connexin , pannexin or GABA ( A ) α1 gene expression between WT and KO animals . CONCLUSION : Increased sensitivity of Cx36KO animals to PTZ - induced seizure suggests that Q9UKL4 gap junctional communication functions as a physiological anti - convulsant mechanism , and identifies the Q9UKL4 gap junction as a potential therapeutic target in epilepsy .", "Construction , expression and characterization of tissue - type plasminogen activator mutants . Three tissue - type plasminogen activator ( t - PA ) mutants were constructed by recombinant and site - directed mutagenesis techniques . They are del ( 296 - 302 ) with deletion of P05121 binding site , N117Q / N184Q with deglycosylation of P04264 and K2 domains , and their combination mutant designated as GGI . Then these three mutants were successfully transiently expressed in COS - 7 cells , and GGI was further stably expressed in CHO cells . The biological characterization of the expression products indicated that del ( 296 - 302 ) and GGI possessed the resistance to inhibition by P05121 . In addition , the specific activity of GGI was increased by about 46 % , the plasma half - life was prolonged by about one fold , while its affinity for fibrin was not affected .", "___MASK47___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .", "DB00642 alters folate phenotype and inflammatory profile in EA . hy 926 cells grown under low - folate conditions . Elevated homocysteine is a risk marker for several major human pathologies . Emerging evidence suggests that perturbations of folate / homocysteine metabolism can directly modify production of inflammatory mediators . DB00642 acts by inhibiting thymidylate synthetase ( P04818 ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) . EA . hy 926 cells grown under low ( \" Lo \" ) and high ( \" Hi \" ) folate conditions were treated with pemetrexed . The concentrations of several intracellular folate derivatives were measured using LC - MRM / MS . Lo cells had lower total folate concentrations and a different distribution of the intracellular folate derivatives than Hi cells . Treatment with pemetrexed caused a decrease in individual folate analytes . Microarray analysis showed that several genes were significantly up or down - regulated in pemetrexed treated Lo cells . Several of the significantly up - regulated transcripts were inflammatory . Changes in transcript levels of selected targets , including P01024 , P10145 , and P00374 , were confirmed by quantitative RT - PCR . P01024 and P10145 transcript levels were increased in pemetrexed - treated Lo cells relative to Lo controls ; P00374 transcript levels were decreased . In Lo cells , P10145 and P01024 protein concentrations were increased following pemetrexed treatment . DB00642 drug treatment was shown in this study to have effects that lead to an increase in pro - inflammatory mediators in Lo cells . No such changes were observed in Hi cells , suggesting that pemetrexed could not modify the inflammatory profile in the context of cellular folate sufficiency .", "Development of 2 , 4 - diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R + S108N mutants of dihydrofolate reductase from pyrimethamine - resistant Plasmodium falciparum . The reduced binding of pyrimethamine to Ser108Asn ( S108N ) mutants of parasite dihydrofolate reductase ( P00374 ) , which forms the basis of resistance of Plasmodium falciparum to pyrimethamine , is largely due to steric constraint imposed by the bulky side chain of N108 on Cl of the 5 - p - Cl - phenyl group . This and other S108 mutants with bulky side chains all showed reduced binding to pyrimethamine and cycloguanil . Less effect on binding to some bulky mutants was observed for trimethoprim , with greater flexibility for the 5 - substituent . S108N P00374 also binds poorly with other pyrimethamine derivatives with bulky groups in place of the p - Cl , and the binding was generally progressively poorer for the double ( C59R + S108N ) mutant . Removal of the p - Cl or replacement with m - Cl led to better binding with the mutant DHFRs . DB00205 analogues with unbranched hydrophobic 6 - substituents showed generally good binding with the mutant DHFRs . A number of compounds were identified with high affinities for both wild - type and mutant DHFRs , with very low to no affinity to human P00374 . Some of these compounds show good antimalarial activities against pyrimethamine - resistant P . falciparum containing the mutant DHFRs with low cytotoxicity to three mammalian cell lines .", "A fluorine - labeled methotrexate as a probe for monitoring tumor antifolate pharmacokinetics : synthesis , in vitro cytotoxicity , and pilot in vivo 19F magnetic resonance spectra . The synthesis and characterization of 3 '- fluoromethotrexate ( FMTX ) , a novel fluorine - labeled analogue of methotrexate , are presented . Molecular modeling studies indicate that the fluorine atom causes only minimal changes in the structure / binding in the complex of the antifolate with thymidine synthetase and dihydrofolate reductase ( P00374 ) . The in vitro cytotoxicity of this compound is shown to be equivalent to that of the parent antifolate compound . While the focus of this report is the synthetic technique of FMTX , it is also demonstrated that tumor accumulation of the labeled compound in vivo can be observed via 19F magnetic resonance spectroscopy ( P59665 ) in a human tumor xenograft model .", "The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK32___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .", "DB00205 resistant mutations in Plasmodium falciparum . Three mutations in Plasmodium falciparum yielding increased resistance to pyrimethamine were obtained following treatment with chemical mutagens and selection in presence of pyrimethamine . From parasite clone TM4 / 8 . 2 a mutant , TM4 / 8 . 2 / 4 . 1 , was produced which raised pyrimethamine resistance about 500 times and was found to involve an amino acid change in the P00374 - TS enzyme molecule from Ser108 to Asn108 . A clone of another isolate , P02786 / 94 , yielded a mutant , P02786 / 94 / 300 . 300 , raising pyrimethamine resistance about 10 times and involving an amino acid change from Ile164 to Met164 . However , another mutant from P02786 / 94 , P02786 / 94 / M1 - 1 ( b3 ) , although it raised the pyrimethamine resistance 100 times , did not involve any changes in the coding sequence of the P00374 - TS gene , but resulted in the production of about twice as much P00374 - TS enzyme as the original clone P02786 / 94 . No amplification of the P00374 - TS gene was detected . It is concluded that changes in pyrimethamine resistance of malaria parasites may arise in at least 2 ways : ( 1 ) by structural changes in the P00374 domain of the P00374 - TS gene ( as previously found by other workers ) ; ( 2 ) by other changes , possibly affecting the expression of the P00374 - TS gene . The relative importance of these 2 mechanisms in causing resistance in wild populations of P . falciparum is discussed .", "Synthesis and in vitro evaluation of potential anti - leishmanial targeted drugs of pyrimethamine . DB00205 , an antimalarial drug , was found to be able to inhibit both enzymes ( P00374 - TS and PTR1 ) of the leishmanial folate pathway , although this effect in vivo appears only in relatively high concentrations . To reach the parasites inside macrophage cells , where they are sheltered , targeted drugs of pyrimethamine , carboxymethyldextran - thiomannopyranoside - pyrimethamine ( CMD - P ) , and succinyldextran - thiomannopyranoside - pyrimethamine ( SD - P ) , were synthesized and assayed against L .( L .) amazonensis amastigotes . CMD - P has 2 . 43 % and SD - P has 2 . 58 % of pyrimethamine attached . At a CMD - P dose of 200 microg / mL ( 4 . 86 microg / mL pyrimethamine ) , the results were very promising , with a destruction of approximately 50 % of the intracellular amastigotes , with no detectable toxicity to macrophage cells . SD - P in similar doses did not show good results , probably due to different patterns of drug release . These results open the possibility of treating leishmaniasis with a safe targeted drug of pyrimethamine released directly inside the macrophage cells , reducing the host systemic toxicity .", "DB00205 - resistant dihydrofolate reductase enzymes of Plasmodium falciparum are not enzymatically compromised in vitro . Plasmodium falciparum , the protozoan that causes the most lethal form of human malaria , has been controlled principally by two safe , affordable drugs , chloroquine and sulfadoxine - pyrimethamine ( SP ) . Studies in the laboratory and in the field have demonstrated that resistance to SP depends on non - synonymous point mutations in the dihydrofolate reductase ( P00374 ) , and dihydropteroate synthase ( P49366 ) coding regions . Parasites that carry dhfr genes with 3 or 4 point mutations ( 51I / 59R / 108N triple mutation or 51I / 59R / 108N / 164L quadruple mutation ) are resistant to pyrimethamine in vitro and patients infected with these parasites respond poorly to SP treatment . The wide spread of these pyrimethamine - resistant alleles demonstrates the increased fitness over drug - sensitive alleles in the presence of the drug . However , it is not clear whether these alleles might reduce the fitness of parasites in the absence of drug pressure . As a first step , we compared the kinetic properties of the wild type , and three mutant alleles to determine whether the native P00374 - thymidylate synthase form of the mutant proteins showed compromised activity in vitro . The mutant enzymes had K ( m ) values for their substrate , dihydrofolate that were significantly lower than the wild type , k ( cat ) values in the same range as the wild type enzyme , and k ( cat )/ K ( m ) values higher than wild type . In contrast , the K ( m ) values for the NADPH cofactor were higher than wild type for the mutant enzymes . These observations suggest that the fitness of these parasites may not be compromised relative to those that carry the wild type allele , even without sustained SP drug pressure .", "DB00205 and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax . Plasmodium vivax is a major public health problem in Asia and South and Central America where it is most prevalent . Until very recently , the parasite has been effectively treated with chloroquine , but resistance to this drug has now been reported in several areas . Affordable alternative treatments for vivax malaria are urgently needed . DB00205 - sulfadoxine is an inhibitor of dihydrofolate reductase ( P00374 ) that has been widely used to treat chloroquine - resistant Plasmodium falciparum malaria . P00374 inhibitors have not been considered for treatment of vivax malaria , because initial trials showed poor efficacy against P . vivax . P . vivax can not be grown in culture ; the reason for its resistance to P00374 inhibitors is unknown . We show that , like P . falciparum , point mutations in the dhfr gene can cause resistance to pyrimethamine in P . vivax . WR99210 is a novel inhibitor of P00374 , effective even against the most pyrimethamine - resistant P . falciparum strains . We have found that it is also an extremely effective inhibitor of the P . vivax P00374 , and mutations that confer high - level resistance to pyrimethamine render the P . vivax enzyme exquisitely sensitive to WR99210 . These data suggest that pyrimethamine and WR99210 would exert opposing selective forces on the P . vivax population . If used in combination , these two drugs could greatly slow the selection of parasites resistant to both drugs . If that is the case , this novel class of P00374 inhibitors could provide effective and affordable treatment for chloroquine - and pyrimethamine - resistant vivax and falciparum malaria for many years to come .", "Insights into antifolate resistance from malarial P00374 - TS structures . Plasmodium falciparum dihydrofolate reductase - thymidylate synthase ( PfDHFR - TS ) is an important target of antimalarial drugs . The efficacy of this class of P00374 - inhibitor drugs is now compromised because of mutations that prevent drug binding yet retain enzyme activity . The crystal structures of PfDHFR - TS from the wild type ( TM4 / 8 . 2 ) and the quadruple drug - resistant mutant ( V1 / S ) strains , in complex with a potent inhibitor WR99210 , as well as the resistant double mutant ( P04264 P21554 ) with the antimalarial pyrimethamine , reveal features for overcoming resistance . In contrast to pyrimethamine , the flexible side chain of WR99210 can adopt a conformation that fits well in the active site , thereby contributing to binding . The single - chain bifunctional PfDHFR - TS has a helical insert between the P00374 and TS domains that is involved in dimerization and domain organization . Moreover , positively charged grooves on the surface of the dimer suggest a function in channeling of substrate from TS to P00374 active sites . These features provide possible approaches for the design of new drugs to overcome antifolate resistance .", "Absence of clinically important Q12809 channel blockade by three compounds that inhibit phosphodiesterase 5 -- sildenafil , tadalafil , and vardenafil . Compounds that inhibit phosphodiesterase 5 ( O76074 ) have been developed for the treatment of erectile dysfunction . Because men with erectile dysfunction frequently have comorbid cardiovascular disease , they may have limited cardiac repolarization reserve and be at risk of arrhythmia if treated with medications that prolong ventricular repolarization . The human ether - a - go - go related gene ( Q12809 ) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval . We studied the ability of three compounds that inhibit O76074 -- sildenafil , tadalafil , and vardenafil -- to block the Q12809 channel . Using a whole cell variant of the patch - clamp method , the Q12809 current was measured in a stably transfected human embryonic kidney cell line expressing the Q12809 channel . The compounds produced dose - dependent reductions in Q12809 current amplitude over a concentration range of 0 . 1 to 100 microM . The IC50 values were 12 . 8 microM for vardenafil and 33 . 3 microM for sildenafil . Because the maximum soluble concentration of tadalafil ( 100 microM ) produced only a 50 . 9 % inhibition of the Q12809 current amplitude , the IC50 value for tadalafil could not be determined with the Hill equation . ___MASK82___ had the weakest capacity to block the Q12809 channel , producing a 50 . 9 % blockade at the maximum soluble concentration ( 100 microM ) , compared with 86 . 2 % for vardenafil ( 100 microM ) and 75 . 2 % for sildenafil ( 100 microM ) . In conclusion , the concentrations of the O76074 inhibitors required to evoke a 50 % inhibition of the Q12809 current were well above reported therapeutic plasma concentrations of free and total compound . None of the three compounds was a potent blocker of the Q12809 channel .", "Mammalian Q99572 receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 receptors rapidly opens a non - selective cation channel . Sustained Q99572 receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species - and single - nucleotide polymorphism - mediated differences in Q99572 receptor activation have been reported that complicate understanding of the physiological role of Q99572 receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 receptors . EXPERIMENTAL APPROACH : Receptor - mediated changes in calcium influx and Yo - Pro uptake were compared between recombinant mouse , rat and human Q99572 receptors . For mouse Q99572 receptors , wild - type ( BALB / c ) and a reported loss of function ( C57BL / 6 ) Q99572 receptor were also compared . KEY RESULTS : BzATP [ 2 , 3 - O -( 4 - benzoylbenzoyl )- DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo - Pro uptake at rat , human , BALB / c and C57BL / 6 mouse Q99572 receptors . Two selective Q99572 receptor antagonists , A - 740003 and A - 438079 , potently blocked Q99572 receptor activation across mammalian species . Several reported P51575 receptor antagonists [ e . g . P59665 2159 ( 4 - [ ( 4 - formyl - 5 - hydroxy - 6 - methyl - 3 - [ ( phosphonooxy ) methyl } - 2 - pyridinyl ) azo ] - benzoic acid ) , PPNDS and NF279 ] blocked Q99572 receptors . NF279 fully blocked human Q99572 receptors , but only partially blocked BALB / c Q99572 receptors and was inactive at C57BL / 6 Q99572 receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 receptor antagonist pharmacology across mammalian species . Q99572 receptor pharmacology in a widely used knockout background mouse strain ( C57BL / 6 ) was similar to wild - type mouse Q99572 receptors . Several structurally novel , selective and competitive Q99572 receptor antagonists show less species differences compared with earlier non - selective antagonists .", "___MASK75___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK75___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .", "Inhibition of poly ( ADP - ribose ) polymerase does not affect the recombination events in CHO xrs6 and wild type cells . Activation of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is an early DNA damage response event that , together with phosphorylation of p53 , prompts various cellular functions important in the maintenance of the genome stability . In mammalian cells , DSB are repaired by nonhomologous end - joining ( NHEJ ) and by homologous recombination ( HR ) . To investigate the role of P09874 in HR , CHO - P04264 wild type and xrs - 6 mutant cell line were transfected with pLrec plasmids which carry two nonfunctional copies of the beta - galactosidase ( lacZ ) gene in a tandem array . In result of HR they can give rise to a functional copy of beta - galactosidase . To test whether P09874 affects the frequency of spontaneous and induced recombination repair , we treated CHO - P04264 and xrs6 clones carrying chromosomally integrated pLrec with the P09874 inhibitor 3 - aminobenzamide ( 3AB ) . Our results show that the spontaneous homologous intrachromosomal recombination frequency between the two lacZ copies was almost two orders of magnitude higher in xrs6 cells than in CHO - P04264 cells , but that it was not affected by 3AB treatment . Induction of DNA damage by irradiation or electroporation of restriction enzymes did not significantly increase the recombination frequency . Furthermore , in both the cell lines , the effect of P09874 inhibition on DSB repair was examined using the neutral comet assay . There was no effect of 3AB treatment on DSB rejoining after 10 Gy irradiation . The results presented support the conclusion that P09874 is not directly involved in HR .", "Repair of benzo ( a ) pyrene diol epoxide - and UV - induced DNA damage in dihydrofolate reductase and adenine phosphoribosyltransferase genes of CHO cells . Using Uvr proteins we have quantified benzo ( a ) pyrene diol epoxide ( BPDE ) - DNA adduct formation and repair at the dihydrofolate reductase ( P00374 ) and adenine phosphoribosyltransferase ( P07741 ) genes in two Chinese hamster ovary cell lines : B - 11 cells , which are 50 - fold amplified for P00374 , and P01008 - 2 cells , which are diploid for P00374 . We have found that : 1 ) BPDE - DNA adduct formation in different regions of the P00374 gene is proportional to the concentration of BPDE . 2 ) There is no significant difference in the repair of BPDE - DNA adducts between the coding and noncoding regions in either amplified or nonamplified P00374 gene domains . 3 ) Repair in the nonamplified P00374 gene is more efficient ( 30 - 40 % ) than in the amplified P00374 genes . 4 ) There are no significant differences of repair in the transcribed or nontranscribed strands of the P00374 gene . 5 ) BPDE - DNA adduct formation and repair in the P07741 gene in B - 11 and P01008 - 2 cells are the same . These results contrast those for the repair of cyclobutane pyrimidine dimers , which occurs preferentially in the transcribed strand of the P00374 gene and in which gene amplification appears to play no role .", "Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK15___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .", "[ Effects of the chemokine MIP - 1alpha on anemia and inflammation in rheumatoid arthritis ] . Macrophage inflammatory protein - 1alpha ( MIP - 1alpha ) is an interesting chemokine because in addition to its variety proinflammatory activities including chemotaxis and immunomodulation , it is a potent inhibitor of hematopoetic stem cell proliferation . Inhibition of erythroid progenitor cells due to MIP - 1alpha or other cytokines can play a role in the pathogenesis of anemia which is one of the most common extra - articular features of active rheumatoid arthritis ( RA ) . In 84 patients with RA , serological and immunological parameters were assessed to detect inflammatory mechanisms and anemia in relation to the serum concentrations of MIP - 1alpha . All patients fulfilled the P10323 criteria for the diagnosis of a definite or classic RA . We used a quantitative enzyme immuno assay for the detection of MIP - 1alpha as well as for the measurement of the acute phase protein serum amyloid A ( P0DJI8 ) , the erythropoiesis inducer erythropoietin ( EPO ) and the transferrin receptor ( P02786 ) . The immune activation marker neopterin was measured radioimmunologically . Half of the patients with RA were anemic with hemoglobin values below 12 g / dl . MIP - 1alpha was found to be elevated significantly in serum of patients with active rheumatoid arthritis and in patients with anemia . Most of the anemic patients with markedly elevated acute phase reactions had an anemia with chronic diseases and not a functional iron deficiency alone . P02786 correlated with EPO . The results show that enhanced expression of MIP - 1alpha is indicative of systemic inflammation in RA . Moreover , besides the regulation of inflammatory processes , this chemokine may influence the pathogenesis of anemia in RA patients .", "In vitro selection of Plasmodium falciparum lines resistant to dihydrofolate - reductase inhibitors and cross resistance studies . A cloned Plasmodium falciparum line was subjected to in vitro drug pressure , by employing a relapse protocol , to select progressively resistant falciparum lines to pyrimethamine and cycloguanil , the two dihydrofolate - reductase ( P00374 ) inhibitor antimalarial drugs . The falciparum lines resistant to pyrimethamine were selected much faster than those resistant to cycloguanil . In 348 days of selection / cultivation , there was 2 , 400 - fold increase in IC50 value to pyrimethamine , whereas only about 75 - fold decrease in sensitivity to cycloguanil was registered in 351 days . DB00205 - resistant parasites acquired a degree of cross resistance to cycloguanil and methotrexate , another P00374 inhibitor , but did not show any cross resistance to some other groups of antimalarial drugs . The highly pyrimethamine - resistant line was not predisposed for faster selection to cycloguanil resistance . Resistance acquired to pyrimethamine was stable . The series of resistant lines obtained form a good material to study the ' evolution ' of resistance more meaningfully at molecular level .", "Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum . DB00205 and cycloguanil are competitive inhibitors of the Plasmodium enzyme dihydrofolate reductase ( P00374 ) . They have been effective treatments for malaria , but rapid selection of populations of the parasite resistant to these drugs has compromised their effectiveness . Parasites resistant to either drug usually have point mutations in the dhfr gene , but the frequency of these mutations is unknown . To study drug resistance more effectively , we transferred the P00374 domain of the dhfr - thymidylate synthase gene from a drug - sensitive line of P . falciparum to a strain of the budding yeast , Saccharomyces cerevisiae , that lacks endogenous P00374 activity . Expression of the P . falciparum dhfr is controlled by the yeast dhfr 5 ' and 3 ' regulatory regions and the heterologous enzyme provided all of the functions of the yeast dhfr gene . These yeast were susceptible to pyrimethamine and cycloguanil at low concentrations that inhibit P . falciparum ( IC50 about 10 (- 8 ) and 10 (- 7 ) M , respectively ) . Yeast expressing constructs with dhfr alleles from pyrimethamine - resistant strains were resistant to both pyrimethamine and cycloguanil ( IC50 > 10 (- 6 ) M ) ; resistance of the yeast depended on the dhfr allele they expressed . The experimental drug WR99210 efficiently killed all three yeast strains ( IC50 about 10 (- 8 ) M ) but the pyrR strains showed collateral hypersensitivity to drug . The yeast transformants carrying the drug - sensitive allele can now be screened quickly and quantitatively to identify new drugs or combinations of drugs and determine which drugs select resistant parasites least efficiently . Such compounds would be excellent candidates for development of treatments with a longer life in clinical practice .", "Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain . The perinatal brain requires a tightly regulated iron transport system . DB01592 regulatory proteins ( IRPs ) 1 and 2 are cytosolic proteins that regulate the stability of mRNA for the two major cellular iron transporters , transferrin receptor ( P02786 ) and divalent metal transporter - 1 ( P49281 ) . We studied the localization of IRPs , their change in expression during perinatal development , and their relationship to P02786 and P49281 in rat brain between postnatal days ( P01160 ) 5 and 15 . Twelve - micron frozen coronal sections of fixed brain tissue were obtained from iron - sufficient Sprague - Dawley rat pups on P01160 5 , 10 , and 15 , and were visualized at 20 to 1 , 000x light microscopy for diaminobenzidine activity after incubation with specific primary P09544 - 1 , P09544 - 2 , P49281 , and P02786 antibodies and a universal biotinylated secondary and tertiary antibody system . P09544 and transport protein expression increased in parallel over time . P21399 , P48200 , and P49281 were partially expressed in the choroid plexus epithelial cells at P01160 5 and 10 , and fully expressed at P01160 15 . The cerebral blood vessels and ependymal cells strongly expressed P21399 , P48200 , and P49281 as early as P01160 5 . Substantive P02786 staining was not seen in the choroid plexus or ependyma until P01160 15 . Glial and neuronal expression of P21399 , P48200 , P49281 , and P02786 in cortex , hippocampal subareas and striatum increased over time , but showed variability in cell number and intensity of expression based on brain region , cell type , and age . These developmental changes in P09544 and transporter expression suggest potentially different time periods of brain structure vulnerability to iron deficiency or iron overload .", "Role of gap junctions in spontaneous activity of the rat bladder . Increased gap junction expression in lamina propria myofibroblasts and urothelial cells may be involved in detrusor overactivity , leading to incontinence . Immunohistochemistry was used to compare connexin ( Cx ) 26 , 43 , and 45 expression in the bladders of neonatal , adult , and spinal cord - transected rats , while optical imaging was used to map the spread of spontaneous activity and the effects of gap junction blockade . Female adult Sprague - Dawley rats were deeply anesthetized , a laminectomy was performed , and the spinal cord was transected ( T8 / P02786 ) . After 14 days , their bladders and those of age - matched adults ( 4 mo old ) and neonates ( 7 - 21 day old ) were excised and studied immunohistochemically using frozen sections or optically using whole bladders stained with voltage - and Ca ( 2 +)- sensitive dyes . The expression of P29033 was localized to the urothelium , P17302 to the lamina propria myofibroblasts , and P36383 to the detrusor smooth muscle . While the expression of P36383 was comparable in all bladders , the expression of P17302 and P29033 was increased in neonate and transected animals . In the bladders of adults , spontaneous activity was initiated at multiple sites , resulting in a lack of coordination . Alternatively , in neonate and transected animals spontaneous activity was initiated at a focal site near the dome and spread in a coordinated fashion throughout the bladder . Gap junction blockade ( 18beta - glycyrrhetinic acid , 1 microM ) abolished this coordinated activity but had no effect on the uncoordinated activity in adult bladders . These data suggest that coordinated spontaneous activity requires gap junction upregulation in urothelial cells and lamina propria myofibroblasts .", "P02533 - EGFP - miR - 31 transgenic mice have high susceptibility to chemical - induced squamous cell tumorigenesis that is associating with P13010 repression . Squamous cell carcinoma ( SCC ) occurring in the head and neck region and the esophagus causes tremendous cancer mortality around the world . miR - 31 is among the most eminently upregulated MicroRNAs in SCC , when it occurs in the head and neck region and the esophagus . We established miR - 31 transgenic mouse lines , in which miR - 31 is under the control of the P02533 promoter . 4 - nitroquinoline 1 - oxide ( 4NQO ) is a mutagen that causes double strand breaks . The transgenic mice exhibited a higher potential for tumor induction than wild - type ( Wt ) mice of the tongue and esophagus after 4NQO treatment . After 4NQO treatment or irradiation , p - γ P16104 expression in squamous epithelium of transgenic mice was increased more than in Wt mice . Exogenous expression of miR - 31 was also found to be associated with the higher p - γ P16104 expression induced by 4NQO in human oral SCC ( OSCC ) cell lines . The repair genes P09874 and P13010 were validated as new targets of miR - 31 in human OSCC cell lines , and were found to be downregulated in the squamous epithelium of the tongue in transgenic mice . However , only the downregulation of P13010 was essential for maintaining the high level of p - γ P16104 induced by 4NQO in OSCC cells . Inverse expression profiles for miR - 31 and P13010 were noted in human OSCC tissue . Our study identifies the high sensitivity of P02533 - EGFP - miR - 31 transgenic mice to chemical carcinogen - induced squamous cell tumorigenesis and shows that this seems to be associated with the downregulation of P13010 and an impairment of repair activity in squamous cells , which are mediated by miR - 31 .", "Rapid increase in resistance of Plasmodium falciparum to chloroquine - Fansidar in Uganda and the potential of amodiaquine - Fansidar as a better alternative . Combinations of chloroquine ( CQ ) and sulfadoxine - pyrimethamine ( SP ) [ CQSP ] as the first line agents in Uganda have replaced CQ monotherapy . The idea of the combination is to delay the development of malaria resistance to either drug when used alone . We compared the clinical , parasitological and molecular findings of two studies with treatment arms of CQSP , amodiaquine ( AQ ) plus SP ( AQSP ) both done in 2003 with a study done 1 year earlier ( 2002 ) using SP alone . There was a notable decrease in adequate clinical response ( P10323 ) by day 14 from 92 . 7 % with SP to 80 % with the combination CQSP , a year later . AQSP combination was found to have the best effect ( 94 . 3 % P10323 ) . There were no early treatment failures in the AQSP group . However , treatment failures were recorded at 20 % on day 14 and 43 % on day 28 for CQSP treatment and 5 . 7 % by day 14 and 28 . 8 % by day 28 in the AQSP group . The number of mutations that are associated with SP resistance increased from 2002 to 2003 at all loci monitored , from 83 . 8 to 100 % at codon 108 , 58 . 7 to 76 % at codon 59 in the P00374 gene , and from 58 . 8 to 86 % at codon 437 and 33 to 43 % at codon 540 in the P49366 gene . We conclude that there has been a rapid development of resistance since the introduction of the new policy guidelines . AQSP was found to be a superior drug combination compared to CQSP and could be used as a low cost alternative at the moment .", "Uptake , cytotoxicity and metabolism of m - azidopyrimethamine and related lipophilic antifolates in SV - P02533 human keratinocytes in vivo . The growth - inhibitory properties of a series of lipophilic diaminopyrimidine antifolates were evaluated in comparison with methotrexate ( MTX ) against SV - P02533 human keratinocytes in vitro under folate - dependent and folate - independent conditions . Under folate - dependent conditions metoprine ( DDMP ) proved more cytotoxic than MTX , despite the greater inhibitory activity of the latter compound against mammalian dihydrofolate reductase ( P00374 ) , possibly reflecting differences in cellular accumulation . The significantly lower activity of both compounds under folate - independent conditions indicated P00374 as the primary target . DB00205 ( Q9BRP8 ) , m - azidopyrimethamine ( MZP ) and m - aminopyrimethamine ( Q96HU1 ) , a metabolite of MZP , were approximately equiactive but less cytotoxic than MTX or DDMP . The unexpected activity of Q96HU1 , an inferior P00374 inhibitor , suggests differences in the mechanism of action or cellular transport of the drug , although the reduction of cytotoxicity observed under folate - independent conditions indicate folate metabolism as the cytotoxic locus . In contrast , the cytotoxicity of Q9BRP8 or MZP was not reduced under folate - independent conditions implying an alternative mechanism of action . The uptake of 2 -[ 14C ] pyrimethamine by SV - P02533 keratinocytes was rapid with steady - state intracellular concentrations being observed after approximately 100 min , partition of drug into the plasma membrane preceding redistribution and extensive accumulation within the particulate cell components . The previously reported NADPH - dependent metabolism of MZP to Q96HU1 by murine liver microsome preparations was not observed with SV - P02533 keratinocytes nor with murine skin homogenates in the present study .", "___MASK32___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK32___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK32___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .", "[ The effect of bunazosin vs captopril on hemodynamic and neurohumoral parameters in patients with congestive heart failure ] . The hemodynamic parameters ( right atrial pressure , mean pulmonary artery pressure , pulmonary capillary wedge pressure , cardiac index , heart rate , blood pressure ) and neurohumoral responses ( alpha - P01160 , plasma renin activity , aldosterone , angiotensin II ) of ___MASK15___ , oral P12821 inhibitor , and Bunazosin , oral alpha 1 - blocker , were investigated in 28 patients with congestive heart failure at rest and after exercise . These data were analysed in both acute and chronic phases . 1 ) Acute effect . ___MASK15___ produced significant improvement of neurohumoral factors at rest and also after exercise . Bunazosin reduced alpha - P01160 , but other neurohumoral factors did not change . Bunazosin produced significant hemodynamic improvement both at rest and after exercise . 2 ) Chronic effect . ___MASK15___ produced significant hemodynamic improvement both at rest and after exercise . Improvement of neurohumoral factors in acute phase was also preserved at chronic phase . On Bunazosin , improvement of hemodynamics at acute phase was also preserved at chronic phase without deterioration of neurohumoral factors .", "___MASK15___ reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin - converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU / ml ) , tissue plasminogen activator ( t - PA ) antigen ( ng / ml ) , and serum P12821 activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37 . 5 mg daily ) and compared them with the values in 15 placebo - treated patients chosen at random . Blood sampling was performed at 07 . 00 h . In the captopril - treated group , serum P12821 activity decreased significantly , from 14 . 0 +/- 0 . 8 to 11 . 5 +/- 1 . 2 IU / L 24 h after captopril therapy ( p < 0 . 01 ) , and those of P05121 activity and t - PA antigen also decreased significantly - from 11 . 9 +/- 2 . 8 to 5 . 5 +/- 2 . 2 IU / ml ( p < 0 . 02 ) and from 9 . 9 +/- 1 . 0 to 7 . 5 +/- 0 . 9 ng / ml ( p < 0 . 05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t - PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .", "___MASK74___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .", "Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK18___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .", "Identification and characterization of an endogenous Q99572 ( P2Z ) receptor in CHO - P04264 cells . CHO - P04264 cells were examined for their cellular responses to the P2 receptor agonist , 2 '- and 3 '- O -( 4 - benzoylbenzoyl )- DB00171 ( DbATP ) , and for the presence of mRNA for P2X receptors . Reverse transcriptase - polymerase chain reactions , using primers directed against the rat P2X subunits , detected the presence of Q99572 but not P51575 - O15547 subunits . DbATP ( EC50 approximately equal to 100 microM ) evoked non - desensitizing inward currents which reversed at approximately equal to 0 mV , suggesting activation of a non - selective cation channel . DB00171 also evoked inward currents but was less potent than DbATP . DbATP also stimulated the accumulation of 45calcium ( 45Ca2 + ) and the DNA binding dye , YO - PRO - 1 , in CHO - KI cells . Both responses were inhibited by NaCl and MgCl2 . In 280 mM sucrose buffer , 45Ca2 + accumulation was measurable within 10 - 20 s of agonist addition , whereas YO - PRO - 1 accumulation was only detectable after 8 min . DB00171 and ATPgammaS were also agonists but were less potent than DbATP , while UTP , 2 - methylthio DB00171 , ADP and ( alphabeta ) methylene DB00171 were inactive at concentrations up to 100 microM . DbATP increased lactate dehydrogenase release from CHO - P04264 cells , suggesting cell lysis , although this effect was only pronounced after 60 - 90 min . These data suggest that CHO - P04264 cells express an endogenous Q99572 receptor which can be activated by DbATP to cause a rapid inward current and accumulation of 45Ca2 + . Prolonged receptor activation results in a delayed , increased permeability to larger molecules such as YO - PRO - 1 and ultimately leads to cell lysis . Importantly , the presence of an endogenous Q99572 receptor should be considered when these cells are used to study recombinant P2X receptors .", "Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone . Chloroquine has been the mainstay of malaria chemotherapy for the past five decades , but resistance is now widespread . DB00205 or proguanil form an important component of some alternate drug combinations being used for treatment of uncomplicated Plasmodium falciparum infections in areas of chloroquine resistance . Both pyrimethamine and proguanil are dihydrofolate reductase ( P00374 ) inhibitors , the proguanil acting primarily through its major metabolite cycloguanil . Resistance to these drugs arises due to specific point mutations in the dhfr gene . Cross resistance between cycloguanil and pyrimethamine is not absolute . It is , therefore , important to investigate mutation rates in P . falciparum for pyrimethamine and proguanil so that P00374 inhibitor with less mutation rate is favored in drug combinations . Hence , we have compared mutation rates in P . falciparum genome for pyrimethamine and cycloguanil . Using erythrocytic stages of P . falciparum cultures , progressively drug resistant lines were selected in vitro and comparing their RFLP profile with a repeat sequence . Our finding suggests that pyrimethamine has higher mutation rate compared to cycloguanil . It enhances the degree of genomic polymorphism leading to diversity of natural parasite population which in turn is predisposes the parasites for faster selection of resistance to some other antimalarial drugs .", "Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .", "P00374 hysteresis and its effect of inhibitor binding analyses . Escherichia coli dihydrofolate reductase was shown to follow slow transient kinetics ( hysteresis ) . Nonlinear reaction velocities were detected during the enzyme assay and required 10 - 15 min to reach a steady - state rate . The degree of hysteresis was influenced by the enzyme concentration and the order of substrate addition . Incubation of the enzyme with NADPH before addition of dihydrofolate resulted in slow initial velocities that increased up to 2 - fold during the course of the assay . Increasing the enzyme concentration from 0 . 2 to 1 nM resulted in diminished hysteresis . NADPH - initiated reactions were linear at all enzyme concentrations tested . Certain drugs had profound effects on hysteresis . DB00205 practically eliminated the hysteresis of dihydrofolate - started reactions , whereas trimethoprime augmented the non - linearities in the sense that hysteresis was detected in both enzyme - and NADPH - started reactions . The shape of these reaction tracings makes trimethoprim is not a slow - binding inhibitor when assayed under conditions that eliminate hysteresis . Contrary to this , sulfamethoxazole did not affect hysteresis or augment inhibition of the enzyme by trimethoprim . Sulfamethoxazole alone ( at 6 mM ) did not inhibit the hysteresis and allow reliable determinations of Ki values of both weak and tight binding inhibitors . For example , Ki values for pyrimethamine , trimethoprim , and methotrexate were found to be 214 nM , 1 . 3 nM , and 0 . 021 nM , respectively .", "A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .", "A novel acoustic evaluation system of scratching in mouse dermatitis : rapid and specific detection of invisibly rapid scratch in an atopic dermatitis model mouse . Scratching is an essential and a skin specific behavior induced by itching , which is a common symptom of atopic dermatitis ( AD ) and other types of dermatitis . Itching sensation and scratching are closely associated and thus scratching times are currently used for evaluating itching in animal models . However , objective measuring systems of scratching to assess the grade of dermatitis and the effectiveness of anti - pruritic drugs in animal dermatitis models are lacking . To investigate a quantitative evaluation system for itching , we have developed a novel acoustic scratching counting system and compared its accuracy with time - consuming slow - motion video recording system . We have also objectively evaluated the efficacy of an antihistamine using this novel system . Scratching behavior of an AD model mouse ( P02533 driven Q14116 transgenic mouse ) was recorded visually and acoustically . Specific scratching sound produced by mice was recorded and counted using a software we have developed , and the results obtained using our acoustic system were not statistically different from data obtained using slow motion video system . Surprisingly , mice scratched more than 10 times / second , which was invisibly rapid motion and revealed inaccuracy of conventional hand counting system . Results were identical to that of measured by 10 times time costing slow - motion video analysis . The antihistamine is clearly effective for suppression of scratching as demonstrated using this objective and accurate method . This novel motion analysis system will open a window for physiological and pathological analysis for animal models and development of anti - pruritic drugs .", "Reporter gene expression in cell culture stages and oocysts of Eimeria nieschulzi ( Coccidia , Apicomplexa ) . The rat parasite Eimeria nieschulzi is a suitable model for transfection studies and was used as an additional model organism for the genus Eimeria . We describe the transfection of this apicomplexan parasites and the cultivation of transformed stages in cell culture and in vivo . The beta - galactosidase or yellow fluorescent protein was expressed in all parasitic stages up to the second merozoite generation in vitro under control of the heterologous promoter region of Eimeria tenella mic1 gene previously described for E . tenella transfection . DB00205 resistant E . nieschulzi parasites were obtained in vitro after transfection with a plasmid encoding the Toxoplasma gondii dhfr / ts - m2m3 gene . Co - transfection experiments with an YFP - plasmid resulted in pyrimethamine resistant and fluorescent parasitic stages . Infection of rats with transfected E . nieschulzi sporozoites directed to expression of beta - galactosidase or YFP in oocysts . Co - transfection with YFP / P00374 - TS allowed selection of resistant parasites in vivo . Excreted transgenic oocysts showed arrangement of YFP expression which lead to questions about meiotic recombination frequency and mechanisms .", "TALEN - mediated targeting of HPV oncogenes ameliorates HPV - related cervical malignancy . Persistent HPV infection is recognized as the main etiologic factor for cervical cancer . HPV expresses the oncoproteins E6 and E7 , both of which play key roles in maintaining viral infection and promoting carcinogenesis . While siRNA - mediated targeting of E6 and E7 transcripts temporarily induces apoptosis in HPV - positive cells , it does not eliminate viral DNA within the host genome , which can harbor escape mutants . Here , we demonstrated that specifically targeting E6 and E7 within host DNA with transcription activator - like effector nucleases ( TALENs ) induces apoptosis , inhibits growth , and reduces tumorigenicity in HPV - positive cell lines . TALEN treatment efficiently disrupted E6 and E7 oncogenes , leading to the restoration of host tumor suppressors p53 and retinoblastoma 1 ( P06400 ) , which are targeted by E6 and E7 , respectively . In the P02533 - HPV16 transgenic mouse model of HPV - driven neoplasms , direct cervical application of HPV16 - E7 - targeted TALENs effectively mutated the E7 oncogene , reduced viral DNA load , and restored P06400 function and downstream targets transcription factor Q01094 and cycling - dependent kinase 2 ( P24941 ) , thereby reversing the malignant phenotype . Together , the results from our study suggest that TALENs have potential as a therapeutic strategy for HPV infection and related cervical malignancy .", "DB00205 - sulfadoxine efficacy and selection for mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase in Mali . To assess pyrimethamine - sulfadoxine ( PS ) efficacy in Mali , and the role of mutations in Plasmodium falciparum dihydrofolate reductase ( P00374 ) and dihydropteroate synthase ( P49366 ) in in vivo PS resistance , 190 patients with uncomplicated P . falciparum malaria were treated with PS and monitored for 56 days . Mutation - specific polymerase chain reactions and digestion with restriction endonucleases were used to detect P00374 and P49366 mutations on filter paper blood samples from pretreatment and post - treatment infections . Only one case each of RI and RII level resistance and no cases of RIII resistance or therapeutic failure were observed . Post - PS treatment infections had significantly higher rates of P00374 mutations at codons 108 and 59 . No significant selection for P49366 mutations was seen . DB00205 - sulfadoxine is highly efficacious in Mali , and while the low level of resistance precludes assessing the utility of molecular assays for in vivo PS resistance , rapid selection of P00374 mutations supports their role in PS failure .", "Differential expression and function of IgA receptors ( P24071 and CD71 ) during maturation of dendritic cells . Dendritic cells ( DC ) are the most efficient antigen - presenting cells residing in mainly peripheral tissues . Antigen uptake by DC is particularly efficient , being mediated by various receptors such as lectin , scavenger receptors , and Fc receptors ( FcRs ) . Immunoglobulin A ( IgA ) is part of the first - line immune barrier in mucosae , where DC are numerous . A member of the FcR family , FcalphaRI , is expressed on interstitial DC . We report here that monocyte - derived DC ( Mo - DC ) express another IgA receptor ( IgA - R ) , the transferrin receptor ( P02786 ) , even in the absence of DC proliferation in vitro . Upon incubation with inflammatory cytokines such as tumor necrosis factor alpha and interleukin ( IL ) - 1beta or maturating agents ( lipopolysaccharide , P29965 ) , FcalphaRI and P02786 expression on Mo - DC was specifically up - regulated , whereas FcgammaRs and FcepsilonRI expression was down - regulated . Both IgA - Rs were functional , being able to mediate endocytosis by immature and activated Mo - DC . Although FcalphaRI internalized IgA complexes on both types of DC , P02786 was only able to mediate IgA complex internalization by immature cells . Cross - linking of FcalphaRI but not of P02786 resulted in up - regulation of major histocompatibility complex ( MHC ) class II / P42081 expression and secretion of P22301 and IL - 12 by immature Mo - DC . Moreover , in activated Mo - DC , cross - linking of FcalphaRI could up - regulated MHC class II / P42081 and triggered P22301 secretion . Our findings led us to propose that FcalphaRI expressed by interstitial - type DC could play a critical role to sample IgA - recognized antigens and also during DC activation .", "DB00205 and proguanil resistance - conferring mutations in Plasmodium falciparum dihydrofolate reductase : polymerase chain reaction methods for surveillance in Africa . As chloroquine resistance spreads across Africa , the dihydrofolate reductase ( P00374 ) inhibitors pyrimethamine and proguanil are being used as alternative first - line drugs for the treatment and prevention of Plasmodium falciparum malaria . Resistance to these drugs is conferred by point mutations in parasite P00374 . These point mutations can be detected by polymerase chain reaction ( PCR ) assays , but better methods for sample collection , DNA extraction , and a diagnostic PCR are needed to make these assays useful in malaria - endemic areas . Here we report methods for collecting fingerstick blood onto filter paper strips that are air - dried , then stored and transported at room temperature . Cell lysis and DNA extraction are accomplished by boiling in Chelex - 100 . We also report a nested PCR technique that has improved sensitivity and specificity . These procedures readily detect mixed infections of parasites with both sensitive and resistant genotypes ( confirmed by direct sequencing ) and are reliable at parasite densities less than 250 / mm3 in field surveys .", "Deviated mechanism of wound healing in diabetic corneas . We examined phenotypic changes during the wound healing process in the corneal epithelium of Goto - Kakizaki ( GK ) rats , a spontaneous model of type 2 diabetes mellitus . In this article , we provide an overview of our and other groups ' research and describe the clinical features of diabetic keratopathy . We observed that the rate of corneal epithelial wound closure was decreased in GK rats compared with Wistar rats . Immunoreactivity for P17302 , P02533 , and Ki - 67 was detected in the 2 layers of cells adjacent to the basement membrane in the corneal epithelium of GK rats , whereas only the single basal layer of cells was positive for these proteins in the corneal epithelium of Wistar rats . The frequency of Ki - 67 - positive cells was greater in GK rats than in Wistar rats in the intact corneal epithelium and during wound healing . The GK rat represents delayed corneal epithelial wound closure as well as that which is observed in human diabetic keratopathy . Furthermore , these results indicate a possibility of functional deviation in corneal epithelial cells with diabetes mellitus .", "Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK77___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .", "Unimpeded skin carcinogenesis in P02533 - HPV16 transgenic mice deficient for plasminogen activator inhibitor . Angiogenesis , extracellular matrix remodeling and cell migration are associated with cancer progression and involve at least , the plasminogen activating system and its main physiological inhibitor , the plasminogen activator inhibitor - 1 ( P05121 ) . Considering the recognized importance of P05121 in the regulation of tumor angiogenesis and invasion in murine models of skin tumor transplantation , we explored the functional significance of P05121 during early stages of neoplastic progression in the transgenic mouse model of multistage epithelial carcinogenesis ( P02533 - HPV16 mice ) . We have studied the effect of genetic deletion of P05121 on inflammation , angiogenesis , lymphangiogenesis and tumor progression . In this model , P05121 deficiency neither impaired keratinocyte hyperproliferation or tumor development nor affected the infiltration of inflammatory cells and development of angiogenic or lymphangiogenic vasculature . We are reporting evidence for concomitant lymphangiogenic and angiogenic switches independent to P05121 status . Taken together , these data indicate that P05121 is not rate limiting for neoplastic progression and vascularization during premalignant progression , or that there is a functional redundancy between P05121 and other tumor regulators , masking the effect of P05121 deficiency in this long - term model of multistage epithelial carcinogenesis .", "Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK82___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK82___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .", "Rational drug design approach for overcoming drug resistance : application to pyrimethamine resistance in malaria . DB00205 acts by selectively inhibiting malarial dihydrofolate reductase - thymidylate synthase ( P00374 - TS ) . Resistance in the most important human parasite , Plasmodium falciparum , initially results from an S108N mutation in the P00374 domain , with additional mutation ( most commonly C59R or N51I or both ) imparting much greater resistance . From a homology model of the 3 - D structure of P00374 - TS , rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance . Compared to pyrimethamine ( Ki 1 . 5 nM ) with purified recombinant P00374 fromP . falciparum , the Ki value of the m - methoxy analogue of pyrimethamine was 1 . 07 nM , but against the P00374 bearing the double mutation ( C59R + S108N ) , the Ki values for pyrimethamine and the m - methoxy analogue were 71 . 7 and 14 . 0 nM , respectively . The m - chloro analogue of pyrimethamine was a stronger inhibitor of both wild - type P00374 ( with Ki 0 . 30 nM ) and the doubly mutant ( C59R + S108N ) purified enzyme ( with Ki 2 . 40 nM ) . Growth of parasite cultures of P . falciparum in vitro was also strongly inhibited by these compounds with 50 % inhibition of growth occurring at 3 . 7 microM for the m - methoxy and 0 . 6 microM for the m - chloro compounds with the P04264 parasite line bearing the double mutation ( S108N + C59R ) , compared to 10 . 2 microM for pyrimethamine . These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P . berghei - infected mice .", "Fitness effects of P00374 - TS mutations associated with pyrimethamine resistance in apicomplexan parasites . DB00205 resistance in the malaria parasite Plasmodium falciparum is characterized by specific point mutations in the dihydrofolate reductase ( P00374 ) domain of the bifunctional dihydrofolate reductase - thymidylate synthase ( P00374 - TS ) gene . We have previously explored the effect of these mutations by engineering homologous alleles of Toxoplasma gondii P00374 - TS , which can readily be expressed as recombinant protein for enzymatic studies , or as allelic replacements in transgenic parasites . In order to directly assess the costs of pyrimethamine - resistance in vivo , we have carried out competition studies between mixtures of T . gondii tachyzoites harbouring wild - type or mutant P00374 - TS alleles , both in tissue culture and in mice . Arg59 + Asn108 mutants ( using the P . falciparum numbering system ) exhibit no significant fitness defects in vitro , but a fitness defect of 1 . 8 % per generation in mice . Arg59 + Ser223 mutants exhibit fitness defects of > 2 . 8 % per generation both in vitro and in vivo , which may explain why this highly pyrimethamine - resistant allele has not been observed in the field . It is important to note that long - term propagation of parasites in vitro or in vivo can produce adaptations affecting fitness by > 3 . 7 % per generation , necessitating careful attention to background in head - to - head competition studies . A sensitive PCR - based assay permits different growth rates to be assessed even in the absence of a drug resistance marker that can be scored by plaque assay .", "Both the ADP receptors P47900 and Q9H244 , play a role in controlling shape change in human platelets . Two types of ADP receptors , P2Y ( 1 ) and P2Y ( 12 ) are involved in platelet aggregation . The P2X ( 1 ) receptor is also present but its role , in terms of platelet function , is not yet defined . The aim of this study was to establish if the ADP receptors , P2Y ( 1 , ) P2Y ( 12 ) and P2X ( 1 ) play a role in controlling platelet shape change ( PSC ) in human platelets . PSC is an early phase of platelet activation that precedes aggregation . Using a high - resolution channelyzer , PSC was assessed by measuring the median platelet volume ( MPV ) . The P2Y ( 1 ) receptor antagonist P59665 2179 ( 1 . 06 - 10 . 25 micro mol / l ) blocked ADP - induced PSC ( by 100 % ) . The median IC ( 50 ) was 3 . 16 micro mol / l . P59665 2179 also significantly ( P = 0 . 01 ) inhibited PSC induced by the combination of ADP + serotonin ( 5HT ) . The P2Y ( 12 ) receptor antagonist AR - C69931MX significantly inhibited ( at 10s , P = 0 . 009 ; 15 s , P = 0 . 001 and 30 s , P = 0 . 015 ) ADP - induced PSC . The P2X ( 1 ) receptor antagonist TNP - DB00171 had no significant effect on ADP - or ADP + 5HT - induced PSC . We conclude that the IC ( 50 ) of a P2Y ( 1 )- blocker can be derived because of the high - resolution and reproducibility of the channelyzer technique . In addition to the P2Y ( 1 ) purinoceptor , the P2Y ( 12 ) receptor appears to be involved in ADP - induced PSC since this process was significantly inhibited by AR - C69931MX . The channelyzer technique may be more reliable than optical aggregometry to assess PSC ." ]

[ "___MASK15___", "___MASK18___", "___MASK32___", "___MASK47___", "___MASK67___", "___MASK74___", "___MASK75___", "___MASK77___", "___MASK82___" ]

[ "1Alpha , 25 ( OH ) 2D3 - induced transrepression by vitamin D receptor through E - box - type elements in the human parathyroid hormone gene promoter . Although transactivation by the liganded vitamin D receptor ( P11473 ) is well described at the molecular level , the precise molecular mechanism of negative regulation by the liganded P11473 remains to be elucidated . We have previously reported a novel class of negative vitamin D response element ( nVDRE ) called 1alphanVDRE in the human 25 ( OH ) D31alpha - hydroxylase [ 1alpha ( OH ) ase ] gene by DB00136 - bound P11473 . This element was composed of two E - box - type motifs that bound to VDIR for transactivation , which was attenuated by liganded P11473 . Here , we explore the possible functions of VDIR and E - box motifs in the human ( h ) PTH and hPTHrP gene promoters . Functional mapping of the DB05829 and hPTHrP promoters identified E - box - type elements acting as nVDREs in both the DB05829 promoter ( hPTHnVDRE ; - 87 to - 60 bp ) and in the hPTHrP promoter ( hPTHrPnVDRE ; - 850 to - 600 bp ; - 463 to - 104 bp ) in a mouse renal tubule cell line . The hPTHnVDRE alone was enough to direct ligand - induced transrepression mediated through P11473 / retinoid X receptor and VDIR . Direct DNA binding of hPTHnVDRE to VDIR , but not P11473 / retinoid X receptor , was observed and ligand - induced transrepression was coupled with recruitment of P11473 and histone deacetylase 2 ( Q92769 ) to the DB05829 promoter . These results suggest that negative regulation of the DB05829 gene by liganded P11473 is mediated by VDIR directly binding to the E - box - type nVDRE at the promoter , together with recruitment of an HDAC corepressor for ligand - induced transrepression .", "New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .", "Translational research in bipolar disorder : emerging insights from genetically based models . Bipolar disorder ( BPD ) is characterized by vulnerability to episodic depression and mania and spontaneous cycling . Because of marked advances in candidate - gene and genome - wide association studies , the list of risk genes for BPD is growing rapidly , creating an unprecedented opportunity to understand the pathophysiology of BPD and to develop novel therapeutics for its treatment . However , genetic findings are associated with major unresolved issues , including whether and how risk variance leads to behavioral abnormalities . Although animal studies are key to resolving these issues , consensus is needed regarding how to define and monitor phenotypes related to mania , depression and mood swing vulnerability in genetically manipulated rodents . In this study we discuss multiple facets of this challenging area , including theoretical considerations , available tests , limitations associated with rodent behavioral modeling and promising molecular - behavioral findings . These include O15516 , glycogen synthase kinase 3beta ( GSK - 3beta ) , glutamate receptor 6 ( Q13002 ) , extracellular signal - regulated kinase - 1 ( P27361 ) , p11 ( or P60903 ) , vesicular monoamine transporter 2 ( Q05940 or Q05940 ) , glucocorticoid receptors ( GRs ) , Bcl - 2 - associated athanogene - 1 ( Q99933 ) and mitochondrial DNA polymerase - gamma ( P54098 ) . Some mutant rodent strains show behavioral clusters or activity patterns that cross - species phenocopy objective / observable facets of mood syndromes , and changes in these clustered behaviors can be used as outcome measures in genetic - behavioral research in BPD .", "Current treatment strategies for non - alcoholic fatty liver disease ( NAFLD ) . Nonalcoholic fatty liver disease ( NAFLD ) is recognized as the most common cause of chronic liver disease worldwide . NAFLD is a clinicopathologic syndrome ranging from simple steatosis , which is relatively benign , to the more severe form known as nonalcoholic steatohepatitis ( NASH ) , which may progress to cirrhosis , liver failure , and hepatocellular carcinoma . NAFLD is associated with significant liver related morbidity and mortality , and its underlying pathophysiology is thought to result from a multiple hit process . The initial insult is the accumulation of hepatic fat secondary to insulin resistance . In the setting of hepatic steatosis , the second hit can be caused by reactive oxygen species , inflammatory cytokines , and adipokines . Several therapeutic modalities that target these mechanisms are under investigation , but no proven treatment has yet emerged . P01308 sensitizers such as thiazolidinediones and metformin show promise , and several studies have explored the role of lipid lowering agents , antioxidants , and cytoprotective agents . Novel agents such as anti - obesity drugs , selective cannabinoid - 1 receptor blockers , and dual Q07869 alpha and gamma agonists are also under investigation . Unfortunately , data on the long - term safety and efficacy of these agents and their impact on liver related histologic outcomes are currently lacking . NAFLD treatment currently focuses on reducing metabolic risk factors , with the mainstay of therapy focusing on life - style modifications such as gradual weight loss through diet and regular exercise .", "Changes in granulosa cells gene expression associated with growth , plateau and atretic phases in medium bovine follicles . BACKGROUND : The objective of this study was to build the transcriptomic profile of granulosa cells originating from follicles 6 to 9 mm in diameter in dairy cattle using microarrays . METHODS : Granulosa cells originating from three different phases of antral follicle growth were compared : growing ( G ) , plateau ( P ) and atresia ( A ) , as categorized by flow cytometry profiles of DNA . The growing and atretic conditions were each hybridized against the plateau condition as a reference in order to understand the specific biological mechanisms modulated in this class of follicles . RESULTS : 2 , 942 genes were differentially expressed ( P < 0 . 05 ) in P vs . G and 1 , 974 in A vs . P . A clear segregation of the 3 phases was confirmed by between group analysis ( BGA ) . The first characteristic of the plateau phase is the activation of the upstream regulators P04637 and P60484 which participate in the reduction of cell growth through MYC , P01100 and Q01094 - 2 - 3 . We also observed the down - regulation of steroidogenesis genes : P05108 and P11511 , in the granulosa cells of the plateau phase relative to the growth phase . On the other hand , the A vs . P contrast showed up - regulation of multiple transcripts associated to apoptosis : P78371 , P98082 , Q14126 and P21980 . CONCLUSIONS : This study offers multiple candidate genes to be further studied in order to elucidate their role in the modulation of follicular development and , ultimately , of oocyte quality .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK13___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "The anti - proliferative effects of DB00136 on breast and prostate cancer cells are associated with induction of P38398 gene expression . The anti - proliferative action of the seco - steroid hormone 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] extends to some , but not all breast and prostate cancer cell lines . By elucidating the molecular mechanisms mediating the sensitivity of these cells , we can identify critical target genes regulated directly or indirectly by DB00136 and pathways potentially disrupted during transformation . In this study , we demonstrated the induction of expression of P38398 mRNA and protein as well as transcriptional activation from the P38398 - promoter by DB00136 in the sensitive breast cancer cell line MCF - 7 . This was not observed in the DB00136 - resistant breast cancer cell line MDA - MB - 436 . The induction of P38398 mRNA was blocked by cyclohexamide . This indicated that transcriptional activation was mediated indirectly by the vitamin D receptor ( P11473 ) . Inhibition of P11473 protein levels by stable transformation of the anti - sense P11473 in MCF - 7 reduced the sensitivity of MCF - 7 to DB00136 by 50 - fold . In addition , the induction of P38398 protein and transcriptional activation of a P38398 promoter - luciferase reporter construct was abrogated in the stable transformant with the greatest reduction of P11473 levels . Examination of other breast and prostate cancer cell lines revealed that sensitivity to the anti - proliferative effects of 1alpha , 25 ( OH ) 2D3 was strongly associated with an ability to modulate P38398 protein . Furthermore , the expression of the estrogen receptor in these cell lines strongly correlated with their sensitivity to DB00136 and their ability to modulate P38398 expression . Taken together , our data support a model whereby the anti - proliferative effects of DB00136 are mediated , in part , by the induction of P38398 gene expression via transcriptional activation by factors induced by the P11473 and that this pathway is disrupted during the development of prostate and breast cancers .", "17 ___MASK16___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .", "___MASK3___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .", "An essential role of the CAAT / enhancer binding protein - alpha in the vitamin D - induced expression of the human steroid / bile acid - sulfotransferase ( Q06520 ) . The vitamin D receptor ( P11473 ) regulates steroid and drug metabolism by inducing the genes encoding phase I and phase II enzymes . Q06520 is a liver - and intestine - expressed sulfo - conjugating enzyme that converts the alcohol - OH of neutral steroids , bile acids , and drugs to water - soluble sulfated metabolites . DB00136 [ 1 , 25 -( OH ) 2D3 ] induces Q06520 gene transcription after the recruitment of P11473 to the vitamin D - responsive chromatin region of Q06520 . A composite element in human Q06520 directs the 1 , 25 -( OH ) 2D3 - mediated induction of natural and heterologous promoters . This element combines a P11473 / retinoid X receptor - alpha - binding site [ vitamin D response element ( VDRE ) ] , which is an imperfect inverted repeat 2 of AGCTCA , and a CAAT / enhancer binding protein ( C / EBP ) - binding site located 9 bp downstream to VDRE . The binding sites were identified by EMSA , antibody supershift , and deoxyribonuclease I footprinting . C / EBP - alpha at the composite element plays an essential role in the P11473 regulation of Q06520 , because 1 ) induction was lost for promoters with inactivating mutations at the VDRE or C / EBP element ; 2 ) Q06520 induction by 1 , 25 -( OH ) 2D3 in C / EBP - alpha - deficient cells required the expression of cotransfected C / EBP - alpha ; and 3 ) C / EBP - beta did not substitute for C / EBP - alpha in this regulation . P11473 and C / EBP - alpha were recruited concurrently to the composite element along with the coactivators p300 , steroid receptor coactivator 1 ( Q15788 ) , and P12931 - 2 , but not Q9Y6Q9 . P11473 and C / EBP - alpha associated endogenously as a DNA - dependent , coimmunoprecipitable complex , which was detected at a markedly higher level in 1 , 25 -( OH ) 2D3 - treated cells . These results provide the first example of the essential role of the interaction in cis between C / EBP - alpha and P11473 in directing 1 , 25 -( OH ) 2D3 - induced expression of a P11473 target gene .", "Cloning of a novel phosphatidylinositol kinase - related kinase : characterization of the human Q96Q15 RNA surveillance protein . We have cloned and characterized a new member of the phosphatidylinositol kinase ( PIK ) - related kinase family . This gene , which we term human Q96Q15 ( Q96Q15 ) , is orthologous to Caenorhabditis elegans Q96Q15 , a protein that functions in nonsense - mediated mRNA decay ( Q53H76 ). cDNA sequencing revealed that Q96Q15 encodes a protein of 3031 amino acids containing a conserved kinase domain , a C - terminal domain unique to the PIK - related kinases and an P62942 - rapamycin binding - like domain similar to that found in the PIK - related kinase P42345 . Immunopurified FLAG - tagged Q96Q15 exhibits protein kinase activity as measured by autophosphorylation and phosphorylation of the generic PIK - related kinase substrate PHAS - 1 . Q96Q15 kinase activity is inhibited by high nanomolar concentrations of wortmannin ( IC ( 50 ) = 105 nm ) but is not inhibited by a P62942 - rapamycin complex . Mutation of conserved residues within the kinase domain of Q96Q15 abolishes both autophosphorylation and substrate phosphorylation , demonstrating that Q96Q15 exhibits intrinsic protein kinase activity . Q96Q15 phosphorylates purified Q92900 protein , a phosphoprotein that plays a critical role in Q53H76 , at sites that are also phosphorylated in whole cells . Based on these data , we conclude that Q96Q15 is the human orthologue to C . elegans Q96Q15 . Our data indicate that Q96Q15 may function in Q53H76 by directly phosphorylating Q92900 protein at physiologically relevant sites .", "Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .", "Regulation of the human P38936 ( waf1 / cip1 ) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor . The main regulator of the human tumor suppresser gene P38936 ( waf1 / cip1 ) is the transcription factor p53 , but more recently it has been suggested to be a primary anti - proliferative target for the nuclear receptor P11473 in the presence of its ligand 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) . To identify P11473 responding regions , we analyzed 20 overlapping regions covering the first 7 . 1 kb of the P38936 ( waf1 / cip1 ) promoter in MCF - 7 human breast cancer cells using chromatin immuno - precipitation assays ( ChIP ) with antibodies against p53 and P11473 . We confirmed two known p53 binding regions at approximate positions - 1400 and - 2300 and identified a novel site at position - 4500 . In addition , we found three P11473 - associated promoter regions at positions - 2300 , - 4500 and - 6900 , i . e . two regions showed binding for both p53 and P11473 . In silico screening and in vitro binding assays using recombinant and in vitro translated proteins identified five p53 binding sites within the three p53 - positive promoter regions and also five DB00136 response elements within the three P11473 - positive regions . Reporter gene assays confirmed the expected responsiveness of the respective promoter regions to the p53 inducer 5 - fluorouracil and DB00136 . Moreover , re - ChIP assays confirmed the functionality of the three DB00136 - reponsive promoter regions by monitoring simultaneous occupancy of P11473 with the co - activator proteins CBP , Q15788 and Q15648 . Taken together , we demonstrated that the human P38936 ( ( waf1 / cip1 ) ) gene is a primary DB00136 - responding gene with at least three P11473 binding promoter regions , in two of which also p53 co - localizes .", "Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines . Although there is growing evidence that estrogens promote tumor progression in epithelial ovarian cancer , the molecular mechanisms accounting for this are still unclear . Selective estrogen receptor modulators ( SERMs ) mimic estrogen action in certain tissues while opposing it in others . The molecular mechanisms of the effects of SERMs such as raloxifene on the tumor progression of epithelial ovarian cancer are also still unclear . Here , we show that various genomic actions of estrogen differ from those of raloxifene in human ovarian cancer cell lines expressing estrogen receptor alpha ( ERalpha ) . 17beta - Estradiol ( E2 ) induced the gene expression of c - Myc and DB01277 and increased the binding of ERalpha to the P05412 site of the promoters of c - Myc and DB01277 . ERalpha silencing abolished the E2 - stimulated c - Myc expression . E2 induced the recruitment of co - activators such as Q15788 , Q9Y6Q9 and CBP to the promoters of c - Myc and DB01277 , and Q15788 silencing abolished both the E2 - stimulated c - Myc expression and cell - cycle progression . In contrast , although raloxifene increased the binding of ERalpha to the P05412 site of the promoters of c - Myc and DB01277 , raloxifene had no effect on the gene expression of c - Myc or DB01277 . Raloxifene induced the recruitment of co - repressors such as Q92769 , O75376 and Q9Y618 to the promoter of DB01277 . Thus , the difference between the genomic actions exerted by estrogen and raloxifene in human ovarian cancer cell lines expressing ERalpha appear to be dependent on the recruitment of co - regulators .", "P38398 - associated breast and ovarian cancer risks in Poland : no association with commonly studied polymorphisms . Polymorphisms in genes involved in DNA repair , steroid hormone biosynthesis / metabolism / signaling , folate metabolism as well as cell growth are prime candidates for possible associations with breast and ovarian cancer risk in women with an inherited predisposition . We investigated 29 polymorphisms in 20 genes encoding key proteins of the above four biological pathways for their breast and ovarian cancer risk modifying effect in Polish women harboring P38398 founder mutations . Of the analyzed genes , P18074 , P18887 , O43543 , O43542 and Lig4 participate in DNA repair , P04637 in cell cycle check point control , Q9Y6Q9 , AR , P21964 , P05108 , P05093 , P11511 , Q8NA42 and P06401 in steroid hormone biosynthesis / metabolism / signaling , P04818 in folate metabolism and P04626 , P05231 , Q07954 , P01137 and P36897 affect cell growth . Using validated methods , we genotyped 319 breast cancer cases , 146 ovarian cancer cases and 290 unaffected controls , all of whom harbored one of three causative mutations in P38398 . Our results revealed no association of any of the investigated polymorphisms with P38398 - associated breast or ovarian cancer risk . Thus , it appears that these polymorphisms do not influence disease risk in Polish women carrying one of the three common P38398 founder mutations .", "DB00136 induces capacitative calcium entry involving a Q13507 protein in skeletal muscle and osteoblastic cells . This work describes the involvement of TRPC proteins in capacitative calcium entry ( CCE ) induced by 1alpha , 25 - dihydroxy - vitamin - D3 [ DB00136 ] in chick skeletal muscle and in rat osteoblast - like cells ( ROS 17 / 2 . 8 ) and the role of the vitamin D receptor ( P11473 ) in this non - genomic rapid response mediated by the hormone . We propose that an endogenous Q13507 protein mediates DB00136 modulation of CCE in these cells , which seems to implicate P11473 - Q13507 association and the participation of an INAD - like scaffold protein .", "Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells . The active vitamin D metabolite 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] has wide but not fully understood antitumor activity . A previous transcriptomic analysis of DB00136 action on human colon cancer cells revealed cystatin D ( P28325 ) , which encodes an inhibitor of several cysteine proteases of the cathepsin family , as a candidate target gene . Here we report that DB00136 induced vitamin D receptor ( P11473 ) binding to , and activation of , the P28325 promoter and increased P28325 RNA and protein levels in human colon cancer cells . In cells lacking endogenous cystatin D , ectopic cystatin D expression inhibited both proliferation in vitro and xenograft tumor growth in vivo . Furthermore , cystatin D inhibited migration and anchorage - independent growth , antagonized the Wnt / beta - catenin signaling pathway , and repressed c - MYC expression . Cystatin D repressed expression of the epithelial - mesenchymal transition inducers O95863 , O43623 , P37275 , and O60315 and , conversely , induced P12830 and other adhesion proteins . P28325 knockdown using shRNA abrogated the antiproliferative effect of DB00136 , attenuated P12830 expression , and increased c - MYC expression . In human colorectal tumors , expression of cystatin D correlated with expression of P11473 and P12830 , and loss of cystatin D correlated with poor tumor differentiation . Based on these data , we propose that P28325 has tumor suppressor activity that may contribute to the antitumoral action of DB00136 in colon cancer .", "___MASK3___ inhibits raft dependent Fcgamma receptor signalling in human monocytes . Statins inhibit P04035 and thus block cholesterol and isoprenoid biosynthesis . Since statins also have anti - inflammatory effects , we investigated the effect of fluvastatin on monocyte Fcgamma receptor function . ___MASK3___ ( 0 . 5 - 20 microM ) inhibited Fcgamma receptor signal transduction at the level of tyrosine kinase activation , in a time and dose dependent manner . Initiation of tyrosine phosphorylation is not thought to involve prenylated proteins ; thus , we hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane rafts to impair signalling . Consistent with this hypothesis , fluvastatin decreased ( and mevalonate rescued ) signalling molecules within membrane rafts in parallel with effects on tyrosine phosphorylation events . Raft integrity was unaffected by prenyl transferase inhibitors . In addition , Fcgamma receptor mediated immune complex trafficking , activation of Q96HU1 kinases ( P29323 and p38 ) , and downstream inflammatory mediator release ( P03956 and P05231 ) were blocked by fluvastatin . Thus , P04035 inhibition alters immune receptor signalling by disrupting membrane rafts essential for the initiation of signal transduction . Inhibition of Fcgamma receptor function may limit development and progression of atherosclerosis by decreasing monocyte / macrophage inflammatory mediator release . Since many receptors utilise cholesterol rich rafts this mechanism may have broader significance given the pleiotropic effects of statins .", "Membrane attack by complement : the assembly and biology of terminal complement complexes . Complement system activation plays an important role in both innate and acquired immunity . Activation of the complement and the subsequent formation of C5b - 9 channels ( the membrane attack complex ) on the cell membranes lead to cell death . However , when the number of channels assembled on the surface of nucleated cells is limited , sublytic C5b - 9 can induce cell cycle progression by activating signal transduction pathways and transcription factors and inhibiting apoptosis . This induction by C5b - 9 is dependent upon the activation of the phosphatidylinositol 3 - kinase / Akt / Q12778 and P27361 pathways in a Gi protein - dependent manner . C5b - 9 induces sequential activation of P11802 and P24941 , enabling the P55008 / S - phase transition and cellular proliferation . In addition , it induces Q9H4X1 , a novel gene that plays a role in cell cycle activation by interacting with Akt and the cyclin B1 - P06493 complex . C5b - 9 also inhibits apoptosis by inducing the phosphorylation of Bad and blocking the activation of FLIP , caspase - 8 , and Bid cleavage . Thus , sublytic C5b - 9 plays an important role in cell activation , proliferation , and differentiation , thereby contributing to the maintenance of cell and tissue homeostasis .", "Apolipoprotein polymorphisms and familial hypercholesterolemia . The majority of apolipoproteins known to play a major role in lipid metabolism were identified over 20 years ago , and nine of them ( P02647 , - A2 , - A4 , - B48 , - B100 , - C1 , - P06681 , - P01024 and - E ) have long been known to be most relevant to the regulation of lipoproteins . Polymorphisms of genes encoding apolipoproteins influence plasma levels of high - density lipoproteins ( HDL ) , very - low - density lipoprotein ( VLDL ) , low - density lipoprotein ( LDL ) chylomicrons or triglycerides . Familial hypercholesterolemia ( FH ) , an autosomal dominant disorder , is caused by mutations mainly located in the low - density lipoprotein receptor ( P01130 ) gene , or more rarely within the apolipoprotein B - 100 gene or the gene encoding a secreted proteinase PSCK9 . FH is characterized by elevated concentrations of LDL , deposition of LDL - derived cholesterol in tendons , skin xanthomas , and premature coronary artery disease . The frequency of heterozygotes is approximately one in 500 persons , placing FH among the most common inborn errors of metabolism . The risk of cardiovascular disease in these patients is influenced not only by the type of the mutations they carry , but also by the haplotype of lipid modifier genes , as is the case of apolipoproteins . In this review , we present current information that demonstrates the impact of apolipoprotein polymorphisms on the FH phenotype .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK93___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .", "[ Pathophysiology of bone metabolism ] . Osteoporosis is a multifactorial disease entailing a high risk to sustain fragility fractures . Its susceptibility is determined by genetic and environmental factors and underlying diseases . Bone is rebuilt and regenerated by osteoclasts , osteoblasts and osteocytes . Local and systemic growth and differentiation factors such as P01308 - like growth factors , bone morphogenetic proteins and wnt - proteins confer anabolic signals , while the Q9Y6Q6 / Q9Y6Q6 - Ligand and O00300 ( O00300 ) system regulates bone resorption . The ratio of osteoclast stimulating O14788 and its soluble decoy receptor O00300 is modulated by sex hormones , vitamin D , parathyroid hormone , local growth factors and mechanical loading . Osteocytes regulate bone mass via the bone formation inhibitor sclerostin . Bone is tightly interconnected with and regulated by the calcium / phosphate / vitamin D system via the parathyroid gland , the gut , liver and kidneys . Sex hormones are important for bone formation during adolescence and their loss in menopause / andropause exaggerates bone resorption . Basically over - activity of osteoclasts and / or functional deficits of osteoblasts can cause negative bone balance and favor osteoporosis .", "DB00877 effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties . Neointima formation , the leading cause of restenosis , is caused by proliferation of coronary artery smooth muscle cells ( CASMCs ) and is associated with infiltration by monocytes . DB00877 inhibits neointima formation after stent implantation in humans . It reduces proliferation by its effects on mammalian target of rapamycin ( P42345 ) kinase . In this study , we investigated the expression of P42345 in human neointima and the effect of rapamycin on global transcriptional events controlling CASMC phenotype . In neointimal CASMCs , P42345 exhibited increased phosphorylation and was translocated to the nucleus compared with control . Comparative gene expression analysis of CASMCs treated with rapamycin ( 100 ng / ml ) revealed down - regulation of the transcription factor Q01094 , a key regulator of G ( 1 )/ S - phase entry , and of various retinoblastoma protein / Q01094 - regulated genes . In addition , we found changes in the expression of genes associated with replication , apoptosis , and extracellular matrix formation . Furthermore , rapamycin decreased the gene expression of endothelial monocyte - activating polypeptide - II ( EMAP - II ) . This decrease of EMAP - II expression was reflected in a reduced adhesiveness of CASMCs for monocytic cells . Addition of EMAP - II counteracted the antiadhesive effect of rapamycin . Therefore , EMAP - II may comprise a mechanism of rapamycin - mediated reduction of the proinflammatory activation of CASMCs . The effects reported here of rapamycin on the down - regulation of genes involved in cell cycle progression , apoptosis , proliferation , and extracellular matrix formation in CASMCs provide an explanation of how rapamycin reduces CASMC proliferation . In addition , rapamycin may contribute to a reduction of inflammatory responses by reducing the adhesiveness of CASMC , a mechanism suggested to be mediated by the production and release of EMAP II .", "[ Hyperlipidemia and peroxisome proliferator - activated receptor ( Q07869 ) -- regulation of the PPARalpha gene by O15516 : O00327 ] . The main pathological findings in atherosclerosis include abnormal reactions of neutrophils , lymphocytes and monocytes / macrophages , vascular smooth muscle cells and vascular endothelial cells , and the accumulation of cholesterol ester in the arterial wall . Therefore , investigating the effects of these abnormal reactions on the arterial wall may improve understanding of the mechanisms underlying atherosclerosis . Three types of peroxisome proliferator - activated receptors ( PPARs ) : PPARalpha , PPARbeta / delta , and PPARgamma are expressed in endothelial cells . In endothelial cells , the ligands / activators for PPARalpha and PPARgamma increase Cu2 + , DB01593 - superoxide dismutase . In addition , the phorbol myristate acetate ( PMA ) - stimulated 22 kDa - subunit ( P13498 ) protein levels and 47 kDa - subunit ( p47phox ) protein levels in NADPH ( superoxide generating enzyme nicotinamide adenine dinucleotide phosphate ( reduced form ) ) oxidase were decreased by treatment with PPARalpha and PPARgamma ligands / activators . Recently , we showed that the O15516 : O00327 heterodimer regulates the PPARalpha gene via promoter of PPARalpha . Moreover , we report a patient with severe hypertriglyceridemia associated with anemia and hypoalbuminemia , in which the former may have caused the latter two conditions . This is the first reported case of abrupt onset of severe hypertriglyceridemia resulting in suppression of bone marrow and liver function . Here , based on recent studies including our own , we describe the relationships between risk factors for atherosclerosis , especially hyperlipidemia and PPARs and the molecular mechanisms that govern lipid metabolism in the arteries .", "___MASK38___ shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the Q9UBN7 - Hsp90 chaperone axis . Mutant p53 ( mutp53 ) cancers are surprisingly dependent on their hyperstable mutp53 protein for survival , identifying mutp53 as a potentially significant clinical target . However , exploration of effective small molecule therapies targeting mutp53 has barely begun . Mutp53 hyperstabilization , a hallmark of p53 mutation , is cancer cell - specific and due to massive upregulation of the HSP90 chaperone machinery during malignant transformation . We recently showed that stable complex formation between HSP90 and its mutp53 client inhibits E3 ligases Q00987 and Q9UNE7 , causing mutp53 stabilization . Histone deacetylase ( HDAC ) inhibitors ( HDACi ) are a new class of promising anti - cancer drugs , hyperacetylating histone and non - histone targets . Currently , suberoylanilide hydroxamic acid ( ___MASK38___ ) is the only FDA - approved HDACi . We show that ___MASK38___ exhibits preferential cytotoxicity for mutant , rather than wild - type and null p53 human cancer cells . Loss / gain - of - function experiments revealed that although able to exert multiple cellular effects , ___MASK38___ ' s cytotoxicity is caused to a significant degree by its ability to strongly destabilize mutp53 at the level of protein degradation . The underlying mechanism is ___MASK38___ ' s inhibition of Q9UBN7 , an essential positive regulator of HSP90 . This releases mutp53 and enables its Q00987 - and Q9UNE7 - mediated degradation . ___MASK38___ also strongly chemosensitizes mutp53 cancer cells for chemotherapy due to its ability to degrade mutp53 . This identifies a novel action of ___MASK38___ with the prospect of ___MASK38___ becoming a centerpiece in mutp53 - specific anticancer strategies .", "DB09145 channel expression in human ADPKD kidneys . Cyst enlargement in autosomal dominant polycystic kidney disease ( ADPKD ) results in part from the transport of solute and fluid into the lumen of the cyst . In proximal tubules and thin descending limbs of normal kidneys , the high transepithelial water permeability of these segments is due to the presence of the water channel protein , aquaporin - Q9UNE7 ( AQP - Q9UNE7 , i . e . , P29972 ) . The collecting ducts of normal kidneys express another member of this gene family , the aquaporin collecting duct ( P41181 , i . e . , P41181 ) . The expression and distribution of these two members of the aquaporin gene family were examined in ADPKD and normal human kidneys . In both tissues , Western blotting with the anti - AQP - Q9UNE7 antibody revealed a major 28 - kDa band . By immunofluorescence , AQP - Q9UNE7 was present in proximal tubules and thin descending limbs of Henle of both normal and ADPKD kidneys . In the latter , AQP - Q9UNE7 was detected in the epithelia lining 71 % of cysts . Many cysts were positive for the proximal tubule marker P98164 ( 44 % ) . Some cysts expressing AQP - Q9UNE7 did not stain for P98164 , suggesting a descending thin limb origin , and a few cysts were negative for both markers . In normal human kidney , Western blotting with the anti - P41181 antibody revealed a band at 28 kDa . P41181 was localized to collecting ducts and did not show colocalization with P98164 in normal human kidney . In ADPKD kidney , P41181 was expressed by only 8 % of cysts . In summary , water channels , primarily AQP - Q9UNE7 , are expressed in epithelial cells lining cysts in approximately 80 % of cysts in ADPKD kidneys . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK13___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .", "Adipose tissue endothelial cells from obese human subjects : differences among depots in angiogenic , metabolic , and inflammatory gene expression and cellular senescence . OBJECTIVE : Regional differences among adipose depots in capacities for fatty acid storage , susceptibility to hypoxia , and inflammation likely contribute to complications of obesity . We defined the properties of endothelial cells ( EC ) isolated from subcutaneous adipose tissue ( P21673 ) and visceral adipose tissue ( VAT ) biopsied in parallel from obese subjects . RESEARCH DESIGN AND METHODS : The architecture and properties of the fat tissue capillary network were analyzed using immunohistochemistry and flow cytometry . P28906 (+)/ CD31 (+) EC were isolated by immunoselection / depletion . Expression of chemokines , adhesion molecules , angiogenic factor receptors , as well as lipogenic and senescence - related genes were assayed by real - time PCR . Fat cell size and expression of hypoxia - dependent genes were determined in adipocytes from both fat depots . RESULTS : Hypoxia - related genes were more highly expressed in VAT than P21673 adipocytes . VAT adipocytes were smaller than P21673 adipocytes . Vascular density and EC abundance were higher in VAT . VAT - EC exhibited a marked angiogenic and inflammatory state with decreased expression of metabolism - related genes , including endothelial lipase , Q8IV16 , and Q07869 gamma . VAT - EC had enhanced expression of the cellular senescence markers , P17936 and γ - P16104 , and decreased expression of Q96EB6 . Exposure to VAT adipocytes caused more EC senescence - associated β - galactosidase activity than P21673 adipocytes , an effect reduced in the presence of vascular endothelial growth factor A ( P15692 ) neutralizing antibodies . CONCLUSIONS : VAT - EC exhibit a more marked angiogenic and proinflammatory state than P21673 - EC . This phenotype may be related to premature EC senescence . VAT - EC may contribute to hypoxia and inflammation in VAT .", "Caveolae and caveolin - 1 are implicated in 1alpha , 25 ( OH ) 2 - vitamin D3 - dependent modulation of Src , MAPK cascades and P11473 localization in skeletal muscle cells . We previously reported that DB00136 induces non - transcriptional rapid responses through activation of MAPKs in C2C12 skeletal muscle cells . However , there is little information on the molecular mechanism underlying the initiation of DB00136 signaling through this pathway . Plasma membrane components have been involved in some non - genomic effects . In this work , we investigated the role of caveolae and caveolin - 1 ( cav - 1 ) in DB00136 - stimulation of c - Src and MAPKs . When proliferating cells were pretreated with methyl beta cyclodextrin ( MbetaCD ) , a caveolae disrupting agent , under conditions in which cell morphology is not affected and no signs of apoptosis are observed , DB00136 - dependent activation of P27361 / 2 , p38 MAPK and c - Src was suppressed . Similar results were obtained by siRNA technology whereby silencing of cav - 1 expression abolished activation of c - Src and MAPKs induced by the hormone . By confocal immunocytochemistry it was observed that cav - 1 colocalizes with c - Src in the periplasma membrane zone at basal conditions . Hormone treatment disrupted the colocalization of these proteins and redistributed them into cytoplasm and nucleus . Co - immunoprecipitation assays corroborated these observations . Changes in P11473 localization after DB00136 exposure were also investigated . Confocal microscopy images showed that the hormone induces P11473 translocation to the plasma membrane , and this effect is abolished by MbetaCD . Altogether , these data suggest that caveolae is involved upstream in c - Src - MAPKs activation by DB00136 and that P11473 and cav - 1 participate in the rapid signaling elicited by the hormone .", "[ Gene polymorphism of the vitamin D receptor , vitamin D - binding protein and calcium - sensing receptor in respect of calcium - phosphate disturbances in chronic dialysis patients ] . Dialysed patients suffering from chronic kidney disease ( CKD ) show varied levels of concentration of parathyroid hormone ( PTH ) in the blood . One of the factors in charge of regulating levels of PTH concentration is DB00136 [ 1 , 25 -( OH ) 2D3 ] . Its deficiency in advanced stages of CKD is common . Vitamin D supplementation is not always effective in reaching levels of PTH concentration recommended by KDIGO for the dialysed patients . That suggests , among other things , disturbances in 1 , 25 -( OH ) 2D3 , reaching its place of target effect and having the desired final result . Disturbances of vitamin D target pathway can be genetically conditioned , hence the aim of this paper is to describe the distribution of polymorphic variants of vitamin D - binding protein gene ( VDBP ) , vitamin D receptor gene ( P11473 ) and gene of the calcium - sensing receptor ( P41180 ) with respect to PTH concentrations in serum and response to cinacalcet treatment in patients with secondary hyperparathyroidism in view of the differences in demographical , clinical and laboratory data of the dialysed patients .", "Stromal adipocyte PPARγ protects against breast tumorigenesis . Peroxisome proliferator - activated receptor ( Q07869 ) γ regulates the expression of genes essential for fat storage , primarily through its activity in adipocytes . It also has a role in carcinogenesis . PPARγ normally stops the in vivo progression of 7 , 12 - dimethylbenz [ a ] anthracene ( DMBA ) - mediated breast tumours as revealed with PPARγ haploinsufficient mice . Since many cell types associated with the mammary gland express PPARγ , each with unique signal patterns , this study aimed to define which tissues are required for PPARγ - dependent antitumour effects . Accordingly , adipocyte - specific PPARγ knockout ( PPARγ - A KO ) mice and their wild - type ( PPARγ - WT ) controls were generated , and treated with DMBA for 6 weeks to initiate breast tumorigenesis . On week 7 , mice were randomized to continue on normal chow diet or one supplemented with rosiglitazone ( ROSI ) , and followed for 25 weeks for tumour outcomes . In PPARγ - A KO versus PPARγ - WT mice , malignant mammary tumour incidence was significantly higher and mammary tumour latency was decreased . DMBA + ROSI treatment reduced average mammary tumour volumes by 50 % . Gene expression analyses of mammary glands by quantitative real - time polymerase chain reaction and immunofluorescence indicated that untreated PPARγ - A KOs had significantly decreased P38398 expression in mammary stromal adipocytes . Compared with PPARγ - WT mice , serum leptin levels in PPARγ - A KOs were also significantly higher throughout the study . Together , these data are the first to suggest that in vivo PPARγ expression in mammary stromal adipocytes attenuates breast tumorigenesis through P38398 upregulation and decreased leptin secretion . This study supports a protective effect of activating PPARγ as a novel chemopreventive therapy for breast cancer .", "The genes of the coactivator Q15596 and the corepressor Q9Y618 are primary DB00136 targets . The complex of the receptor for the hormone 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1alpha , 25 ( OH )( 2 ) D ( 3 ) ) , Vitamin D ( 3 ) receptor ( P11473 ) , the retinoid X receptor ( RXR ) and a 1alpha , 25 ( OH )( 2 ) D ( 3 ) response element ( VDRE ) is considered to be the molecular switch for nuclear 1alpha , 25 ( OH )( 2 ) D ( 3 ) signaling . In the presence of ligand the P11473 - RXR complex interacts with coactivator ( DB01992 ) proteins that in turn contact components of the basal transcriptional machinery resulting in an enhanced transcription of 1alpha , 25 ( OH )( 2 ) D ( 3 ) target genes . In the absence of ligand the P11473 remains bound to the DNA and interacts with corepressor ( CoR ) proteins that are involved in gene silencing activity . We treated MCF - 7 breast cancer cells with 1alpha , 25 ( OH )( 2 ) D ( 3 ) for increasing amounts of time , extracted mRNA and screened by real - time PCR the members of the P52701 DB01992 and NCoR CoR families . We find that of the P52701 coactivators , only Q15596 was responsive to 1alpha , 25 ( OH )( 2 ) D ( 3 ) . Similarly Q9Y618 but not NCoR1 gene transcription was sensitive to 1alpha , 25 ( OH )( 2 ) D ( 3 ) treatment . In silico analysis revealed that both Q15596 and Q9Y618 promoters have substantial numbers of VDREs compared to the promoters of the other family members . These VDREs are formed by direct repeats of the core binding motif RGKTCA with a three nucleotide spacing ( Q93038 ) . We suggest that some or all of these Q93038 - type VDREs are responsible for the observed responsiveness of Q15596 and Q9Y618 to 1alpha , 25 ( OH )( 2 ) D ( 3 ) .", "Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK15___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK15___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK15___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK15___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK15___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .", "Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O ( 6 )- methylguanine due to high Q01094 regulated mismatch repair . Exposure of stem cells to genotoxins may lead to embryonic lethality or teratogenic effects . This can be prevented by efficient DNA repair or by eliminating genetically damaged cells . Using undifferentiated mouse embryonic stem ( ES ) cells as a pluripotent model system , we compared ES cells with differentiated cells , with regard to apoptosis induction by alkylating agents forming the highly mutagenic and killing DNA adduct O ( 6 )- methylguanine . Upon treatment with N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) , ES cells undergo apoptosis at much higher frequency than differentiated cells , although they express a high level of the repair protein O ( 6 )- methylguanine - DNA methyltransferase ( P16455 ) . Apoptosis induced by MNNG is due to O ( 6 )- methylguanine DNA adducts , since inhibition of P16455 sensitized ES cells . The high sensitivity of ES cells to O ( 6 )- methylating agents is due to high expression of the mismatch repair proteins P43246 and P52701 ( MutSalpha ) , which declines during differentiation . High MutSalpha expression in ES cells was related to a high hyperphosphorylated retinoblastoma ( ppRb ) level and Q01094 activity that upregulates P43246 , causing , in turn , stabilization of P52701 . Non - repaired O ( 6 )- methylguanine adducts were shown to cause DNA double - stranded breaks , stabilization of p53 and upregulation of Fas / CD95 / Apo - 1 at significantly higher level in ES cells than in fibroblasts . The high apoptotic response of ES cells to O ( 6 )- methylguanine adducts may contribute to reduction of the mutational load in the progenitor population .", "___MASK67___ improves renal ischemia - reperfusion injury by inhibiting the mevalonate pathway . Statins are known to lessen the severity of renal ischemia - reperfusion injury . The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model . Treatment of mice with pravastatin , a widely used statin , improved renal function after renal ischemia - reperfusion without lowering the plasma cholesterol level . Administration of pravastatin with mevalonate , a product of P04035 , eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism . In hypercholestrolemic apolipoprotein E knockout mice with reduced P04035 activity ; the degree of injury was less severe than in control mice , however , there was no protective action of pravastatin on renal injury in the knockout mice . Treatment with a farnesyltransferase inhibitor ( L - 744832 ) mimicked pravastatin ' s protective effect but co - administration with the statin provided no additional protection . Both pravastatin and L - 744832 inhibited the injury - induced increase in plasma P05231 concentration to a similar extent . Our results suggest the protective effect of pravastatin on renal ischemia - reperfusion injury is mediated by inhibition of the mevalonate - isoprenoid pathway independent of its lipid lowering action .", "Critical role of toll - like receptors and the common TLR adaptor , MyD88 , in induction of granulomas and liver injury . BACKGROUND / AIMS : Toll - like receptors ( TLR ) recognize pathogens and regulate innate immune activation . Here , we investigated the roles of Q9NR96 and the common TLR adaptor , MyD88 , in liver injury . METHODS : C57BL6 , Q9NR96 (-/-) , IFNgamma (-/-) or MyD88 (-/-) mice were primed with Propionibacterium acnes , Q9NR96 ( CpG ) or O60603 ( lipoteichoic acid ) ligands followed by LPS challenge . ALT , cytokines and liver histology were assessed . RESULTS : Selective priming through Q9NR96 but not O60603 induced granulomas , elevated serum ALT , and sensitized C57BL6 mice to increased LPS - induced serum P05231 , IL - 12 and IFNgamma levels . Further , O60603 and Q9NR96 ligands synergized in induction of granulomas and sensitization to LPS - induced inflammation . IFNgamma induction by P . acnes , O60603 and Q9NR96 ligands required MyD88 . In MyD88 (-/-) mice P . acnes failed to induce granulomas and both MyD88 and Q9NR96 deficiency prevented P . acnes - induced sensitization to LPS . Increased mRNA expression of genes of the O00206 signaling complex ( O00206 , P08571 , MD - 2 , and MyD88 ) and the NADPH complexes ( p47phox , p67phox , gp91phox , and P13498 ) was induced by priming with P . acnes or Q9NR96 plus O60603 suggesting mechanisms for LPS sensitization and liver injury . CONCLUSIONS : Q9NR96 +/- O60603 activation via MyD88 - dependent pathways plays a pivotal role in liver sensitization and granuloma formation .", "Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK36___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .", "P98164 - mediated endocytosis of vitamin D binding protein correlates with DB00146 actions in human mammary cells . The major circulating form of vitamin D is DB00146 [ DB00146 ] , which is delivered to target tissues in complex with the serum vitamin D binding protein ( DBP ) . We recently observed that mammary cells can metabolize DB00146 to DB00136 [ 1 , 25 ( OH )( 2 ) D3 ] , the vitamin D receptor ( P11473 ) ligand , and the objective of our study was to elucidate the mechanisms by which the DB00146 - DBP complex is internalized by mammary cells prior to metabolism . Using fluorescent microscopy and temperature - shift techniques , we found that T - 47D breast cancer cells rapidly internalize DBP via endocytosis , which is blunted by receptor - associated protein , a specific inhibitor of megalin - mediated endocytosis . Endocytosis of DBP was associated with activation of P11473 by DB00146 but not 1 , 25 ( OH )( 2 ) D3 ( as measured by induction of the P11473 target gene , Q07973 ) . We also found that megalin and its endocytic partner , cubilin , are coexpressed in normal murine mammary tissue , in nontransformed human mammary epithelial cell lines , and in some established human breast cancer cell lines . To our knowledge , our studies are the first to demonstrate that mammary - derived cells express megalin and cubilin , which contribute to the endocytic uptake of DB00146 - DBP and activation of the P11473 pathway .", "___MASK67___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK67___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK67___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .", "A mechanism underlying the effects of polyunsaturated fatty acids on breast cancer . Breast cancer is the most frequent cancer in women . Evidence suggests that the polyunsaturated fatty acids ( PUFAs ) , eicosapentaenoic acid ( EPA ) , and docosahexaenoic acid ( DB01708 ) affect breast cancer proliferation , differentiation and prognosis . However , the mechanism still remains unclear . In this study , the expression of transient receptor potential canonical ( TRPC ) 3 was detected throughout the cell cytoplasm and at the cell surface of MCF - 7 cells . Ca ( 2 +) entry was induced in these cells via activated Q13507 by either the diacylglycerol analogue ( OAG ) or by intracellular Ca ( 2 +) store depletion . TRPC - mediated Ca ( 2 +) entry was inhibited by PUFAs including arachidonic acid ( AA ) and linolenic acid ( LA ) but not saturated fatty acids . Overexpression of the PUFA degradation enzyme , cyclooxygenase 2 ( P35354 ) , enhanced capacitative Ca ( 2 +) entry . In addition , inhibition of P35354 reduced [ Ca ( 2 +)]( i ) . Nevertheless , inhibition of TRPC reduced the cell cycle S phase and cell migration , implicating a functional role for TRP - mediated Ca ( 2 +) entry in cell proliferation and invasion . Exogenous PUFA as well as a Q13507 antagonist consistently attenuated breast cancer cell proliferation and migration , suggesting a mechanism in which PUFA restrains the breast cancer partly via its inhibition of TRPC channels . Additionally , our results also suggest that Q13507 appears as a new mediator of breast cancer cell migration / invasion and represents a potential target for a new class of anticancer agent .", "V - ATPase / P42345 signaling regulates megalin - mediated apical endocytosis . P42345 kinase is a master growth regulator that can be stimulated by multiple signals , including amino acids and the lysosomal small GTPase Rheb . Recent studies have proposed an important role for the V - ATPase in the sensing of amino acids in the lysosomal lumen . Using the Drosophila wing as a model epithelium , we show here that the V - ATPase is required for Rheb - dependent epithelial growth . We further uncover a positive feedback loop for the control of apical protein uptake that depends on V - ATPase / P42345 signaling . This feedback loop includes Rheb - dependent transcriptional regulation of the multiligand receptor P98164 , which itself is required for Rheb - induced endocytosis . In addition , we provide evidence that long - term P42345 inhibition with rapamycin in mice causes reduction of P98164 levels and proteinuria in the proximal tubular epithelium of the kidney . Thus , our findings unravel a homeostatic mechanism that allows epithelial cells to promote protein uptake under normal conditions and to prevent uptake in lysosomal stress conditions .", "The human peroxisome proliferator - activated receptor delta gene is a primary target of 1alpha , 25 - dihydroxyvitamin D3 and its nuclear receptor . Peroxisome proliferator - activated receptor ( Q07869 ) delta is the most widely expressed member of the Q07869 family of nuclear receptor fatty acid sensors . Real - time PCR analysis of breast and prostate cancer cell lines demonstrated that PPARdelta expression was increased 1 . 5 to 3 . 2 - fold after three hours stimulation with the natural vitamin D receptor ( P11473 ) agonist , 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) . In silico analysis of the 20 kb of the human PPARdelta promoter revealed a Q93038 - type DB00136 response element approximately 350 bp upstream of the transcription start site , which was able to bind P11473 - retinoid X receptor ( RXR ) heterodimers and mediate a DB00136 - dependent upregulation of reporter gene activity . Chromatin immuno - precipitation assays demonstrated that a number of proteins representative for DB00136 - mediated gene activation , such as P11473 , RXR and RNA polymerase II , displayed a DB00136 - dependent association with a region of the proximal PPARdelta promoter that contained the putative Q93038 - type VDRE . This was also true for other proteins that are involved in or are the subject of chromatin modification , such as the histone acetyltransferase CBP and histone 4 , which displayed ligand - dependent association and acetylation , respectively . Finally , real - time PCR analysis demonstrated that DB00136 and the synthetic PPARdelta ligand L783483 show a cell and time - dependent interference in each other ' s effects on P11473 mRNA expression , so that their combined application shows complex effects on the induction of P11473 target genes , such as Q07973 . Taken together , we conclude that PPARdelta is a primary DB00136 - responding gene and that P11473 and PPARdelta signaling pathways are interconnected at the level of cross - regulation of their respective transcription factor mRNA levels .", "Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK38___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .", "c - Fos protein as a target of anti - osteoclastogenic action of vitamin D , and synthesis of new analogs . Although active vitamin D drugs have been used for the treatment of osteoporosis , how the vitamin D receptor ( P11473 ) regulates bone cell function remains largely unknown . Using osteoprotegerin - deficient mice , which exhibit severe osteoporosis due to excessive receptor activator of NF - kappaB ligand / receptor activator of NF - kappaB ( O14788 / Q9Y6Q6 ) stimulation , we show herein that oral treatment of these mice with 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] inhibited bone resorption and prevented bone loss , suggesting that P11473 counters O14788 / Q9Y6Q6 signaling . In P09603 - dependent osteoclast precursor cells isolated from mouse bone marrow , DB00136 potently and dose - dependently inhibited their differentiation into multinucleate osteoclasts induced by O14788 . Among signaling molecules downstream of Q9Y6Q6 , DB00136 inhibited the induction of c - Fos protein after O14788 stimulation , and retroviral expression of c - Fos protein abrogated the suppressive effect of DB00136 on osteoclast development . By screening vitamin D analogs based on their c - Fos - suppressing activity , we identified a new analog , named DD281 , that inhibited bone resorption and prevented bone loss in ovariectomized mice , more potently than DB00136 , with similar levels of calcium absorption . Thus , c - Fos protein is an important target of the skeletal action of P11473 - based drugs , and DD281 is a bone - selective analog that may be useful for the treatment of bone diseases with excessive osteoclastic activity .", "Nongenotropic , anti - apoptotic signaling of 1alpha , 25 ( OH ) 2 - vitamin D3 and analogs through the ligand binding domain of the vitamin D receptor in osteoblasts and osteocytes . Mediation by Src , phosphatidylinositol 3 - , and JNK kinases . Because sex steroids regulate the life span of bone cells by modulating cytoplasmic kinase activity via a nongenotropic action of their classical receptors , we have explored the possibility that the vitamin D nuclear receptor ( P11473 ) might exhibit similar nongenotropic actions . We report that the conformationally flexible full P11473 agonist , 1alpha , 25 ( OH ) 2 - vitamin D3 ( DB00136 ) , and the 6 - s - cis - locked 1alpha , 25 ( OH ) 2 - lumisterol3 ( JN ) analog , also acting through the P11473 but with poor transcriptional activity , protected murine osteoblastic or osteocytic cells from apoptosis . This effect was reproduced in HeLa cells transiently transfected with either wild type P11473 or a mutant consisting of only the P11473 ligand binding domain . The P11473 ligand binding domain bound [ 3H ] DB00136 as effectively as wild type P11473 but did not induce vitamin D response element - mediated transcription . The anti - apoptotic effects of DB00136 and the 6 - s - cis - locked 1alpha , 25 ( OH ) 2 - lumisterol3 analog in calvaria cells were blocked by three cytoplasmic kinase inhibitors : Src kinase inhibitor 4 - amino - 5 -( 4 - methylphenyl )- 7 -( t - butyl ) pyrazolo [ 3 , 4 - d ] pyrimidine ( P50391 ) , phosphatidylinositol 3 kinase inhibitor Wortmannin , and the JNK kinase inhibitor SP600125 . However , inhibition of p38 with SB203580 or P29323 with either U0126 or a transfected dominant negative MEK did not interfere with these anti - apoptotic actions . Further , DB00136 induced rapid ( 5 min ) association of P11473 with Src kinase in OB - 6 cells . Finally , actinomycin D or cycloheximide prevented the anti - apoptotic effect of DB00136 , indicating that transcriptional events are also required . These findings suggest that nongenotropic modulation of kinase activity is also a general property of the P11473 and that ligands that activate nongenotropic signals , but lack transcriptional activity , display different biological profiles from the steroid hormone DB00136 .", "A concise and efficient route to 2alpha -( omega - hydroxyalkoxy )- 1alpha , 25 - dihydroxyvi tam in D3 : remarkably high affinity to vitamin D receptor . [ reaction : see text ] A convenient and potentially valuable synthetic approach to the novel 2alpha - functionalized 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] derivatives ( 1a - c ) , which are the P06681 - epimer of ED - 71 and its analogues , has been developed . The C2alpha - modified ring A precursors ( 1 , 7 - enynes 16 , n = 0 , 1 , and 2 ) were constructed stereoselectively starting from D - glucose in high yield . In the synthesized 2alpha -( omega - hydroxyalkoxy )- DB00136 derivatives , 1a and 1b showed a greater binding affinity to vitamin D receptor ( P11473 ) , up to 1 . 8 times that of the native hormone .", "Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK38___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK38___ . Tubacin in combination with ___MASK38___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK38___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK38___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .", "P62942 , the 12 - kDa FK506 - binding protein , is a physiologic regulator of the cell cycle . P62942 , the 12 - kDa FK506 - binding protein , is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506 , binds tightly to intracellular calcium release channels and to the transforming growth factor beta ( TGF - beta ) type I receptor . We now demonstrate that cells from P62942 - deficient ( P62942 (-/-) ) mice manifest cell cycle arrest in G ( 1 ) phase and that these cells can be rescued by P62942 transfection . This arrest is mediated by marked augmentation of P38936 ( P38936 / CIP1 ) levels , which can not be further augmented by TGF - beta1 . The P38936 up - regulation and cell cycle arrest derive from the overactivity of TGF - beta receptor signaling , which is normally inhibited by P62942 . Cell cycle arrest is prevented by transfection with a dominant - negative TGF - beta receptor construct . TGF - beta receptor signaling to gene expression can be mediated by SMAD , p38 , and P29323 / Q96HU1 kinase ( extracellular signal - regulated kinase / mitogen - activated protein kinase ) pathways . SMAD signaling is down - regulated in P62942 (-/-) cells . Inhibition of P29323 / Q96HU1 kinase fails to affect P38936 up - regulation . By contrast , activated phosphorylated p38 is markedly augmented in P62942 (-/-) cells and the P38936 up - regulation is prevented by an inhibitor of p38 . Thus , P62942 is a physiologic regulator of cell cycle acting by normally down - regulating TGF - beta receptor signaling .", "Heregulin regulates the ability of the ErbB3 - binding protein Ebp1 to bind E2F promoter elements and repress E2F - mediated transcription . The ErbB3 / 4 ligand heregulin ( P04196 ) profoundly affects cell growth and differentiation , but its mechanism of action is poorly understood . Ebp1 , a protein isolated by its binding to ErbB3 , inhibits cell growth and represses transcription of E2F - regulated cell cycle genes . Since Ebp1 shares 38 % identity with a Schizosaccharomyces pombe DNA - binding protein , we postulated that Ebp1 could bind E2F consensus elements in an P04196 - inducible manner , leading to transcriptional repression . We show here that Q86UG4 - Ebp1 bound to the DNA sequence bound by the S . pombe protein . Whereas Q86UG4 - Ebp1 alone failed to bind Q01094 promoter elements , Ebp1 contained in nuclear lysates associated with Q01094 consensus sequences in the Q01094 promoter . Endogenous Ebp1 was recruited to the Q01094 promoter in vivo as demonstrated by chromatin immunoprecipitation assays . Ebp1 bound E2F consensus oligonucleotides in association with Q01094 , retinoblastoma protein , and Q92769 . P04196 regulated the association of Ebp1 with E2F promoter sequences and enhanced the ability of Ebp1 to repress transcription . Our findings suggest that Ebp1 , by linking P04196 activation of membrane receptors to E2F gene activity , may be a downstream modulator of the effects of P04196 on cell cycle progression .", "___MASK29___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK29___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .", "Loss of desmocollin 1 - 3 and homeobox genes P78337 and Q99626 are associated with tumor progression and survival in colorectal carcinoma . BACKGROUND : Genomewide expression profiling has identified a number of genes differentially expressed in colorectal carcinomas ( CRCs ) compared to normal tissue . Some of these genes were linked to epithelial - mesenchymal transition . We tested whether genes including desmocollins and homeobox genes were distinct on the protein level and correlated the expression with clinicopathological data . METHODS : Tissue microarrays of 402 R0 - resected colorectal carcinomas of UICC stage II or III were constructed to evaluate ten biomarkers . Furthermore , mRNA expression of desmocollins was evaluated in eight colon cancer cell lines . Demethylation test was performed by treatment with 5 - aza - 2 ´- deoxycytide in five colon cancer cell lines . RESULTS : On protein level , high expression of desmocollin 1 ( DSC1 ) was observed in 41 . 6 % , Q02487 in 58 . 0 % , DSC3 in 61 . 4 % , P12830 in 71 . 4 % , Q99626 in 58 . 0 % , P78337 in 55 . 0 % , P11802 in 0 . 2 % , Q04724 in 1 . 3 % , Factor H in 42 . 5 % , and Q00987 in 0 . 2 % . Reduced expression of DSC1 - 3 was statistically linked to higher grading and Q02487 , P12830 and Q99626 with shorter survival in high - grade carcinomas . Multivariate analysis showed that pathological stage and low P78337 expression were statistically associated with shorter patients survival . On mRNA level , seven out of eight cell lines exhibited no expression of DSC1 , and four out of seven restored DSC1 expression after demethylation test . CONCLUSIONS : Reduced expression of P78337 was independently correlated to shorter patients survival and could serve as a prognostic marker . Decreased expression of DSC1 - 3 is significantly correlated with higher tumor grading . Downregulation of DSC1 could be explained by DNA hypermethylation in colon cancer cells .", "Characterization of L - aminocarnitine , an inhibitor of fatty acid oxidation . The pathogenesis of hypoketotic hypoglycemia and cardiomyopathy in patients with fatty acid oxidation ( FAO ) disorders is still poorly understood . In vitro studies are hampered by the lack of natural mutants to asses the effect of FAO inhibition . In addition , only a few inhibitors of FAO are known . Furthermore , most inhibitors of FAO are activating ligands of peroxisome proliferator - activated receptors ( PPARs ) . We show that l - aminocarnitine ( L - AC ) , a carnitine analog , inhibits FAO efficiently , but does not activate Q07869 . L - AC inhibits carnitine palmitoyltransferase ( CPT ) with different sensitivities towards CPT1 and P23786 , as well as carnitine acylcarnitine translocase ( O43772 ) . We further characterized L - AC using fibroblasts cell lines from controls and patients with different FAO defects . In these cell lines acylcarnitine profiles were determined in culture medium after loading with [ U -( 13 ) C ] palmitic acid . In control fibroblasts , L - AC inhibits FAO leading to a reduction of P06681 - acylcarnitine and elevation of C16 - acylcarnitine . In very long - chain acyl - DB01992 dehydrogenase ( P49748 ) - deficient fibroblasts , L - AC decreased the elevated C14 - acylcarnitine and increased C16 - acylcarnitine . In O43772 and P23786 - deficient cell lines , L - AC did not change the already elevated C16 - acylcarnitine level , showing that CPT1 is not inhibited . Oxidation of pristanic acid was only partly inhibited at high L - AC concentrations , indicating minimal O43772 inhibition . Therefore , we conclude that in intact cells L - AC inhibits P23786 . Combined with our observation that l - AC does not activate Q07869 , we suggest that L - AC is useful to simulate a FAO defect in cells from different origin .", "Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor - derived endothelial cells and tumor angiogenesis in vivo . Calcitriol ( DB00136 ) , the major active form of vitamin D , is antiproliferative in tumor cells and tumor - derived endothelial cells ( TDEC ) . These actions of calcitriol are mediated at least in part by vitamin D receptor ( P11473 ) , which is expressed in many tissues including endothelial cells . To investigate the role of P11473 in calcitriol effects on tumor vasculature , we established TRAMP - 2 tumors subcutaneously into either P11473 wild - type ( WT ) or knockout ( KO ) mice . Within 30 days post - inoculation , tumors in KO mice were larger than those in WT ( P < 0 . 001 ) . TDEC from WT expressed P11473 and were able to transactivate a reporter gene whereas TDEC from KO mice were not . Treatment with calcitriol resulted in growth inhibition in TDEC expressing P11473 . However , TDEC from KO mice were relatively resistant , suggesting that calcitriol - mediated growth inhibition on TDEC is P11473 - dependent . Further analysis of the TRAMP - P06681 tumor sections revealed that the vessels in KO mice were enlarged and had less pericyte coverage compared with WT ( P < 0 . 001 ) . Contrast - enhanced magnetic resonance imaging showed an increase in vascular volume of TRAMP tumors grown in P11473 KO mice compared with WT mice ( P < 0 . 001 ) and FITC - dextran permeability assay suggested a higher extent of vascular leakage in tumors from KO mice . Using ELISA and Western blot analysis , there was an increase of hypoxia - inducible factor - 1alpha , vascular endothelial growth factor , angiopoietin 1 , and platelet - derived growth factor - BB levels observed in tumors from KO mice . These results indicate that calcitriol - mediated antiproliferative effects on TDEC are P11473 - dependent and loss of P11473 can lead to abnormal tumor angiogenesis .", "Recruitment and subnuclear distribution of the regulatory machinery during 1alpha , 25 - dihydroxy vitamin D3 - mediated transcriptional upregulation in osteoblasts . The architectural organization of the genome and regulatory proteins within the nucleus supports gene expression in a physiologically regulated manner . In osteoblastic cells ligand activation induces a nuclear punctate distribution of the 1alpha , 25 - dihydroxy vitamin D3 ( DB00136 ) receptor ( P11473 ) and promotes its interaction with transcriptional coactivators such as Q15788 , NCoA - 62 / Skip , and Q15648 . Here , we discuss evidence demonstrating that in osteoblastic cells P11473 binds to the nuclear matrix fraction in a DB00136 - dependent manner . This interaction occurs rapidly after exposure to DB00136 and does not require a functional P11473 DNA binding domain . The nuclear matrix - bound P11473 molecules colocalize with the also nuclear matrix - associated coactivator Q15648 . We propose a model where the rapid association of P11473 with the nuclear matrix fraction represents an event that follows DB00136 - dependent nuclear localization of P11473 , but that precedes DB00136 - dependent transcriptional upregulation at target genes .", "Osteoclast progenitors from cats with and without tooth resorption respond differently to 1 , 25 - dihydroxyvitamin D and interleukin - 6 . Both vitamin D and inflammatory cytokines can stimulate osteoclast formation and activity . We studied the effect of DB00136 ( 1 , 25 ( OH )( 2 ) D ) , and interleukin - 6 ( P05231 ) , on the formation and activity of feline osteoclasts , using peripheral blood mononuclear cells ( PBMCs ) from cats with and without tooth resorption ( TR (+) and TR (-) ) as a source of osteoclast precursors . The formation of osteoclast - like cells ( defined as multinucleated , tartrate - resistant acid phosphatase - positive cells ) was assessed at 7 and 14 days . In the presence of P09603 and O14788 , with and without P05231 , more osteoclasts were formed from TR (-) PBMCs than from TR (+) PBMCs on plastic . More osteoclasts were formed from TR (+) PBMCs on bone slices in the presence of P09603 / O14788 with 1 , 25 ( OH )( 2 ) D . This opposite effect may be due to a higher expression of the vitamin D receptor ( P11473 ) in TR (+) osteoclasts and precursors on bone . Formation of resorption pits was analyzed and confirmed with scanning electron microscopy . In conclusion , we propose that TR (+) PBMCs when cultured on bone are sensitive to 1 , 25 ( OH )( 2 ) D , whereas the differentiation of TR (-) PMBCs on bone seem more sensitive to P05231 , suggesting that osteoclast precursors from cats with and without tooth resorption respond differently to osteoclast stimulating factors .", "Antisense inhibition of vitamin D receptor expression induces apoptosis in monoblastoid U937 cells . The active vitamin D3 metabolite DB00136 ( 1 , 25 ( OH ) 2D3 ) acts as an antiproliferative and differentiating agent for the monoblastoid cell line U937 and as an important immunologic mediator implicated particularly in the function of cells belonging to the monocyte / macrophage lineage . These effects are controlled by the vitamin D receptor ( P11473 ) , a member of the steroid hormone receptor family . The objective of this study was to develop U937 transfectants expressing antisense P11473 mRNA , and to use these to examine the role of 1 , 25 ( OH ) 2D3 - P11473 interaction in this lineage . A 2 - kb P11473 cDNA insert ( including the complete P11473 coding region ) was cloned in an antisense orientation into the EBV episomal vector pMEP4 under the control of an inducible promoter and transfected into U937 . The resultant cell line , DH42 , was hygromycin resistant , contained P11473 cDNA , expressed fewer VDRs than controls , and showed a substantial decrease in antiproliferative response to 1 , 25 ( OH ) 2D3 . However , 1 , 25 ( OH ) 2D3 increased the number of cells expressing macrophage cell surface Ags , including P08571 and CD11b . A subpopulation of smaller cells did not express the differentiation markers after cadmium stimulation . Cell cycle analysis showed shifts in the distribution of cells from P55008 to S phase , which were more pronounced after cadmium treatment . A considerable proportion of cells were outside the cycle and DNA fragmentation confirmed apoptosis . Thus , the functional outcome of the P11473 antisense transfection suggests that in the myelomonocytic lineage , P11473 expression may act as a protective mechanism against programmed cell death .", "The potential role of PD0332991 ( ___MASK29___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK29___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .", "Stable expression of antisense Rb - 1 RNA inhibits terminal differentiation of mouse myoblast P06681 cells . To determine the roles of the retinoblastoma gene ( Rb - 1 ) in skeletal muscle differentiation in vitro , we isolated P06681 myoblasts stably expressing an antisense RNA directed to the 3 '- untranslated region ( 3 ' UTR ) of Rb - 1 mRNA . The levels of Rb - 1 mRNA and its product ( P06400 ) in the clones transfected with antisense Rb were markedly decreased to 25 - 35 % of those in the control clone . Cell growth of the clones was accelerated , especially in medium containing low concentrations of fetal calf serum . Even in differentiation medium with a low mitogen level , the antisense Rb clones proliferated as single - nucleated myoblast - like cells without expressing the sarcometric myosin heavy chain protein , whereas the control clone formed highly multinucleated myotubes after 4 days of culture under the same conditions . Under this condition , the levels of Rb - 1 mRNA and P06400 in the antisense Rb clones were 30 - 50 % of those in the control clone , and no divergent increase in the Rb - family protein P28749 expression was observed . This inhibited differentiation was abrogated by reintroducing expression vectors for the sense 3 ' UTR of Rb - 1 mRNA or Rb - 1 mRNA lacking its 3 ' UTR to the clone transfected with antisense Rb . In the antisense Rb clone cultured in differentiation medium , the amounts of MyoD and myogenin mRNA were markedly decreased on the 2nd day of culture in the differentiation medium . The expression of cell cycle - promoting genes including Q01094 and cyclin D1 was up - regulated throughout the experiment . These results demonstrate that P06400 is essential for the completion of terminal differentiation in P06681 cells .", "Cytological properties of stromal cells derived from giant cell tumor of bone ( GCTSC ) which can induce osteoclast formation of human blood monocytes without cell to cell contact . When human blood monocytes were cocultured with stromal cells derived from human giant cell tumor of bone ( GCTSC ) and a Millipore filter ( 0 . 4 microm ) was interposed between monocytes and GCTSC , multinucleated giant cell formation of monocytes was induced . The multinucleated giant cells have characters as osteoclast - like cells , indicating that a soluble osteoclast - inducing factor ( s ) is secreted from GCTSC expressing Q9Y6Q6 , O14788 / O14788 / O14788 and P78536 mRNA . Furthermore , O00300 / O00300 inhibited GCTSC - induced osteoclastogenesis , showing that the Q9Y6Q6 - O14788 system is involved in GCTSC - induced osteoclastogenesis and that soluble form of O14788 / O14788 induces osteoclasts from monocytes . GCTSC expressed the cytokine mRNAs such as P09603 , GM - P04141 , P08700 , P05112 , P05231 , and P01579 mRNAs . None of IL - 1ralpha , IL - 1alpha , IL - 1beta , P60568 , P05112 , P22301 , Q14116 , P01375 , G - P04141 and P01579 could be detected in all culture media . A significant amount of P05231 could be detected in the culture media of all GCTSC . P10145 was found in the culture media of two GCTSC and two osteosarcoma - derived cells . P09603 was detected in all culture media . GCTSC express P41180 , and stimulation of GCTSC with either extracellular Ca ( 2 +) or neomycin , agonist of P41180 , augmented the expression of O14788 . Some lines of GCTSC expressed alkaline phosphatase , osteocalcin and Cbfa1 , suggesting that GCTSC are intimately related to osteoblastic lineage .", "20 - Hydroxycholecalciferol , product of vitamin D3 hydroxylation by P450scc , decreases NF - kappaB activity by increasing IkappaB alpha levels in human keratinocytes . The side chain of vitamin D3 is hydroxylated in a sequential manner by cytochrome P450scc ( P05108 ) to form 20 - hydroxycholecalciferol , which can induce growth arrest and differentiation of both primary and immortalized epidermal keratinocytes . Since nuclear factor - kappaB ( NF - kappaB ) plays a pivotal role in the regulation of cell proliferation , differentiation and apoptosis , we examined the capability of 20 - hydroxycholecalciferol to modulate the activity of NF - kappaB , using DB00136 ( calcitriol ) as a positive control . 20 - hydroxycholecalciferol inhibits the activation of NFkappaB DNA binding activity as well as NF - kappaB - driven reporter gene activity in keratinocytes . Also , 20 - hydroxycholecalciferol induced significant increases in the mRNA and protein levels of the NF - kappaB inhibitor protein , IkappaB alpha , in a time dependent manner , while no changes in total NF - kappaB - p65 mRNA or protein levels were observed . Another measure of NF - kappaB activity , p65 translocation from the cytoplasm into the nucleus was also inhibited in extracts of 20 - hydroxycholecalciferol treated keratinocytes . Increased IkappaB alpha was concomitantly observed in cytosolic extracts of 20 - hydroxycholecalciferol treated keratinocytes , as determined by immunoblotting and immunofluorescent staining . In keratinocytes lacking vitamin D receptor ( P11473 ) , 20 - hydroxycholecalciferol did not affect IkappaB alpha mRNA levels , indicating that it requires P11473 for its action on NF - kappaB activity . Comparison of the effects of calcitrol , hormonally active form of vitamin D3 , with 20 - hydrocholecalciferol show that both agents have a similar potency in inhibiting NF - kappaB . Since NF - kappaB is a major transcription factor for the induction of inflammatory mediators , our findings indicate that 20 - hydroxycholecalciferol may be an effective therapeutic agent for inflammatory and hyperproliferative skin diseases ." ]

[ "___MASK13___", "___MASK15___", "___MASK16___", "___MASK29___", "___MASK36___", "___MASK38___", "___MASK3___", "___MASK67___", "___MASK93___" ]

[ "[ Immunoregulatory genes in autoimmune thyroid disease ] . Autoimmune thyroid diseases ( AITD ) has a strong genetic basis . Although several candidate genes have been studied , the AITD causing genes are still unknown . Major candidate immune regulatory genes include human leukocyte antigen ( HLA ) gene , Ig heavy chain genes , T cell receptor genes , IL - 1 receptor antagonist gene , P01583 gene and cytotoxic T lymphocyte antigen - 4 ( P16410 ) gene . The relation between HLA and AITD has extensively been studied . In addition , polymorphism of the 3 '- untranslated region and codon 17 of the P16410 gene has been reported to associate positively with AITD . However , no linkage analyses have showed positive relation between AITD and these candidate genes except for HLA .", "Circulating endothelial progenitor cells decreased in patients with sclerodermatous chronic graft - versus - host disease . Chronic graft - versus - host disease ( cGVHD ) is a common late complication of allogeneic stem cell transplantation ( allo - P09683 ) . Some cGVHD patients develop skin lesions , and the skin lesions in sclerodermatous cGVHD ( s - cGVHD ) patients resemble those in progressive systemic sclerosis ( PSS ) , which is characterized by impaired production of circulating endothelial progenitor cells ( EPCs ) . We investigated , retrospectively , whether low EPC production may promote the development of sclerodermatous lesions in cGVHD . Peripheral blood ( PB ) was obtained from 14 healthy volunteers and 27 allo - P09683 patients . Five patients developed s - cGVHD . P28906 (+) cells were purified by using the magnetic cell - sorting separation system , and the P28906 (+)/ CD133 (+)/ vascular endothelial growth factor ( P15692 ) receptor - 2 (+) EPCs were quantified . The endothelial cell colony - formation potential was evaluated . Serum P15692 and basic fibroblast growth factor ( b - FGF ) concentrations were measured by ELISA . The s - cGVHD patients had significantly lower median circulating EPCs frequencies than non - s - cGVHD patients or control ( 145 of 20 mL [ interquartial range - IQR 107 - 193 ] versus 1083 . 5 [ IQR 669 . 3 - 2151 ] ; P = . 0023 , and versus 1530 . 5 [ IQR 961 . 3 - 2158 ] ; P = . 0012 , respectively ) . They also had impaired median endothelial - forming ability compared to non - s - cGVHD patients or controls ( 3 . 8 [ IQR 1 . 0 - 4 . 3 ] versus 12 . 8 [ IQR 8 . 8 - 28 . 8 ] , and versus 26 . 4 [ IQR 23 . 6 - 30 . 6 ] , respectively ; P = . 0012 ) . Their P15692 and b - FGF serum levels were also higher than in controls . In conclusion , s - cGVHD patients show findings consistent with those seen in PSS with impaired vasculogenesis that may limit blood perfusion and may contribute to the development of sclerodermatous lesions .", "Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin ' s lymphoma . PURPOSE : DB08870 is an antibody - drug conjugate ( ADC ) that selectively delivers monomethyl auristatin E , an antimicrotubule agent , into P28908 - expressing cells . In phase I studies , brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory P28908 - positive lymphomas . PATIENTS AND METHODS : In this multinational , open - label , phase II study , the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin ' s lymphoma ( HL ) after autologous stem - cell transplantation ( auto - P09683 ) . Patients had histologically documented P28908 - positive HL by central pathology review . A total of 102 patients were treated with brentuximab vedotin 1 . 8 mg / kg by intravenous infusion every 3 weeks . In the absence of disease progression or prohibitive toxicity , patients received a maximum of 16 cycles . The primary end point was the overall objective response rate ( ORR ) determined by an independent radiology review facility . RESULTS : The ORR was 75 % with complete remission ( CR ) in 34 % of patients . The median progression - free survival time for all patients was 5 . 6 months , and the median duration of response for those in CR was 20 . 5 months . After a median observation time of more than 1 . 5 years , 31 patients were alive and free of documented progressive disease . The most common treatment - related adverse events were peripheral sensory neuropathy , nausea , fatigue , neutropenia , and diarrhea . CONCLUSION : The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75 % of patients with relapsed or refractory HL after auto - P09683 . Durable CRs approaching 2 years were observed , supporting study in earlier lines of therapy .", "Beta2 - adrenergic receptor signaling in P01730 + Foxp3 + regulatory T cells enhances their suppressive function in a PKA - dependent manner . Beta2 - adrenergic receptor ( P07550 ) signaling is known to impair Th1 - cell differentiation and function in a DB02527 - dependent way , leading to inhibition of cell proliferation and decreased production of P60568 and IFN - γ . P01730 (+) Foxp3 (+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self - tolerance . Nevertheless , very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function . Here we show that Foxp3 (+) Treg cells express functional P07550 . P07550 activation in Treg cells leads to increased intracellular DB02527 levels and to protein kinase A ( PKA ) - dependent CREB phosphorylation . We also found that signaling via P07550 enhances the in vitro suppressive activity of Treg cells . P07550 - mediated increase in Treg - cell suppressive function was associated with decreased P60568 mRNA levels in responder P01730 (+) T cells and improved Treg - cell - induced conversion of P01730 (+) Foxp3 (-) cells into Foxp3 (+) induced Treg cells . Moreover , P07550 signaling increased P16410 expression in Treg cells in a PKA - dependent way . Finally , we found that PKA inhibition totally prevented the P07550 - mediated increase in Treg - cell suppressive function . Our data suggest that sympathetic fibers are able to regulate Treg - cell suppressive activity in a positive manner through P07550 signaling .", "The human secretin gene : fine structure in 11p15 . 5 and sequence variation in patients with autism . Secretin is a peptide hormone involved in digestion that has been studied as a potential therapeutic agent in patients with autism . We characterized the human secretin locus to determine whether mutations in this gene might play a role in a fraction of autism patients . While the secretin gene ( P09683 ) was not found to be mutated in the majority of autistic patients , rare heterozygous sequence variants were identified in three patients . We also investigated length variation in a variable number of tandem repeats ( VNTR ) immediately upstream of P09683 and found no significant differences in length between patients with autism and normal controls . P09683 is located on 11p15 . 5 , adjacent to P21917 and P01112 . This region has been reported to be associated with both autism and attention deficit hyperactivity disorder ( ADHD ) . Although imprinting is a characteristic of some genes in the vicinity , we could find no evidence for methylation of P09683 in lymphoblast cells from patients or control individuals .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK51___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .", "Hypoxia - microRNA - 16 downregulation induces P15692 expression in anaplastic lymphoma kinase ( Q9UM73 ) - positive anaplastic large - cell lymphomas . The anaplastic lymphoma kinase ( Q9UM73 ) , tyrosine kinase oncogene is implicated in a wide variety of cancers . In this study we used conditional onco - Q9UM73 ( P06748 - Q9UM73 and P06753 - Q9UM73 ) mouse MEF cell lines ( Q9UM73 + fibroblasts ) and transgenic models ( Q9UM73 + B - lymphoma ) to investigate the involvement and regulation of angiogenesis in Q9UM73 tumor development . First , we observed that Q9UM73 expression leads to downregulation of miR - 16 and increased Vascular Endothelial Growth Factor ( P15692 ) levels . Second , we found that modification of miR - 16 levels in P06753 - Q9UM73 MEF cells greatly affected P15692 levels . Third , we demonstrated that miR - 16 directly interacts with P15692 mRNA at the 3 '- untranslated region and that the regulation of P15692 by miR - 16 occurs at the translational level . Fourth , we showed that expression of both the Q9UM73 oncogene and hypoxia - induced factor 1α ( HIF1α ) is a prerequisite for miR - 16 downregulation . Fifth , in vivo , miR - 16 gain resulted in reduced angiogenesis and tumor growth . Finally , we highlighted an inverse correlation between the levels of miR - 16 and P15692 in human P06748 - Q9UM73 + Anaplastic Large Cell Lymphomas ( ALCL ) . Altogether , our results demonstrate , for the first time , the involvement of angiogenesis in Q9UM73 + ALCL and strongly suggest an important role for hypoxia - miR - 16 in regulating P15692 translation .", "The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues . It has become evident that the tumor microenvironment plays a pivotal role in the maintenance of cancerous growth . One of the acquired functions of the tumor microenvironment is the suppression of immune responses . Indeed , blocking the inhibitory pathways operational in the microenvironment results in enhanced T - cell - dependent , anti - tumor immunity . Chemotherapeutic drugs not only directly kill tumor cells but also shape the tumor microenvironment and potentiate anti - tumor immunity . Here , we demonstrate that the chemotherapeutic compound oxaliplatin acts as a double - edged sword . Besides killing tumor cells , oxaliplatin bolsters immunosuppressive pathways , resulting in decreased activation of T cells by human plasmacytoid dendritic cells ( pDCs ) . Exposure to oxaliplatin markedly increased expression of the T - cell inhibitory molecule programmed death receptor - ligand 1 ( Q9NZQ7 ) on human pDCs and also Q9NR96 - induced IFNα secretion . Furthermore , oxaliplatin decreased TLR - induced P42224 and P40763 expression , and NF - κB - mediated responses . The oxaliplatin induced upregulation of Q9NZQ7 and downregulation of costimulatory molecules P33681 and P42081 resulted in decreased T - cell proliferation . Our results demonstrate that platinum - based anticancer drugs adapt TLR - induced signaling in human pDCs and myeloid DCs ( mDCs ) , thereby downgrading their immunostimulatory potential .", "Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \" nongenomic \" pathway which , is clearly discernable from the classical , \" genomic \" action pathway of the P35869 by not requiring the participation of P27540 .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . ___MASK78___ is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK65___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .", "Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK16___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .", "G - P04141 downregulates natural killer cell - mediated cytotoxicity in donors for hematopoietic P09683 . In G - P04141 - mobilized hematopoietic P09683 ( HSCT ) , natural killer ( NK ) cells have a critical role in GVHD and GVL effects . However , regulation of NK cell response to G - P04141 remains unclear . This study assayed G - P04141 effects in both HSCT donors and NK - 92MI cells . The donors who received G - P04141 had significantly decreased NK cell cytotoxicity . Levels of phosphatidylinositol 3 - kinase ( PI3K ) and phosphorylated ( p )- Akt , but not mammalian target of rapamycin ( P42345 ) , were downregulated in NK cells from G - P04141 - injected donors . G - P04141 also decreased cytotoxicity without affecting viability and NF - κB of NK - 92MI cells . PI3K and p - P29323 expression were also decreased in G - P04141 - treated NK - 92MI cells , and their inhibitors , wortmannin and PD98059 , respectively , both enhanced the downregulation of cytotoxicity . These effects were accompanied by decreased expression of a cytotoxicity - related gene , triosephosphate isomerase ( P60174 ) . Wortmannin , but not PD98059 , enhanced the downregulation of P60174 in G - P04141 - treated NK - 92MI cells , indicating a correlation between PI3K and P60174 . We conclude that G - P04141 - impaired NK cell cytotoxicity may accompany PI3K / Akt signaling . The effect is transient and NK cells may recover after G - P04141 clearance , suggesting that G - P04141 - mobilized HSCT may benefit both acute GVHD prevention and late - phase GVL promotion in HSCT recipients .", "Direct and indirect striatal efferent pathways are differentially influenced by low and high dyskinetic drugs : behavioural and biochemical evidence . Clinical evidence suggests that stimulation of the D ( 1 ) rather than P14416 is related to the development of dyskinesias in Parkinson ' s disease ( PD ) . We evaluated , in the 6 - hydroxydopamine rat model of PD , sensitization of contralateral turning ( P09683 ) behaviour and abnormal involuntary movements ( AIMs ) as behavioural parameters of dyskinetic response , and changes in zif - 268 mRNA expression in striatonigral and striatopallidal neurons on subchronic administration of the D ( 2 )/ D ( 3 ) agonist ropinirole , defined as a mild dyskinetic drug in the clinic . Results were compared with previous findings on repeated L - dopa treatment . Ropinirole displayed a mild dyskinetic response characterized by P09683 only , which contrasted with the presence of P09683 in association with AIMs elicited by repeated L - dopa . Zif - 268 mRNA levels were decreased in both striatonigral and striatopallidal neurons by ropinirole , in contrast to hyper - expression of zif - 268 mRNA selectively induced by L - dopa in striatonigral neurons . Unbalanced responsiveness of striatal efferent neurons might represent a molecular correlate of high dyskinetic potential and AIMs in rats ; in contrast , a balanced striatal output might underlie the low dyskinetic potential displayed by ropinirole .", "Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK79___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .", "P14416 occupancy by risperidone : implications for the timing and magnitude of clinical response . The objective of the study is to investigate whether dopamine D2 receptor occupancy by risperidone and plasma levels over time can account for therapeutic efficacy and the latency period to response . Thirty - eight examinations with ( 123 ) I - IBZM single photon emission computed tomography were performed on 22 patients with schizophrenia , at diagnosis , 48 h after starting risperidone treatment and at a stable dose . ___MASK78___ plasma levels were determined and psychopathologic evaluations ( Brief Psychiatric Rating Scale , Positive and Negative Syndrome Scale ) were carried out . No differences in the striatal / occipital ( S / O ) ratio or plasma levels were found between examinations at the 48 - h time point and when a stable dose level had been established , so these parameters could not account for the latency period required for clinical response . D2 receptor occupancy at 48 h correlated positively with clinical improvement after 2 weeks of treatment . Therefore , if these results are confirmed , D2 receptor occupancy at the beginning of treatment with risperidone may be a predictor of subsequent clinical response .", "Microtubule - depolymerizing agents used in antibody - drug conjugates induce antitumor immunity by stimulation of dendritic cells . Antibody - drug conjugates ( ADC ) are emerging as powerful treatment strategies with outstanding target - specificity and high therapeutic activity in patients with cancer . DB08870 represents a first - in - class ADC directed against P28908 (+) malignancies . We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response . In this study , we demonstrate that the dolastatin family of microtubule inhibitors , from which the cytotoxic component of brentuximab vedotin is derived , comprises potent inducers of phenotypic and functional dendritic cell ( DC ) maturation . In addition to the direct cytotoxic effect on tumor cells , dolastatins efficiently promoted antigen uptake and migration of tumor - resident DCs to the tumor - draining lymph nodes . Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells . Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins , the antitumor effect was far less pronounced in immunocompromised mice . We observed substantial therapeutic synergies when combining dolastatins with tumor antigen - specific vaccination or blockade of the P18621 - Q9NZQ7 and P16410 coinhibitory pathways . Ultimately , treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients . Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin - based therapies , such as brentuximab vedotin , with immune - based therapies .", "Design and application of a novel PNA probe for the detection at single cell level of JAK2V617F mutation in Myeloproliferative Neoplasms . BACKGROUND : Mutation ( s ) of the O60674 gene ( V617F ) has been described in a significant proportion of Philadelphia negative Myeloproliferative Neoplasms ( Q9BQR3 ) patients and its detection is now a cornerstone in the diagnostic algorithm . METHODS : We developed a novel assay based on peptide nucleic acid ( PNA ) technology coupled to immuno - fluorescence microscopy ( PNA - Q5TCZ1 ) for the specific detection at a single cell level of O60674 - mutation thus improving both the diagnostic resolution and the study of clonal prevalence . RESULTS : Using this assay we found a percentage of mutated P28906 + cells ranging from 40 % to 100 % in Polycythemia Vera patients , from 15 % to 80 % in Essential Thrombocythemia and from 25 % to 100 % in Primary Myelofibrosis . This method allows to distinguish , with a high degree of specificity , at single cell level , between P28906 + progenitor stem cells harbouring the mutated or the wild type form of O60674 in P06748 patients . CONCLUSIONS : This method allows to identify multiple gene abnormalities which will be of paramount relevance to understand the pathophysiology and the evolution of any type of cancer .", "VIPhyb , an antagonist of vasoactive intestinal peptide receptor , enhances cellular antiviral immunity in murine cytomegalovirus infected mice . Vasoactive intestinal peptide ( P01282 ) is a neuropeptide hormone that suppresses Th1 - mediated cellular immunity . We previously reported that P01282 - knockout ( P01282 - KO ) mice have enhanced cellular immune responses and increased survival following murine cytomegalovirus ( mCMV ) infection in C57BL / 6 mice . In this study , we tested whether treatment with a P01282 receptor antagonistic peptide protects C57BL / 6 and BALB / c mice from mCMV - infection . One week of daily subcutaneous injections of VIPhyb was non - toxic and did not alter frequencies of immune cell subsets in non - infected mice . VIPhyb administration to mCMV - infected C57BL / 6 and BALB / c mice markedly enhanced survival , viral clearance , and reduced liver and lung pathology compared with saline - treated controls . The numbers of effector / memory CD8 + T - cells and mature NK cells were increased in VIPhyb - treated mice compared with PBS - treated groups . Pharmacological blockade of P01282 - receptor binding or genetic blockade of P01282 - signaling prevented the up - regulation of Q9NZQ7 and P18621 expression on DC and activated CD8 + T - cells , respectively , in mCMV - infected mice , and enhanced P33681 , P42081 , and MHC - II expression on conventional and plasmacytoid DC . VIPhyb - treatment increased type - I IFN synthesis , numbers of IFN - γ - and P01375 - α - expressing NK cells and T - cells , and the numbers of mCMV - M45 epitope - peptide - MHC - I tetramer CD8 + T - cells following mCMV infection . P01282 - treatment lowered the percentage of Treg cells in spleens compared with PBS - treated WT mice following mCMV infection , while significantly decreasing levels of serum P15692 induced by mCMV - infection . The mice in all treated groups exhibited similar levels of anti - mCMV antibody titers . Short - term administration of a P01282 - receptor antagonist represents a novel approach to enhance innate and adaptive cellular immunity in a murine model of CMV infection .", "Chemical coding of the human gastrointestinal nervous system : cholinergic , VIPergic , and catecholaminergic phenotypes . The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal ( GI ) tract . For this purpose , antibodies against the vesicular monoamine transporters ( P54219 / 2 ) , the vesicular acetylcholine transporter ( Q16572 ) , tyrosine hydroxylase ( TH ) , dopamine beta - hydroxylase ( P09172 ) , serotonin ( 5 - HT ) , vasoactive intestinal peptide ( P01282 ) , and protein gene product 9 . 5 ( P09936 ) were used . For in situ hybridization ( 35 ) S - labeled P54219 , Q05940 , and Q16572 riboprobes were used . In all regions of the human GI tract , 50 - 70 % of the neurons were cholinergic , as judged by staining for Q16572 . The human gut unlike the rodent gut exhibits a cholinergic innervation , which is characterized by an extensive overlap with VIPergic innervation . Neurons containing Q05940 constituted 14 - 20 % of all intrinsic neurons in the upper GI tract , and there was an equal number of TH - positive neurons . In contrast , P09172 was absent from intrinsic neurons . Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes . In conclusion , the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species , but also significant differences . P01282 is a cholinergic cotransmitter in the intrinsic innervation of the human gut . The substantial overlap between Q05940 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life . The absence of P09172 from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype .", "P42224 is phosphorylated and downregulated by the oncogenic tyrosine kinase P06748 - Q9UM73 in Q9UM73 - positive anaplastic large - cell lymphoma . The tumorigenicity of most cases of Q9UM73 - positive anaplastic large - cell lymphoma ( Q9UM73 + ALCL ) is driven by the oncogenic fusion protein P06748 - Q9UM73 in a P40763 - dependent manner . Because it has been shown that P40763 can be inhibited by P42224 in some experimental models , we hypothesized that the P42224 signaling pathway is defective in Q9UM73 + ALCL , thereby leaving the P40763 signaling unchecked . Compared with normal T cells , Q9UM73 + ALCL tumors consistently expressed a low level of P42224 . Inhibition of the ubiquitin - proteasome pathway appreciably increased P42224 expression in Q9UM73 + ALCL cells . Furthermore , we found evidence that P06748 - Q9UM73 binds to and phosphorylates P42224 , thereby promoting its proteasomal degradation in a P40763 - dependent manner . If restored , P42224 is functionally intact in Q9UM73 + ALCL cells , because it effectively upregulated interferon - γ , induced apoptosis / cell - cycle arrest , potentiated the inhibitory effects of doxorubicin , and suppressed tumor growth in vivo . P42224 interfered with the P40763 signaling by decreasing P40763 transcriptional activity / DNA binding and its homodimerization . The importance of the P42224 / P40763 functional interaction was further highlighted by the observation that short interfering RNA knockdown of P42224 significantly decreased apoptosis induced by P40763 inhibition . Thus , P42224 is a tumor suppressor in Q9UM73 + ALCL . Phosphorylation and downregulation of P42224 by P06748 - Q9UM73 represent other mechanisms by which this oncogenic tyrosine kinase promotes tumorigenesis .", "P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .", "Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases . BACKGROUND : Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases ( Q9UKU7 ) . To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis , we investigated their effects on endotoxin - induced tumour necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 1 beta and P05231 release by elutriation - purified human monocytes in vitro . METHODS : Drugs tested were dexamethasone , DB00244 , sulphapyridine and zileuton ( a P09917 inhibitor ) . Monocytes were isolated and stimulated with endotoxin , and P01375 , IL - 1 and P05231 levels were determined using an enzyme - linked immunosorbent assay . RESULTS : Monocyte stimulation with endotoxin resulted in an average P01375 release of 2464 +/- 64 pg / 10 ( 6 ) cells , IL - 1 release of 616 +/- 47 pg / 10 ( 6 ) cells and P05231 release of 2259 +/- 148 pg / 10 ( 6 ) cells . Addition of dexamethasone resulted in a reduction of P01375 , IL - 1 and P05231 release to below background levels . DB00891 significantly reduced P01375 and induced IL - 1 release in a dose - dependent fashion , but had no significant effect on P05231 release . 5 - ___MASK50___ did not modulate P05231 synthesis , but significantly reduced IL - 1 and enhanced P01375 synthesis . Zileuton reduced P01375 and P05231 release , but enhanced IL - 1 release . CONCLUSION : We conclude that these anti - inflammatory drugs are able to modulate cytokine release by human monocytes . Further studies are needed to determine whether these effects are related to their therapeutic efficacy in Q9UKU7 .", "JunB induced by constitutive P28908 - extracellular signal - regulated kinase 1 / 2 mitogen - activated protein kinase signaling activates the P28908 promoter in anaplastic large cell lymphoma and reed - sternberg cells of Hodgkin lymphoma . High expression of P28908 and JunB is characteristic of tumor cells in anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . Possible interactions of P28908 and JunB were examined in this study . We found that the P28908 promoter in tumor cells of both nucleophosmin ( P06748 ) - anaplastic lymphoma kinase ( Q9UM73 ) - positive and P06748 - Q9UM73 - negative ALCL and HL is regulated by a constitutively active P28908 - extracellular signal - regulated kinase ( P29323 ) 1 / 2 mitogen - activated protein kinase ( MAPK ) . Phosphorylation of P27361 / 2 MAPK was confirmed in nuclei of tumor cells in both ALCL and HL . P28908 - P27361 / 2 MAPK signals induce JunB expression , which maintains high activity of the P28908 promoter . JunB induction seems to be largely independent of nuclear factor kappaB in ALCL and HL . These results show a common mechanism of P28908 overexpression in ALCL and HL , although the outcome of P28908 signaling differs between P06748 - Q9UM73 - positive ALCL and P06748 - Q9UM73 - negative ALCL , cutaneous ALCL , and HL as we recently reported .", "Gene expression by PBMC in primary sclerosing cholangitis : evidence for dysregulation of immune mediated genes . Primary sclerosing cholangitis ( PSC ) is a chronic disease of the bile ducts characterized by an inflammatory infiltrate and obliterative fibrosis . The precise role of the immune system in the pathogenesis of PSC remains unknown . We used RNA microarray analysis to identify immune - related genes and pathways that are differentially expressed in PSC . Messenger RNA ( mRNA ) from peripheral blood mononuclear cells ( PBMC ) was isolated from both patients with PSC and age and sex matched healthy controls . Samples from 5 PSC patients and 5 controls were analyzed by microarray and based upon rigorous statistical analysis of the data , relevant genes were chosen for confirmation by RT - PCR in 10 PSC patients and 10 controls . Using unsupervised hierarchical clustering , gene expression in PSC was statistically different from our control population . Interestingly , genes within the P60568 receptor beta , P05231 and Q96HU1 Kinase pathways were found to be differently expressed in patients with PSC compared to controls . Further , individual genes , P01375 induced protein 6 ( TNFaip6 ) and membrane - spanning 4 - domains , subfamily A ( ms4a ) were found to be upregulated in PSC while similar to Q99717 ( Q99717 ) was downregulated . In conclusion , several immune - related pathways and genes were differentially expressed in PSC compared to control patients , giving further evidence that this disease is systemic and immune - mediated .", "Kinetics of Th1 / Th2 cytokines and lymphocyte subsets to predict chronic GVHD after allo - P09683 : results of a prospective study . The role of different cytokines and cells of immune system in the pathogenesis of chronic GVHD ( cGVHD ) is still controversial . Earlier studies , which were either retrospective or analysed one or a few factors , did not show unequivocal results . We prospectively evaluated cytokine levels and lymphocyte subsets in 30 patients who underwent Allo - P09683 to investigate their possible correlation with cGVHD . Levels of P05112 , P05231 , P22301 , P01579 , tumour necrosis factor - alpha ( P01375 ) and its soluble receptors were assessed by ELISA in 30 patients at different times after P09683 . Lymphocyte subsets were evaluated by flow cytometry in peripheral blood at the same times as cytokines . A multivariate analysis was performed using principal component analysis and multi - factor Q9UNW9 ( analysis of variance ) . Eighteen patients developed cGVHD at a median time of 6 months ( range , 5 - 9 ) after P09683 . In multivariate analysis , we observed a correlation between cGVHD and clusters of cytokines and lymphocyte subsets from the third to the sixth month after P09683 . These clusters changed their composition over time , but they constantly included natural killer ( NK ) and P16410 + T cells as negative predictors of cGVHD . P01375 prevailed among other cytokines before the onset of cGVHD . This prevalence could be related partly to the defect of immunoregulatory cells .", "Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK81___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .", "[ ___MASK79___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .", "Regulation of MHC class II expression and antigen processing in murine and human mesenchymal stromal cells by P01579 , TGF - beta , and cell density . Mesenchymal stromal cells ( O60682 ) possess immunosuppressive properties , yet when treated with P01579 they acquire P25054 functions . To gain insight into O60682 immune plasticity , we explored signaling pathways induced by P01579 required for MHC class II ( MHC II ) - dependent Ag presentation . P01579 - induced MHC II expression in mouse O60682 was enhanced by high cell density or serum deprivation and suppressed by TGF - beta . This process was regulated by the activity of the type IV P33076 promoter independently of P42224 activation and the induction of the IFN regulatory factor 1 - dependent Q9NZQ7 / Q9NZQ7 encoding gene . The absence of direct correlation with the cell cycle suggested that cellular connectivity modulates P01579 responsiveness for MHC II expression in mouse O60682 . TGF - beta signaling in mouse O60682 involved P36897 and P37023 TGF - beta RI , leading to the phosphorylation of Q15796 / P84022 and Q15797 / Q99717 / Smad8 . An opposite effect was observed in human O60682 where P01579 - induced MHC II expression occurred at the highest levels in low - density cultures ; however , TGF - beta reduced P01579 - induced MHC II expression and its signaling was similar as in mouse O60682 . This suggests that the P01579 - induced P25054 features of O60682 can be modulated by TGF - beta , serum factors , and cell density in vitro , although not in the same way in mouse and human O60682 , via their convergent effects on P33076 expression .", "P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK18___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .", "Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A ( 2 ) in the P01375 - activated endothelial cells by Q9UNN8 and P25116 dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 ) - alpha up - regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 ) down - regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A ( 2 ) ( sPLA ( 2 )- IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 and thrombin on the expression of sPLA ( 2 )- IIA and extracellular signal - regulated kinase ( P29323 ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA ( 2 )- IIA was quantitatively measured by an enzyme - linked - immunosorbent - assay following stimulation of HUVECs with either thrombin or P01375 in the absence and presence of the phosphatidylinositol 3 - kinase ( P19957 - kinase ) inhibitor LY294002 and the cholesterol - depleting drug methyl - beta - cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA ( 2 )- IIA in HUVECs , however , P01375 potently induced its expression . The prior treatment of cells with P25054 inhibited expression of sPLA ( 2 )- IIA through the Q9UNN8 - dependent cleavage of P25116 . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 - mediated expression of sPLA ( 2 )- IIA through the cleavage of P25116 . The Q9UNN8 - dependent cleavage of P25116 by both P25054 and thrombin increased the phosphorylation of P29323 1 / 2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 and thrombin against sPLA ( 2 )- IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 - kinase dependent protective activity for thrombin such that its cleavage of the lipid - raft localized P25116 inhibits the P01375 - mediated expression of sPLA ( 2 )- IIA in HUVECs .", "Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK78___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .", "Gene expression analysis of 1 , 25 ( OH ) 2D3 - dependent differentiation of HL - 60 cells : a cDNA array study . The alterations in gene expression associated with 1 , 25 ( OH ) 2D3 - induced differentiation of HL - 60 cells were studied in order to identify potential targets for further investigation of the genetic basis of acute myeloid leukaemia . Atlas human haematology filters , including 406 genes ( Clontech ) , were used to study gene expression in response to 1 , 25 ( OH ) 2D3 ( concentration , 5 x 10 - 8 mol / l ) for 24 and 72 h . Compared with untreated cells , expression differences were found in 43 genes . Downregulated genes at both time - points were : P01589 , CMYC , P06748 , P35659 , P51825 , Q01543 , htlf , P41218 , P11274 , Q13422 , P17213 and Q12968 . Upregulated genes at both time - points were P01584 , P08571 and Q07820 . P08174 , P19256 , P14316 , P16220 , P18848 , P63000 , TIAR , P42331 , P48634 , Q06187 , RCK , EV12B and P10153 were downregulated at 24 h , while P17947 , P46734 , P62324 and P10145 were upregulated . At 72 h the upregulated genes were IL1RA , P31785 , P61073 , P22362 , P10147 , P13236 , P13501 , O00626 , P07355 , Q01151 and Q03405 . cDNA array results were confirmed on randomly selected genes using quantitative real - time polymerase chain reaction for three upregulated ( P61073 , P01584 and P08571 ) and three downregulated ( P35659 , P51825 and Q01543 ) genes . Gene expression analysis after differentiation induction may provide a tool to study the roles of P35659 , P51825 and Q01543 in cell proliferation and differentiation . To demonstrate the genes that initiate differentiation , sequential gene expression analysis has to be performed during the first 24 h of the differentiation process .", "Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . ___MASK78___ non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .", "[ Molecular - target therapy for advanced malignant melanoma ] . Malignant melanoma is insensitive to chemotherapy , and standard therapy for metastatic melanoma has been dacarbazine for years . Molecular abnormalities of malignant melanoma , mainly of Q96HU1 kinase signals such as P15056 mutation , have been clarified , and molecular target therapy for melanoma has been developed recently . ___MASK18___ , an inhibitor for mutated P15056 , has shown its efficacy for the first time , with response rate of more than 50 % , and an overall improvement in survival compared with dacarbazine in a phase III study . Skin toxicities including squamous cell carcinoma , are the most severe adverse events . Another P15056 inhibitor , dabrafenib , and a MEK inhibitor , trametinib , have shown excellent efficacy in clinical studies . Melanoma also has high immunogenicity , and cytokines or cell immunotherapy have shown some efficacy . Recently , the importance of immune checkpoints which adjust T - cell activation , such as the cytotoxic T - lymphocyte - associated antigen 4 ( P16410 ) , - P33681 or the programmed cell death protein - 1 ( PD1 )- PD1 ligand ( Q9NZQ7 ) , have been clarified . Targeting those immune checkpoints is expected to be effective for enhancing tumor immunity . P16410 antibody ipilimumab has been reported to improve overall survival in two phase III studies . Major adverse events were autoimmune response such as colitis , eruption , liver dysfunction and endocrineopathies . Antibodies to PD1 or Q9NZQ7 have shown a higher response rate than those of ipilimumab , and seem to accompany fewer autoimmune responses in phase I studies . These two types of targeting therapy are expected to be standard therapies for melanoma .", "Plasma cells from multiple myeloma patients express Q9NZQ7 ( Q9NZQ7 ) and increase expression after stimulation with IFN -{ gamma } and TLR ligands via a MyD88 - , Q9Y4K3 - , and MEK - dependent pathway . Multiple myeloma ( MM ) cells inhibit certain T - cell functions . We examined the expression of Q9NZQ7 ( Q9NZQ7 ) , a P33681 - related protein that inhibits T - cell responses , in CD138 - purified plasma cells isolated from MM patients , monoclonal gammopathy of undetermined significance patients , and healthy donors . We observed that Q9NZQ7 was expressed in most MM plasma cells , but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors . This expression was increased or induced by P01579 and Toll - like receptor ( TLR ) ligands in isolated MM plasma cells . Blocking the MEK / P29323 pathway inhibited P01579 - mediated and TLR - mediated expression of Q9NZQ7 . Inhibition of the MyD88 and Q9Y4K3 adaptor proteins of the TLR pathway blocked not only Q9NZQ7 expression induced by TLR ligands but also that mediated by P01579 . P01579 - induced P42224 activation , via MEK / P29323 and MyD88 / Q9Y4K3 , and inhibition of P42224 reduced Q9NZQ7 expression . MM plasma cells stimulated with P01579 or TLR ligands inhibited cytotoxic T lymphocytes ( CTLs ) generation and this immunosuppressive effect was inhibited by preincubation with an anti - Q9NZQ7 antibody , the UO126 MEK inhibitor , or by transfection of a dominant - negative mutant of MyD88 . Thus , Q9NZQ7 expression by MM cells represents a possible immune escape mechanism that could be targeted therapeutically through inhibition of MyD88 / Q9Y4K3 and MEK / P29323 / P42224 .", "P28908 (+) anaplastic large - cell lymphoma in children : analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology . The purpose of this study was ( 1 ) to investigate the efficacy of chemotherapy regimens designed by the French Society of Pediatric Oncology for childhood anaplastic large - cell lymphoma ( ALCL ) and ( 2 ) to identify prognostic factors in these children . Eighty - two children with newly diagnosed ALCL were enrolled in two consecutive studies , P61073 and HM91 . The diagnosis of ALCL was based on immuno - morphological features and all the cases but 2 were investigated using P37023 antibody directed to the P06748 / Q9UM73 protein associated with the 2 ; 5 translocation . Treatment consisted of 2 courses of COPADM ( methotrexate , cyclophosphamide , doxorubicin , vincristine , and prednisone ) and a maintenance treatment of 5 to 7 months . Seventy - eight patients ( 95 % ) achieved a complete remission and 21 relapsed . The probability of survival and event - free survival at 3 years was of 83 % ( 72 % to 90 % ) and 66 % ( 54 % to 76 % ) , respectively , with a median follow - up of 49 months . In multivariate analysis , visceral involvement , mediastinal involvement , and lacticodeshydrogenase ( LDH ) level >/= 800 UI / L were shown to be predictive of a higher risk of failure . In conclusion , this type of regimen demonstrated efficacy in childhood ALCL . However , therapeutic results have to be improved for children with adverse prognostic parameters such as visceral or mediastinal involvement or a high LDH level .", "Methyl gallate exhibits potent antitumor activities by inhibiting tumor infiltration of P01730 + CD25 + regulatory T cells . P01730 (+) CD25 (+) regulatory T ( Treg ) cells play crucial roles in the host response to tumors . Increasing evidence supports the existence of elevated numbers of Treg cells in solid tumors and hematologic malignancies . In this study , the effects of methyl gallate on Treg cells were examined . Methyl gallate inhibited Treg cell - suppressive effects on effector P01730 (+) T cells and Treg migration toward tumor environment . The expression of Treg surface markers including P16410 , CCR4 , P61073 , and glucocorticoid - induced TNFR was significantly suppressed upon methyl gallate treatment . Furthermore , forkhead box P09131 ( Foxp3 ) expression was also significantly decreased by methyl gallate , suggesting that the suppressive effects of methyl gallate on Treg were medicated by decrease of Treg - specific transcription factor Foxp3 . In tumor - bearing hosts , methyl gallate treatment substantially reduced tumor growth and prolonged the survival rate . In contrast , nu / nu mice did not show decreased tumor progression in response to methyl gallate . In addition , in tumor - bearing Treg - depleted mice , tumor growth and the survival rates were not changed by methyl gallate treatment , strongly suggesting that the main therapeutic target of methyl gallate in tumor suppression was related to modulation of the P01730 (+) CD25 (+) Treg cell functions . In the spleen of tumor - bearing mice , methyl gallate treatment induced a significant decrease in the P01730 (+) CD25 (+) Foxp3 ( high ) Treg cell population . Especially , the number of tumor - infiltrating CD25 (+) Foxp3 ( high ) Treg cells was significantly lower in methyl gallate - treated mice . These results suggest that methyl gallate can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune - based cancer therapy .", "DB08870 followed by allogeneic transplantation as salvage regimen in patients with relapsed and / or refractory Hodgkin ' s lymphoma . Patients with relapsed or refractory Hodgkin lymphoma ( RR - HL ) have poor outcomes . DB08870 ( BV ) , an antibody - drug conjugate comprising an anti - P28908 antibody conjugated to the potent anti - microtubule agent , monomethyl auristatin E , induces high tumour responses with moderate adverse effects . In a retrospective study , we describe objective response rates and subsequent allogeneic stem cell transplantation ( allo - P09683 ) in patients with RR - HL treated by BV in a named patient program in two French institutions . Twenty - four adult patients with histologically proven P28908 (+) RR - HL treated with BV were included from July 2009 to November 2012 . Response to BV treatment was evaluated after four cycles . Eleven patients were in complete response ( 45 . 8 % ) , while five patients were in partial response ( 20 . 8 % ) , with an overall response rate of 66 . 6 % . Eight patients failed to respond to BV ( 33 . 3 % ) . All of the responding patients could receive consolidation treatment after BV : three patients underwent autologous stem cell transplantation ( auto - P09683 ) , three patients received a tandem auto - P09683 / allo - P09683 , nine patients received allo - P09683 and one patient was treated with donor lymphocyte infusion . We found no treatment - related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation . With a median follow - up of 20 months ( range 10 . 5 - 43 . 2 ) , none of them relapsed or died . BV followed by allo - P09683 represents an effective salvage regimen in patients with RR - HL .", "___MASK100___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK100___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .", "Identifying apoptosis - evasion proteins / pathways in human hepatoma cells via induction of cellular hormesis by UV irradiation . Evading apoptosis is pivotal in both of carcinogenesis and resistance to anticancer therapy . We investigated the molecules and pathways of apoptosis evasion in human hepatoma cells by irradiating hepatoma cells with optimized UV ( so - called \" hormetic responses \" ) . Proteins and pathways related to hormetic responses were identified via proteomic approaches followed by reconstruction of function - networks . Of the 2326 defined protein spots , 42 distinct proteins significantly changed their expression . Eleven hormetic response proteins ( P49773 , P35232 , P07339 , P04083 , LGASL1 , P13693 , P06748 , P32119 , P09936 , Q8TCT0 , and Q07021 ) were involved in 5 death - regulatory pathways , including the p53 - dependent apoptotic pathway , protein ubiquinization , cellular redox , calcium - mediated signaling pathway , and sphingomyelin - metabolism pathway . Knockdown of P49773 expression via RNA interference increased tumor cell resistance to apoptosis induction , while silencing P06748 , P09936 , or Q8TCT0 greatly sensitized tumor cells to apoptosis induction . In conclusion , P06748 , P09936 , and Q8TCT0 act as apoptosis - evasion proteins that may serve as therapeutic targets for hepatoma . Silencing their expression would increase therapeutic efficacy , thereby reducing the corresponding doses and side - effects of anticancer therapy . This model of induction of cellular hormetic responses to identify apoptosis - evasion molecules / pathways via proteomic approaches can be applied to other modalities of anticancer therapy .", "An assessment of the effect of human herpesvirus - 6 replication on active cytomegalovirus infection after allogeneic stem cell transplantation . Human herpesvirus - 6 ( HHV - 6 ) may enhance cytomegalovirus ( CMV ) replication in allogeneic stem cell transplant ( allo - P09683 ) recipients either through direct or indirect mechanisms . Definitive evidence supporting this hypothesis are lacking . We investigated the effect of HHV - 6 replication on active CMV infection in 68 allo - P09683 recipients . Analysis of plasma HHV - 6 and CMV DNAemia was performed by real - time PCR . Enumeration of pp65 and IE - 1 CMV - specific IFNgamma CD8 (+) and P01730 (+) T cells was performed by intracellular cytokine staining . HHV - 6 DNAemia occurred in 39 . 8 % of patients , and was significantly associated with subsequent CMV DNAemia in univariate ( P =. 01 ) , but not in multivariate analysis ( P =. 65 ) . The peak of HHV - 6 DNAemia was not predictive of the development of CMV DNAemia . Timing and kinetics of active CMV infection were comparable in patients either with or without a preceding episode of HHV - 6 DNAemia . The occurrence of HHV - 6 DNAemia had no impact on CMV - specific T cell immunity reconstitution early after transplant . The receipt of a graft from an HLA - mismatched donor was independently associated with HHV - 6 ( P =. 009 ) and CMV reactivation ( P =. 04 ) . The data favor the hypothesis that a state of severe immunosuppression leads to HHV - 6 and CMV coactivation , but argue against a role of HHV - 6 in predisposing to the development of CMV DNAemia or influencing the course of active CMV infection .", "Genetic basis of delay discounting in frequent gamblers : examination of a priori candidates and exploration of a panel of dopamine - related loci . INTRODUCTION : Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards . It has been consistently linked to pathological gambling and other forms of addictive behavior , and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders ( i . e . , an endophenotype ) . Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission . The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine - related variants in a sample of frequent gamblers . METHODS : Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva . RESULTS : In a priori tests , two loci previously associated with delayed reward discounting ( rs1800497 and rs4680 ) were not replicated , however , the long form of P21917 VNTR was significantly associated with lower discounting of delayed rewards . Exploratory analysis of the dopamine - related panel revealed 11 additional significant associations in genes associated with dopamine synthesis , breakdown , reuptake , and receptor function ( P35462 , Q01959 , DDC , P09172 , and Q05940 ) . An aggregate genetic risk score from the nominally significant loci accounted for 17 % of the variance in discounting . Mediational analyses largely supported the presence of indirect effects between the associated loci , delay discounting , and pathological gambling severity . CONCLUSIONS : These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting .", "Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .", "Rescue from failed growth factor and / or chemotherapy P19526 mobilization with G - P04141 and plerixafor ( DB06809 ) : an institutional experience . Auto - P09683 has been shown to be a potentially curative treatment for a variety of hematological malignancies . Auto - P09683 is dependent on the successful mobilization and collection of hematopoietic stem cells to ensure engraftment . The inability to mobilize sufficient number of hematopoietic stem cells using standard cytokine - assisted mobilization strategies excludes eligible patients from potentially curative auto - P09683 . DB06809 ( DB06809 ; DB06809 ) , a novel bicyclam antagonist of the SDF - 1alpha / P61073 complex , has been reported previously to augment PBSC mobilization in patients undergoing their first planned stem cell mobilization and collection attempt . In our experience , 17 of 20 patients otherwise eligible for auto - P09683 who failed previous mobilization attempts had successful mobilization of P28906 (+) hematopoietic stem cells with one apheresis procedure , and an additional patient required two aphereses procedures , when treated with the combination of plerixafor and G - P04141 on a compassionate use protocol available at our institution .", "DB08870 : its role in the treatment of anaplastic large cell and Hodgkin ' s lymphoma . DB08870 is being developed in a joint collaboration between Seattle Genetics and Millennium : The Takeda Oncology Company . In August 2011 , it was approved by the FDA for the treatment of patients with Hodgkin ' s lymphoma ( HL ) and anaplastic large cell lymphoma ( ALCL ) . DB08870 is an antibody - drug conjugate that specifically targets the P01375 receptor superfamily member 8 ( P28908 ) antigen on the surface of cancer cells to induce cell death . DB08870 has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express P28908 and reducing tumor size in preclinical models . DB08870 is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children . It is being investigated for use as a combination agent with pre - existing frontline chemotherapies and as a stand - alone salvage therapy for use prior to autologous stem cell transplant . Treatment with brentuximab vedotin is generally well tolerated although it is associated with grade 1 - 2 adverse reactions such as neutropenia and there have been reports of grade 3 - 4 serious adverse events . In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects .", "Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK50___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .", "DB08870 in anaplastic large cell lymphoma . INTRODUCTION : DB08870 , a novel anti - P28908 antibody - drug conjugate , delivers a cytotoxic agent into P28908 (+) cells . P28908 expression is characteristic of anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . AREAS COVERED : We reviewed data on brentuximab vedotin , focusing on ALCL and discuss pharmacology , clinical trials leading to approval and future research directions . Systemic ALCL , 3 % of adult Q9NZ71 , is characterized by large anaplastic P28908 (+) cells . The fusion protein P06748 - Q9UM73 , when present in systemic ALCL , confers better prognosis , although even Q9UM73 - patients with IPI score ≥ 3 are high - risk . For patients with systemic ALCL , 25 - 45 % relapse after frontline therapy , and > 50 % of patients will relapse following high - dose chemotherapy with autologous stem - cell support . There has been no standard therapy for relapsed / refractory systemic ALCL . DB08870 , combines a monoclonal antibody targeted to P28908 with a microtubule disrupting agent and was recently approved for treatment of patients with systemic ALCL that is refractory or relapsed after at least one multiagent chemotherapy regimen . EXPERT OPINION : DB08870 provides targeted therapy to P28908 (+) lymphomas , including ALCL and HL , with high response rates and manageable toxicity , predominantly myelosuppression and peripheral neuropathy .", "Suppression of experimental autoimmune encephalomyelitis using peptide mimics of P10747 . The P33681 : P10747 / P16410 costimulatory pathway plays a critical role in regulating the immune response and thus provides an ideal target for therapeutic manipulation of autoimmune disease . Previous studies have shown that blockade of P10747 signaling by mAbs can both prevent and exacerbate experimental autoimmune encephalomyelitis ( EAE ) . In this study , we have designed two P10747 peptide mimics that selectively block P33681 : P10747 interactions . By surface plasmon resonance , both the end group - blocked P10747 peptide ( EL - P10747 ) and its retro - inverso isomer ( RI - P10747 ) compete effectively with the extracellular domain of P10747 for binding to P33681 - 1 . Both the P10747 peptide mimics inhibited expansion of encephalitogenic T cells in vitro . A single administration of EL - P10747 or RI - P10747 peptide significantly reduced disease severity in EAE . Importantly , we show that either P10747 peptide mimic administered during acute disease dramatically improved clinical signs of EAE , suppressing ongoing disease . The ratio of P33681 : P42081 expression was significantly lower on P01730 (+) and F4 / 80 (+) spleen cells in P10747 peptide - treated mice . Peripheral deletion of Ag - specific P01730 (+) T cells occurs following in vivo blockade of P10747 with synthetic P10747 peptides .", "Mutated regions of nucleophosmin 1 elicit both P01730 (+) and CD8 (+) T - cell responses in patients with acute myeloid leukemia . Mutations in the nucleophosmin gene ( P06748 ( mut ) ) are one of the most frequent molecular alterations in acute myeloid leukemia ( AML ) , and immune responses may contribute to the favorable prognosis of AML patients with P06748 ( mut ) . In the present study , we were able to demonstrate both P01730 (+) and CD8 (+) T - cell responses against P06748 ( mut ) . Ten peptides derived from wild - type P06748 and P06748 ( mut ) were subjected to ELISPOT analysis in 33 healthy volunteers and 27 AML patients . Tetramer assays against the most interesting epitopes were performed and Cr ( 51 )- release assays were used to show the cytotoxicity of peptide - specific T cells . Moreover , HLA - DR - binding epitopes were used to test the role of P01730 (+) T cells in P06748 immunogenicity . Two epitopes ( epitopes # 1 and # 3 ) derived from P06748 ( mut ) induced CD8 (+) T - cell responses . A total of 33 % of the P06748 ( mut ) AML patients showed immune responses against epitope # 1 and 44 % against epitope # 3 . Specific lysis of leukemic blasts was detected . To obtain robust immune responses against tumor cells , the activation of P01730 (+) T cells is crucial . Therefore , overlapping ( OL ) peptides were analyzed in ELISPOT assays and OL8 was able to activate both CD8 (+) and P01730 (+) T cells . The results of the present study show that P06748 ( mut ) induces specific T - cell responses of P01730 (+) and CD8 (+) T cells and therefore is a promising target for specific immunotherapies in AML ." ]

[ "___MASK100___", "___MASK16___", "___MASK18___", "___MASK50___", "___MASK51___", "___MASK65___", "___MASK78___", "___MASK79___", "___MASK81___" ]

[ "Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK74___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .", "Immune reconstitution following rabbit antithymocyte globulin . Depletional induction therapies are routinely used to prevent acute rejection and improve transplant outcome . The effects of depleting agents on T - cell subsets and subsequent T - cell reconstitution are incompletely defined . We used flow cytometry to examine the effects of rabbit antithymocyte globulin ( DB00098 ) on the peripheral T - cell repertoire of pediatric and adult renal transplant recipients . We found that while DB00098 effectively depleted CD45RA + P26842 + naïve and CD45RO + P26842 + central memory P01730 + T cells , it had little effect on CD45RO + P26842 - P01730 + effector memory or CD45RA + CD31 - , CD45RO + P26842 + and CD45RO + P26842 - CD8 + T cell subsets . When we performed a kinetic analysis of CD31 + recent thymic emigrants and CD45RA +/ RO + T cells , we found evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution . We additionally examined the impact of DB00098 on peripheral P01730 + Foxp3 + T cells . We found that in adults , administration of DB00098 - induced peripheral expansion and new thymic emigration of T cells with a Treg phenotype , while P01730 + Foxp3 + T cells of thymic origin predominated in children , providing the first evidence that DB00098 induces Treg in vivo . Collectively our data indicate that DB00098 alters the balance of regulatory to memory effector T cells posttransplant , providing an explanation for how it positively impacts transplant outcome .", "Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation . Experimental studies have shown that rabbit antithymocyte polyclonal globulin ( ATG ) can expand human P01730 + CD25 ++ Foxp3 + cells ( Tregs ) . We investigated the major biological effects of a self - manufactured rabbit polyclonal anti - rat thymoglobulin ( DB00098 ) in vitro , as well as its effects on different peripheral T - cell subsets . Moreover , we evaluated the allogeneic suppressive capacity of DB00098 - induced Tregs in an experimental rat renal transplant model . Our results show that DB00098 has the capacity to induce apoptosis in T lymphocyte lymphocytes as a primary mechanism of T - cell depletion . Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T cell subsets , directly proportional to the DB00098 dose used , but not of the effector memory T cells , which required significantly higher DB00098 doses . After DB00098 administration , we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats , leading to an increase in the Treg / T effector ratio . Importantly , DB00098 - induced Tregs displayed a strong donor - specific suppressive capacity when assessed in an antigen - specific allogeneic co - culture . All of these results were associated with better renal graft function in rats that received DB00098 . Our study shows that DB00098 has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post - transplant homeostatic proliferation .", "___MASK59___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK59___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .", "Kinetics of homeostatic proliferation and thymopoiesis after DB00098 induction therapy in kidney transplant patients . BACKGROUND : Lymphocyte - depleting therapy is associated with long - lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies . The mechanisms of T - cell repopulation and their posttransplantation kinetics are not fully understood . METHODS : We studied thymopoiesis by CD31 (+) naïve T cells ( recent thymic emigrants ) and homeostatic proliferation by Ki - 67 (+) T cells in rabbit antithymocyte globulin ( DB00098 ) - treated patients the first 6 months after transplantation . Patients receiving basiliximab or no induction therapy served as controls . RESULTS : At 6 months after transplantation , T - cell numbers were lower than before transplantation in DB00098 - treated patients , whereas T - cell numbers remained stable in both control groups . In this time period , thymopoiesis was similar between the three treatment groups ; CD8 (+) T cells showed the highest percentage of recent thymic emigrants . At month 1 , percentages of Ki - 67 (+) naïve and memory P01730 (+) and CD8 (+) T cells were the highest in DB00098 - treated patients , but these percentages declined in the months thereafter . When CD31 was used to distinguish between cytokine - and antigen - driven proliferation in naïve T cells , we found evidence for cytokine - dependent proliferation . Cytokine - dependent proliferation was also shown by in vivo increased percentages of phosphorylated P42229 and high expression levels of the interleukin - 7 receptor - α and interleukin - 15 receptor - α by T cells . CONCLUSION : These findings demonstrate that , in the first month after DB00098 therapy , cytokine - induced homeostatic proliferation is involved in T - cell repopulation of both naïve and memory T cells . At later time points , the contribution of homeostatic proliferation diminished , which explains the observed incomplete T - cell recovery .", "P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .", "The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK28___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK28___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .", "ATG - induced expression of Q9BZS1 in human P01730 (+) T cells in vitro is associated with T - cell activation and not the induction of Q9BZS1 (+) T regulatory cells . Several recent reports have suggested that in vitro exposure of P01730 (+) T cells to rabbit antithymocyte globulin ( DB00098 ) , which is commonly used to prevent and treat graft - versus - host disease and allograft rejection , is an effective method to induce P01730 (+) CD25 (+) Q9BZS1 (+) T regulatory cells ( Tregs ) . We and others , however , have shown that Q9BZS1 is also expressed in activated T cells . We therefore investigated whether the induction of Q9BZS1 expression by DB00098 resulted in a stable population of suppressive Tregs . We found that exposure of peripheral blood mononuclear cells ( PBMCs ) or conventional T cells to DB00098 resulted in induction of transient rather than stable expression of CD25 and Q9BZS1 . Furthermore , DB00098 - treated T effector cells acquired neither an immunosuppressive profile of cytokine production nor suppressive capacity , even at the time of maximal Q9BZS1 expression . These findings indicate that the notion that DB00098 can be used to induce Tregs in vitro for cellular therapy in vivo should be re - evaluated .", "Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen - induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( ___MASK90___ ) - induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 - Px , MDA , NO and P35228 , and the activities of serum ALT and Q9NRA2 caused by ___MASK90___ . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT - mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 ) , pro - inflammatory mediators ( IL - 1β , P05112 , P05231 , P01375 - α , P35228 , Bax , HMGB - 1 and P35354 ) , pro - inflammatory transcription factors ( NF - κB and AP - 1 ) , pro - apoptotic proteins ( cytochrome C , p53 , caspase - 3 , caspase - 9 , p - JNK , p - p38 and p - P29323 ) , and increased the protein expressions of Bcl - 2 and Bcl - xL . Moreover , the gene expression of P22301 , and the proteins including LC3 , Q14457 and Atg5 induced by ___MASK90___ were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat ___MASK90___ - induced liver damage in the future .", "Subcutaneous alemtuzumab vs ATG in adjusted conditioning for allogeneic transplantation : influence of Campath dose on lymphoid recovery , mixed chimerism and survival . Sixty - nine consecutive patients ( median age 54 years ) were prospectively enrolled in a single - institution protocol for allogeneic transplantation with adjusted non - myeloablative fludarabine - melfalan - based conditioning including cyclosporin A and DB00688 , and one of three modes of serotherapy . Thirty - one donors ( 45 % ) were unrelated . The first cohort of 29 had ATG ( DB00098 2 mg / kg x 3 days ) , the subsequent 26 had Campath 30 mg x 3 days subcutaneously , and the final cohort of 14 had 30 mg Campath once . The groups were similar as regards age , diagnosis and risk factors . Campath - patients had no acute toxicity , fewer days with fever and antibiotics , and required fewer transfusions than ATG - treated patients . 3 - d - Campath patients showed lower lymphocyte counts from day + 4 , and P01730 + , CD8 + , P15391 + and NK cells recovered slower than in ATG - treated patients . More Campath patients developed mixed chimerism that required DLI . 3 - d - Campath induced more serious and opportunistic infections than ATG , which resulted in a greater non - relapse mortality and an impaired overall survival despite a low tumor - related mortality . The change of the Campath dosing schedule to one dose abrogated the deleterious effect of 3 - d - Campath on immune recovery , severe infections and survival . Subcutaneous Campath is simple and provides strong immune suppression with no early toxicity , but dose limitation to 30 mg once is recommended .", "A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients . PURPOSE : Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin ( DB00098 , DB00098 (®) ) to the hematopoietic cell transplant ( HCT ) conditioning regimen of IV fludarabine monophosphate ( fludarabine ) and targeted intravenous ( IV ) busulfan ( fludarabine /( T ) busulfan ) . Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients . METHODS : We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan , specifically busulfan concentration at steady state , and fludarabine , specifically F - ara - A area under the curve ( AUC ) and fludarabine triphosphate ( F - ara - DB00171 ) intracellular accumulation and concentration in separate P01730 (+) and CD8 (+) T - lymphocyte populations . RESULTS : Acute and chronic graft versus host disease ( GvHD ) occurred in 11 patients and one patient , respectively . Four patients died before day + 100 of non - relapse causes , which met the protocol stopping guidelines . The cumulative incidence of relapse was 25 % at 3 year post - HCT . Interpatient variability in the busulfan - and fludarabine - relevant pharmacologic biomarkers was 2 . 1 - to 2 . 5 - fold . F - ara - A AUC and accumulated F - ara - DB00171 in CD8 (+) cells had the highest hazard ratio for non - relapse mortality and overall survival , respectively . However , neither achieved statistical significance . CONCLUSIONS : The low rates of GvHD , particularly in its chronic form , were encouraging , and further biomarker studies are warranted to optimize the fludarabine /( T ) busulfan / DB00098 conditioning regimen .", "Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK32___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK32___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK32___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK32___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK32___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK32___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK32___ .", "Comparative polyclonal antithymocyte globulin and antilymphocyte / antilymphoblast globulin anti - CD antigen analysis by flow cytometry . Polyclonal antithymocyte globulin ( ATG ) / antilymphocyte and antilymphoblast globulins ( ALG ) antibodies have been used successfully in transplantation , aplastic anemia and graft - versus - host disease . Flow cytometry has been used to analyze peripheral blood lymphocyte populations in transplant patients receiving polyclonal ATG / ALG preparations for immunosuppression . Recent reports have indicated clinical dose adjustment based on levels of patient ' s cells expressing various CD antigens . In vitro analysis of individual polyclonal ATG / ALG CD antigen specificity could identify appropriate antigens for clinical monitoring as well as provide useful in vitro activity data . Therefore , a flow cytometry based assay to characterize and compare activities to specific CD antigens found on the surface of peripheral blood lymphocytes has been developed . Activities found in four lots each of horse ATG ( ATGAM , Upjohn ) , rabbit and horse ATG ( thymoglobulin and lymphoglobulin , Merieux ) , horse ALG ( Minnesota ) , and DB00098 ( Fresenius ) have been compared for P06729 , CD3 , P01730 , P06127 , P09564 , CD8 , CD11a , P05107 , P10747 , P16070 , P08575 , and TCR - alpha / beta antigens . Quantitation is achieved by measuring the concentration of ATG / ALG required to give 50 % inhibition of antigen specific fluorescent - labeled monoclonal antibody relative to buffer controls . The three horse products tested have similar activity to most antigens tested . However , Fresenius DB00098 has the lowest activity for almost all antigens tested whereas the Merieux DB00098 has activities closer to the horse products . This technique allows for rapid in vitro comparison of reactivities to individual lymphocyte antigens as well as in vitro analysis of consistency .", "DB00098 - associated Cd4 + T - cell depletion and infection risk in HIV - infected renal transplant recipients . HIV - infected patients are increasingly referred for kidney transplantation , and may be at an increased risk for rejection . Treatment for rejection frequently includes thymoglobulin . We studied thymoglobulin ' s effect on P01730 + T - cell count , risk of infection and rejection reversal in 20 consecutive HIV - infected kidney recipients . All patients used antiretroviral therapy and opportunistic infection prophylaxis . Maintenance immunosuppression consisted of prednisone , mycophenolate mofetil and cyclosporine . Eleven patients received thymoglobulin ( 7 for rejection and 4 for delayed / slow graft function ) while 9 did not . These two groups were similar in age , gender , race , donor characteristics and immunosuppression . Mean P01730 + T - cell counts remained stable in patients who did not receive thymoglobulin , but became profoundly suppressed in those who did , decreasing from 475 +/- 192 to 9 +/- 10 cells / microL ( p < 0 . 001 ) . Recovery time ranged from 3 weeks to 2 years despite effective HIV suppression . Although opportunistic infections were successfully suppressed , low P01730 + T - cell count was associated with increased risk of serious infections requiring hospitalization . Rejection reversed in 6 of 7 patients receiving thymoglobulin . We conclude that thymoglobulin reverses acute rejection in HIV - infected kidney recipients , but produces profound and long - lasting suppression of the P01730 + T - cell count associated with increased risk of infections requiring hospitalization .", "Antithymocyte globulins suppress dendritic cell function by multiple mechanisms . BACKGROUND : The polyclonal rabbit antithymocyte and anti - T - cell immunoglobulins ( ATGs ) DB00098 ( TG ) and DB05320 ( ATG - F ) have been widely used for the prevention and therapy of allograft rejection and graft versus host disease in transplantation . Although immunosuppressive mechanisms of ATGs on T cells are well studied , less is known about their impact on dendritic cells ( DCs ) . METHODS : Effects of TG and ATG - F on immune functions and signaling pathways of human monocyte - derived DCs were determined by flow cytometry , enzyme - linked immunosorbent assay , Western blot , apoptosis assays , endocytosis assays , and T cell stimulation assays . RESULTS : TG and ATG - F bind rapidly and with high affinity to CD11c , P33681 , P42081 , P25942 , P16671 , P28907 , CD206 , and human leukocyte antigen - DR on DCs . TG and , to a lesser extent , ATG - F induce apoptosis in immature and mature DCs . Macropinocytotic and receptor - mediated endocytotic antigen uptake in immature DCs is inhibited by TG and ATG - F due to their binding of the C - type lectins CD206 and Q9NNX6 . TG and ATG - F induce activation of the mitogen - activated protein kinases P27361 / 2 and p38 that contributes to the induction of apoptosis . TG and ATG - F also induce cytoplasmic - nuclear translocation of the NF - kappaB / Rel transcription factors RelB , RelA , p50 , and p52 . Production of interleukin - 12p70 in mature DCs is suppressed by TG and ATG - F . TG and ATG - F reduce the capacity of mature DCs to stimulate allogeneic and autologous T cells . CONCLUSIONS : ATGs interfere with basic DC functions , suggesting that DCs are relevant targets for the immunosuppressive action of ATGs in transplantation .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK9___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "Contact sensitization to oxazolone : involvement of both interferon - gamma and interleukin - 4 in oxazolone - specific Ig and T - cell responses . The synthesis and role of several lymphokines were examined during contact sensitization to oxazolone ( OX ) . Application of OX to the skin of mice increased the delayed - type hypersensitivity ( DTH ) response to challenge , serum titres of OX - specific IgG1 and IgG2a , and draining lymph node cell ( LNC ) numbers . At day 3 , LN contained detectable interleukin - 4 ( P05112 ) , interferon - gamma ( P01579 ) and granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) but not P60568 or P08700 mRNAs ; P08700 and higher levels of P05112 , P01579 and GM - P04141 mRNAs were measured after 24 hr culture with anti - CD3 antibody in OX - primed but not unprimed LNC . As a result of sensitization , LNC secreted P08700 constitutively and produced elevated levels of P60568 , P08700 , P05112 and P01579 in response to anti - CD3 antibody ; a similar but weaker lymphokine response was recalled by OX - protein conjugate . P01730 + cells were the major source of the anti - CD3 - induced lymphokines except P01579 , which was derived mainly from CD8 + cells . Since both P05112 and P01579 were synthesized by OX - primed LNC in vivo and in vitro , their role was investigated by administering anti - lymphokine antibodies at the time of sensitization . Anti - P05112 treatment reduced OX - specific serum IgG1 titres without affecting IgG2a titres , whereas anti - P01579 treatment reduced IgG2a but not IgG1 titres . Although neither antibody altered DTH responsiveness , anti - P01579 treatment markedly increased P05112 production by P01730 + LNC and reduced P01579 production in vitro , particularly by P01730 + cells . We conclude that endogenous P05112 and P01579 reciprocally influence the isotype of the Ig response to OX and that P01579 also affects the relative levels of P05112 and P01579 synthesis by P01730 + LNC .", "Upregulation of molecules associated with T - regulatory function by thymoglobulin pretreatment of human P01730 + cells . BACKGROUND : This study evaluated the immunologic effects of thymoglobulin in modulating human P01730 + cells . METHODS : Human P01730 + cells were purified from peripheral blood mononuclear cells by negative selection method . P01730 + cells were pretreated with thymoglobulin and incubated for 72 hr . Cells and culture supernatants were collected and studied by real - time quantitative polymerase chain reaction , fluorescence activated cell scanning , multiplex cytokine assay , and mixed lymphocyte reaction ( P08235 ) . RESULTS : DB00098 pretreated P01730 + cells demonstrated up - regulation of gene transcripts for P16410 , OX40 , forkhead box P09131 ( Foxp3 ) , CD25 , P01579 , P22301 , and P60568 as determined by real - time quantitative polymerase chain reaction . Fluorescence - activated cell scanning analysis demonstrated that P01730 + cells , pretreated with thymoglobulin , up - regulated CD25 expression on their surface , and the surface expression of P16410 and OX40 and the expression of intracellular Foxp3 were observed in these P01730 + CD25 + cells . Additionally , P08235 demonstrated that thymoglobulin - pretreated cells partially inhibited proliferation of untreated autologous P01730 + cells in response to allogeneic cells . The high levels of P01579 , P22301 , P60568 , and P05112 were detected by multiplex cytokine assay in supernatants collected from cultures of thymoglobulin - pretreated P01730 + cells . The lymphocyte proliferation of allogeneic P08235 was also partially blocked in the presence of supernatants from cultures of thymoglobulin - pretreated P01730 + cells . CONCLUSIONS : This study demonstrates that the unique effects of thymoglobulin in modulating P01730 + cells may be an important mechanism for its action in inducing immunosuppression and transplant tolerance .", "A new epigenetic challenge : systemic lupus erythematosus . In recent years , compelling evidence has been gathered that supports a role for epigenetic alterations in the pathogenesis of systemic lupus erythematosus ( SLE ) . Different blood cell populations of SLE patients are characterized by a global loss of DNA methylation . This process is associated with defects in P29323 pathway signalling and consequent P26358 1 downregulation . Hypomethylation of gene promoters has been described , which permits transcriptional activation and therefore functional changes in the cells and also hypomethylation of the ribosomal RNA gene cluster . Among the identified targets undergoing demethylation are genes involved in autoreactivity ( P20701 ) , osmotic lysis and apoptosis ( P14222 , P50281 and P80188 ) , antigen presentation ( Q99062 ) , inflammation ( MMP 14 ) , B - T - cell interaction ( P32970 and P29965 ) and cytokine pathways ( Q99062 , P05112 , P05231 and P38484 ) . DNA methylation inhibitors are also known to induce autoreactivity in vitro and cause a lupus - like disease in vivo . Further , altered patterns of histone modifications have been described in SLE . P01730 + lymphocytes undergo global histone H3 and H4 deacetylation and consequent skewed gene expression . Although multiple lines of evidence highlight the contribution of epigenetic alterations to the pathogenesis of lupus in genetically predisposed individuals , many questions remain to be answered . Attaining a deeper understanding of these matters will create opportunities in the promising area of epigenetic treatments .", "Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK92___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .", "Effect of thymoglobulin induction on HIV - infected renal transplant recipients : differences between HIV - positive and HIV - negative patients . The best immunosuppressive regimen in HIV - infected renal transplant recipients has not been established . DB00098 has been associated with an increased risk of serious bacterial infections in HIV - negative patients and , for this reason , there is some concern over its use in the HIV - infected population . We describe three consecutive HIV - infected renal transplant recipients who received thymoglobulin as induction therapy , and we compared their progress with a cohort of 23 HIV - negative recipients . Median follow - up was 24 and 11 months , respectively . Nadir lymphocytopenia was observed at 1 week in both groups , and their absolute lymphocyte count recovery was similar . An early and deep ( < 30 cells / mm ( 3 ) ) P01730 (+) T cell lymphocytopenia was seen in two of the three HIV - infected patients . No opportunistic infections were diagnosed in HIV - positive patients . One HIV - positive patient had a bacterial infection and five HIV - negative patients had one or more bacterial infections . DB00098 was safe in our three HIV - infected renal transplant recipients . Until those data are confirmed in larger studies , close monitoring is recommended during the thymoglobulin - induced P01730 (+) T cell lymphocytopenia period .", "Atypical acute rejection after hand transplantation . Skin rejection after hand transplantation is characterized by a maculopapular erythematous rash that may be diffuse , patchy or focal , and distributed over forearms and dorsum of the hands . This ' classical ' pattern of rejection usually spares the skin of the palm and does not affect the nails . Herein , we report the experience on four cases presenting with an ' atypical ' pattern of rejection that is novel in involving the palmar skin and the nails . All patients were young and exposed to repetitive and persistent mechanical stress of the palm . Characteristic features of rejection included a desquamative rash associated with dry skin , red papules , scaling and lichenification localized to the palm . Skin lesions were associated with nail dystrophy , degeneration , deformation or loss . Histology of the skin and nail bed revealed a lymphocytic infiltrate with predominance of T cells ( CD3 + , P01730 + and CD8 + ) , with small numbers of B cells ( P11836 + and CD79a + ) and a low number of Forkhead transcription factor 3 ( Q9BZS1 ) - positive cells in one patient . The lesions persisted over weeks to months , responded poorly to steroid treatment and were managed with antithymocyte globulin ( ATG ; DB00098 , Genzyme , Cambridge , MA ) , alemtuzumab and / or intensified maintenance immunosuppression .", "The effect of rabbit antithymocyte globulin on human DB05914 . Mesenchymal stem cells ( MSCs ) possess immunomodulatory properties which are of key interest for their application in autoimmunity and transplantation . In transplantation , administration of MSCs has shown promising results in preclinical models and has recently moved to clinical trials . Therefore , it is important to study the interactions between MSCs and immunosuppressive drugs currently used in transplantation . We aimed to analyze the effect of rabbit antithymocyte globulin ( DB00098 ) MSCs . MSCs were obtained from perirenal fat of kidney donors and exposed to ranging doses of DB00098 ( DB00098 (®) , Genzyme ; 0 . 5 - 100 μg / ml ) . Binding of DB00098 , effects on viability and susceptibility to be killed by cytotoxic lymphocytes as well as effects on their immunosuppressive potential of MSCs were tested . DB00098 binds dose - dependently to MSCs . This binding was associated with slightly impaired viability after 48 and 72 h when compared with nonexposed MSCs . In contrast to nontreated MSCs , DB00098 preexposed MSCs were susceptible to be lysed by cytokine - activated CD8 (+) cytotoxic cells and NKT cells . The capacity of MSCs to suppress the proliferation of anti - CD3 / P10747 activated P01730 and CD8 T cells were reduced by the presence of DB00098 in the culture . DB00098 reduces the viability and antiproliferative capacity of MSCs in a dose - dependent manner and converts them into targets for CD8 T cells and NKT cell lysis .", "Acute cellular rejection . The incidence of acute rejection of the kidney allograft in the world has been around 15 % during the period between 2001 and 2003 . It is clinically defined as an elevation in the level of serum creatinine by more than 0 . 3 mg / dL and is diagnosed by kidney biopsy . On pathologic examination , the interstitium of the allograft is diffusely edematous and infiltrated by P01730 and CD8 lymphocytes . Tubulitis occurs when the lymphocytes and monocytes extend into the walls and lumina of the tubules . Presence of leukocytes determines infection or antibody - mediated rejection . Typically C4d staining is negative . Other causes of acute allograft dysfunction included prerenal factors , interstitial nephritis , infection , acute tubular necrosis , toxicity by drugs , and obstruction in the urinary tract . The primary diagnostic assessments include history , especially adherence to immunosuppressive therapy , physical examination , blood and urine laboratory tests , measurement of the serum levels of the drugs , and ultrasonography . Diagnosis of acute cellular rejection depends on biopsy , P11836 staining for refractory cases , negative C4d staining , presence of markers of activating lymphocyte , and proteomic study . Treatment of acute cellular rejection in kidney transplant recipients include pulse steroid for the first rejection episode . It can be repeated for recurrent or resistant rejection . DB00098 and OKT3 are used as the second line of treatment if graft function is deteriorating . Changing the protocol from cyclosporine to tacrolimus or adding mycophenolate mofetil or sirolimus might be effective . Prognosis depends on number of rejection episodes , the use of potent drugs , time of rejection from transplantation , and response to treatment .", "Autoreactive T cell hybridoma - derived B cell stimulatory factor ( s ) governing IgA isotype immunoglobulin production by murine Peyer ' s patch B cells . In the present study we investigated whether autoreactive T cells derived from murine Peyer ' s patches ( PP ) have the capacity to regulate mucosal B cell differentiation to IgA - producing plasma cells in vitro . We also examined whether B cell development is mediated by lymphokines from immunoregulatory T cells - that is , B cell stimulatory factors ( BSF ) and cofactors ( coBSF ) - which include B cell growth factor ( BCGF ) , putative alpha B cell immunoglobulin ( Ig ) heavy chain switch factor ( BSWF alpha ) , and B cell differentiation factor ( BCDF ) , as well as interleukin - 2 ( P60568 ) . To this purpose we developed in vitro a variety of BSF ( especially putative BSWF alpha ) - producing autoreactive ( self - class II molecules responsive ) T cell hybridoma cell clones from murine PP , and studied the functional activity of the BSF , especially a putative alpha Ig heavy chain switch ( mu ---- alpha ) factors ( s ) . These T hybridome cell lines possessed the surface phenotypes of Thy 1 . 2 , P01730 + , P06127 + and CD8 - and produced a variety of BSF , including two kinds of BCGF ( P05113 , and a BCGF that did not require additional costimulators to induce proliferation of preactivated B cells ) , putative BSWF alpha / gamma , BCDF , and / or P60568 . The results strongly support the view that the autologous T cell plays an important role not only in B cell proliferation and terminal maturation , but also in alpha heavy chain switching in PP . This T - B cell interation is mediated at least in part through BSF lymphokines elaborated by the autoreactive T cell , probably activated in situ in the lymphoid tissue microenvironment .", "Zeranol upregulates corticotropin releasing hormone expression in the placental cell line JEG - 3 . ___MASK17___ - releasing hormone ( P06850 ) plays a pivotal role in the control of parturition in human . Increased amount of plasma P06850 is associated with pre - mature delivery . Zeranol or α - zearalanol is a mycotoxin produced by fungi in the Fusarium family . Unlike other mycotoxins , exposure to zeranol appears to have minimal health risk . In North America , it is used as a growth - promoting agent in livestock . Because of the health concern of zeranol residue in meat , this practice has not been adopted in Europe . In our study zeranol could induce P06850 protein expression in JEG - 3 cells as low as 0 . 1nM . As electrophoretic mobility shift assay indicated an increase in the CRE binding activity in P06850 promoter , the induction was likely triggered by transcriptional regulation . We further looked into the signal transduction pathway and PKCδ and P27361 / 2 were found to be activated . This study showed that zeranol could increase P06850 expression in placental cells , and the findings might be a concern for pregnant women .", "Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK46___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .", "Monocyte - mediated suppression of P60568 - induced NK - cell activation . Regulation by P08908 - type serotonin receptors . In the present study , the effects of serotonin on human natural killer ( NK ) - cell responsiveness to interleukin 2 ( P60568 ) was investigated . Concomitant treatment of human lymphocytes , enriched for NK effector cells by Percoll density - gradient centrifugation , with serotonin and P60568 yielded a synergistic activation of NK - cell cytotoxicity ( NKCC ) in the presence but not in the absence of monocytes . The monocyte - dependent , regulatory effects of serotonin and / or P60568 were prostaglandin - independent and could be reconstituted when monocytes , recovered by countercurrent centrifugal elutriation ( CCE ) , were added to purified NK effector cells . The effects of serotonin on baseline and P60568 - activated NK cells were mimicked by the P08908 receptor - specific agonists 8 - OH - DPAT and (+)- Q9UM73 . Our data suggest that serotonin regulates NK - cell responsiveness to P60568 via P08908 receptors .", "Altered balance between effector T cells and Q9BZS1 + Q9UKS7 + regulatory T cells after thymoglobulin induction in kidney transplant recipients . This study examined the effect of thymoglobulin induction therapy on leukocyte population dynamics in kidney transplant patients . Patients receiving standard immunosuppression were compared with those who received additional thymoglobulin at the time of kidney transplantation . DB00098 induction led to an immediate and significant decrease of all T cells and NK cells , but not B cells or monocytes . CD8 (+) T cells recovered to near pretransplant level by 4 weeks post - transplant . P01730 (+) T cells remained at less than 30 % of pretransplant level for the entire study period of 78 weeks . Both P01730 (+) and CD8 (+) T cells showed reduced cytokine production after recovery . Deletion of P01730 (+) Q9BZS1 (+) Q9UKS7 (+) regulatory T cells ( Tregs ) was less profound than that of P01730 (+) Q9BZS1 (-) cells , thus the relative percentage of Tregs elevated significantly when compared with pretransplant levels in thymoglobulin - treated patients . In contrast , the percentages of Tregs and their expression of Q9BZS1 in the standard immunosuppression group decreased steadily and by 12 weeks after transplant the average percentage of Tregs was 56 % of the pretransplant level . Thus , thymoglobulin - induced deletion of T cells led to significant and long - lasting alterations of the T - cell compartment characterized by a preservation of Tregs and long - lasting reduction in P01730 (+) , and potentially pathogenic , T cells .", "___MASK90___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .", "Low - dose rabbit antithymocyte globulin induction therapy results in prolonged selective lymphocyte depletion irrespective of maintenance immunosuppression . Rabbit antithymocyte globulin therapy ( DB00098 ) is a potent lymphocyte - depleting agent commonly used following renal transplantation to reduce the risk of acute rejection . Standard doses ( 7 - 10 mg / kg ) of DB00098 result in profound lymphopenia and predispose patients to infection and malignancy . The effects of lower doses of DB00098 ( LoD - DB00098 , 3 - 5 mg / kg ) on peripheral blood lymphocytes ( PBL ) are as yet unknown . In this prospective clinical trial , PBL subsets were characterized by flow cytometry over 12 months following LoD - DB00098 therapy . All patients were initially treated with standard doses of tacrolimus , mycophenolic acid , and prednisone . At 3 months , patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence . LoD - DB00098 therapy resulted in prolonged suppression of P15391 + B cells , total CD3 + T cells , as well as naïve and memory P01730 + T cell and P01730 / CD25 / Foxp3 + T - regulatory subsets irrespective of chronic immunosuppressive therapy . Selective depletion was only noted in the CD4CD45RA + naïve T - cell subset resulting in an altered memory / naïve P01730 + ratio . LoD - DB00098 failed to deplete CD8 + T cells , which increased their relative contribution to the total CD3 + pool . All other lymphocyte subsets maintained near normal proportions . Thus , LoD - DB00098 therapy may lessen the adverse effects of full dose DB00098 while maintaining overall efficacy .", "Risk factors for impaired P01730 + T - cell reconstitution following rabbit antithymocyte globulin treatment in kidney transplantation . To describe long - term P01730 + T - cell reconstitution after rabbit antithymocyte globulin ( DB00098 ) treatment and identify predictive factors following kidney transplantation . A single - center retrospective study analyzed lymphocyte subsets in DB00098 - treated kidney transplant recipients ( 1986 - 2009 ) . 589 patients were analyzed ( maximum follow - up 21 years ) . A comparator group ( n = 298 ) received an anti - P60568 receptor monoclonal antibody . P01730 + T - cell lymphopenia ( < 200 / mm3 ) was present in 48 . 5 % , 9 . 2 % , 6 . 7 % , 2 . 0 % , and 0 % of patients at one , three , five , 10 , and 20 years post - transplant , respectively . P01730 + T - cell count increased during the first 10 years but remained below the pretransplant count even after 20 years . At 1 , 3 , and 6 months post - transplant , mean P01730 + T - cell count was significantly lower in patients with P01730 + T - cell lymphopenia at 12 months versus patients without lymphopenia . On multivariate analyses , significant independent predictors for long - term impaired P01730 T - cell reconstitution were recipient age , pretransplant P01730 + T - cell count , 12 - month P01730 + T - cell count , and tacrolimus or DB00688 therapy . Recipient age > 40 years was identified as a cutoff point . P01730 + T - cell reconstitution following DB00098 treatment remains impaired even after 21 years . Most risk factors for long - term impaired P01730 + T - cell reconstitution may be evaluated pretransplant or are modifiable post - transplant .", "Modulation of the P22301 / IL - 12 cytokine circuit by interferon - beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis . IFN - beta has been shown to be effective in the treatment of multiple sclerosis ( MS ) . However , the primary mechanism by which IFN - beta mediates its therapeutic effect remains unclear . Recent studies indicate that under defined conditions , IFN - beta may downregulate DC expression of IL - 12 . We and others have shown that IFN - beta may also downregulate P22301 . In light of the recently proposed paradigm that an P22301 / IL - 12 immunoregulatory circuit controls susceptibility to autoimmune disease , we examined the effect of IFN - beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis ( EAE ) , an animal model sharing many features with MS . SWXJ mice were immunized with the immunodominant p139 - 151 determinant of myelin proteolipid protein ( PLP ) , and at onset of EAE were treated every other day with IFN - beta . After eight weeks of treatment , we assessed autoreactivity and observed no significant IFN - beta effect on splenocyte proliferation or splenocyte production of P01579 , P60568 , P05112 , or P05113 in response to the priming determinant used to initiate disease . However , in IFN - beta treated mice , the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of P22301 and a concurrent decreased production of IL - 12 . Moreover , the in vivo modulation of the P22301 / IL - 12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading . Our results indicate that IFN - beta induces a reciprocal modulation of the P22301 / IL - 12 cytokine circuit in vivo . This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self - priming thereby inhibiting the progression of disease associated with epitope spreading .", "Acute and chronic vascular rejection in nonhuman primate kidney transplantation . A nonhuman primate ( NHP ) study was designed to evaluate in nonlife - supporting kidney allografts the progression from acute rejection with transplant endarteritis ( TXA ) to chronic rejection ( CR ) with sclerosing vasculopathy . Group P55008 ( n = 6 ) received high cyclosporine A ( DB00091 ) immunosuppression and showed neither TXA nor CR during 90 days post - transplantation . Group G2 ( n = 6 ) received suboptimal DB00091 immunosuppression and showed severe TXA with graft loss within 46 days ( median ) . Arterial intimal changes included infiltration of macrophages and T lymphocytes ( CD3 , P01730 , CD8 ) with few myofibroblasts , abundant fibronectin / collagen IV , scant collagens I / III , high rate of cellular proliferation and no C4d accumulation along peritubular capillaries . Group P46379 ( n = 12 ) received suboptimal DB00091 and anti - rejection therapy ( DB00098 + methylprednisolone + DB00091 ) of TXA . Animals developed CR and lost grafts within 65 days ( median ) . As compared to G2 , the arterial intimal changes showed less macrophages and T lymphocytes , an increased number of myofibroblasts , abundant fibronectin / collagen IV and scar collagens I / III , C4d deposition along capillaries in 60 % of animals and transplant glomerulopathy in 80 % of animals . In conclusion , CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts , and progressive deposition of collagens in the intima . Our experimental design appears well suited to study events leading to CR .", "Demethoxycurcumin suppresses migration and invasion of MDA - MB - 231 human breast cancer cell line . Demethoxycurcumin ( Q6UXB2 ) is one of the main active compounds of curcuminoids found in turmeric powder , which is used as a spice in Asian cooking and traditional medicine . Recent studies reveal that Q6UXB2 has several biological activities including anti - inflammation and anti - cancer activities . However , the molecular mechanism by which Q6UXB2 has anti - metastasis activity in breast cancer cells remains poorly understood . Here , we report for the first time that Q6UXB2 inhibited adhesion , migration and invasion of MDA - MB - 231 human breast cancer cells . For cancer cell migration and invasion , extracellular matrix ( Q13201 ) degradation processes are required . MDA - MB - 231 cells treated with Q6UXB2 had decreased levels of Q13201 degradation - associated proteins including matrix metalloproteinase - 9 ( P14780 ) , membrane type - 1 matrix metalloproteinase ( P50281 ) , urokinase plasminogen activator ( uPA ) and uPA receptor ( Q03405 ) , while the level of uPA inhibitor ( P05121 ) was up - regulated . Moreover , Q6UXB2 also reduced the expression of intercellular adhesion molecule - 1 ( P05362 ) and chemokine receptor 4 , ( P61073 ) , which is involved in modulation of the tumor metastasis process . We also found that Q6UXB2 treatment inhibited the DNA binding activity of nuclear factor - kappa B ( NF - kappaB ) , which is known to mediate the expression of MMPs , uPA , Q03405 , P05362 , and P61073 . These findings strongly suggest that the mechanism of Q6UXB2 - mediated anti - invasive activity involves modulation of the expression of invasion - associated proteins , possibly by targeting NF - kappaB in MDA - MB - 231 cells .", "The ischemic preconditioning paradox in deceased donor liver transplantation - evidence from a prospective randomized single blind clinical trial . While animal studies show that ischemic preconditioning ( IPC ) is beneficial in liver transplantation ( LT ) , evidence from few smaller clinical trials is conflicting . From October 2003 to July 2006 , 101 deceased donors ( DD ) were randomized to 10 min IPC ( n = 50 ) or No IPC ( n = 51 ) . Primary objective was efficacy of IPC to decrease reperfusion ( RP ) injury . Both groups had similar donor risk index ( DRI ) ( 1 . 54 vs . 1 . 57 ) . Aminotransferases on days 1 and 2 were significantly greater ( p < 0 . 05 ) in IPC recipients . In multivariate analyses , IPC had an independent effect only on day 2 aspartate transferase . P00734 time , bilirubin and histological injury were similar in both groups . IPC had no significant effect on plasma P01375 , P05231 and P22301 in the donor and P01375 and P05231 in the recipient . In contrast , IPC recipients had a significant rise in systemic P22301 levels after RP ( p < 0 . 05 ) and had fewer moderate / severe rejections within 30 days ( p = 0 . 09 ) . Hospital stay was similar in both groups . One - year patient and graft survival in IPC versus No IPC were 88 % versus 78 % ( p = 0 . 1 ) and 86 versus 76 % ( p = 0 . 25 ) , respectively . IPC increases RP injury after DDLT , an ' IPC paradox ' . Other potential benefits of IPC are limited . IPC may be more effective in combination with other preconditioning regimens .", "The effect of different ATG preparations on immune recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia . Anti - thymocyte globulin ( ATG ) is widely used in the conditioning regimen before allogeneic stem cell transplantation for aplastic anemia . However , there are several different preparations of ATG and little is known about the difference of their effects on transplantation outcome . Therefore , in this study , we retrospectively compared the effect of two different DB00098 preparations [ DB00098 ( ATG - G ) and ATG - Fresenius ( ATG - F ) ] on immune recovery and cytomegalovirus infection after transplantation . The conditioning regimen was a combination of fludarabine , cyclophosphamide , and ATG . Low dose total body irradiation was added in alternative donor transplantation . Four patients received ATG - F at 5 mg / kg / day from day - 7 to day - 3 , whereas ATG - G was given at 2 . 5 mg / kg / day from day - 5 to day - 2 in three patients . There was no graft rejection and no grade II - IV acute graft - versus - host disease . All three patients in the ATG - G group developed positive cytomegalovirus antigenemia including two with high - grade antigenemia , whereas two of the four patients in the ATG - F group were persistently negative . Immunological evaluation on day 60 revealed that both P01730 + and CD8 + T - cell recoveries were delayed in the ATG - G group . These findings suggested that ATG - G has a stronger immunosuppressive activity than the ATG - F with a dose ratio of 1 : 2 . 5 .", "Polyclonal rabbit antithymocyte globulin exhibits consistent immunosuppressive capabilities beyond cell depletion . BACKGROUND : Polyclonal antithymocyte globulins ( ATGs ) are used clinically to prevent and treat acute allograft rejection and are believed to modulate the immune response primarily by depleting T cells . However , nondepleting mechanisms may also be important mediators of graft survival . In the present study , 14 lots of thymoglobulin ( DB00098 ) were analyzed and compared for nondepletive immunomodulatory activities in vitro . METHODS : Coincubation of human peripheral blood mononuclear cells with thymoglobulin induces P01730 + CD25 ( high ) Foxp3 + regulatory T cells , which were evaluated for consistent ability to suppress T - cell activation in mixed lymphocyte reactions . The consistency of P06729 , CD3 , CD11a , and P08575 antigen specificities in thymoglobulin was determined using flow cytometry to measure inhibition of fluorescent monoclonal antibody binding to Jurkat T cells . A transwell chemotaxis assay was established and used to evaluate ATG - mediated inhibition of stromal cell - derived factor ( SDF ) - 1alpha - driven Jurkat T - cell migration . RESULTS : Physiologic levels of thymoglobulin produced nondepletive immunomodulatory activities , which were consistent from batch to batch . All lots of thymoglobulin induced functionally immunosuppressive regulatory T cells and inhibited monoclonal antibody binding to key T - cell surface antigens . In addition , these studies provide the first demonstration that thymoglobulin effectively inhibits P61073 / SDF - 1alpha - driven T - cell chemotaxis . CONCLUSIONS : This novel , systematic in vitro analysis of 14 different manufactured lots of thymoglobulin demonstrates the overall consistency of this product and provides further insights into nondepletive mechanisms by which thymoglobulin may generate durable immunoregulation and allograft survival .", "Murine antithymocyte globulin T - cell depletion is mediated predominantly by macrophages , but the Fas / P48023 pathway selectively targets regulatory T cells . BACKGROUND : DB00098 is a T - cell - depleting polyclonal rabbit anti - human thymocyte antibody used clinically for immunosuppression in solid organ and hematopoietic stem - cell transplantation . By using a surrogate rabbit anti - mouse thymocyte globulin ( mATG ) , we previously demonstrated that murine regulatory and memory T cells are preferentially spared from mATG depletion in vivo . The current studies were designed to determine whether different effector mechanisms are involved in differential depletion of T - cell subsets by mATG . METHODS : Complement - dependent cytotoxicity , antibody - dependent cellular cytotoxicity ( ADCC ) , and apoptotic mechanisms of depletion by mATG were evaluated in vitro and in vivo . RESULTS : In vitro , there was evidence of differential susceptibility of T - cell subsets by different effector mechanisms where naïve and P01730 effector memory T cells show reduced susceptibility to apoptosis , whereas regulatory T cells are less susceptible to mATG - mediated complement - dependent cytotoxicity and ADCC . However , mATG treatment of mice depleted of ADCC effector cell types ( neutrophils , natural killer cells , or macrophages ) or deficient in complement P01031 or Fas demonstrated that mATG depletion of all T - cell subsets is mediated primarily by macrophages and that the role of neutrophils , natural killer cells , and complement is minimal in vivo . Interestingly , the Fas / P48023 pathway does play a role in regulatory T - cell depletion , which is likely a result of increased basal expression of Fas on these cells . CONCLUSIONS : These data suggest that macrophages deplete most T cells by mATG in mice , but regulatory T cells are also uniquely susceptible to mATG - mediated Fas - dependent depletion .", "ATG induction in renal transplant recipients : Long - term hazard of severe infection is associated with long - term functional T cell impairment but not the ATG - induced P01730 cell decline . BACKGROUND AND METHODS : We showed previously that DB00098 induction induces a strong decrease of P01730 + T cells together with impaired in vitro P60568 secretion up to 1 year post - transplant . To further characterize long - term immunological effects of ATG induction 2 and 5 years post - transplant , we used sensitive intracellular cytokine analysis in the same prospective study of 84 renal transplant recipients ( ATG , n = 44 ) . RESULTS : A significantly increased frequency of severe infectious disease ( HR = 2 . 0 , p = 0 . 027 ) as well as suppressed T cell functions were found within 2 years after ATG induction but not beyond ( logistic regression ( logreg ) : P01730 cell P22301 responses , p = 0 . 064 ; T cell proliferation , p = 0 . 038 ) . Impaired T cell proliferation at 2 years was associated with occurrence of severe infection ( p = 0 . 017 ) . Importantly , a strong and persistent decrease of P01730 cell counts ( p < 0 . 0005 at 5 years ) was independently associated with ATG induction ( logreg p = 0 . 002 ) but not related to functional P01730 cell impairment ( helper activity / cytokine production ) or an increased risk of infection . CONCLUSIONS : Severe infection up to 2 years after ATG induction was associated with impaired T cell proliferative capacity but not with the profound decline in P01730 cell counts that occurred after ATG induction and persisted up to 5 years .", "Rabbit anti - rat thymocyte immunoglobulin preserves renal function during ischemia / reperfusion injury in rat kidney transplantation . Ischemia / reperfusion ( I / R ) injury is an important cause of renal graft dysfunction in humans . Increases in cold and warm ischemia times lead to a higher risk of early post - transplant complications including delayed graft function and acute rejection . Moreover , prolonged cold ischemia is a predictor of long - term kidney graft loss . The protective effect of rabbit anti - rat thymocyte immunoglobulin ( DB00098 ) was evaluated in a rat model of I / R injury following syngeneic kidney transplantation . Serum creatinine concentration was evaluated at 16 h and 24 h post - transplant . Animals were sacrificed 24 h post - transplant for evaluation of histology , infiltrating leukocytes , nitrotyrosine staining , and apoptosis . DB00098 was effective in preventing renal function impairment , tissue damage and tubular apoptosis associated with I / R only when was given 2 h before transplantation but not at the time of reperfusion . Pretransplant DB00098 treatment of recipient animals effectively reduced the amount of macrophages , P01730 (+) , CD8 (+) T cells and LFA - 1 (+) cells infiltrating renal graft subjected to cold ischemia as well as granzyme - B expression within ischemic kidney . On the other hand , granulocyte infiltration and oxidative stress were not modified by DB00098 . If these results will be translated into the clinical setting , pretransplant administration of Thymoglobuline (®) could offer the additional advantage over peri - transplant administration of limiting I / R - mediated kidney graft damage .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK46___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "Rabbit ATG but not horse ATG promotes expansion of functional P01730 + CD25highFOXP3 + regulatory T cells in vitro . Regulatory T cells ( Treg ) play important roles in suppressing immune responses and maintaining tolerance . Rabbit antithymocyte globulin ( DB00098 ) and horse ATG ( hATG ) are widely used in the treatment of immune - mediated syndromes , but their effects on Treg are unknown . We show here that in vitro culture of normal human peripheral blood mononuclear cells ( PBMCs ) with a low - dose DB00098 resulted in marked expansion of functional Treg by converting P01730 + CD25 - T cells to P01730 + CD25 + T cells . hATG did not expand but rather decreased Treg . Immuno - blot showed increased expression of Q9BZS1 and Q13469 in P01730 + CD25 - and P01730 + CD25 + T cells exposed to DB00098 . PBMCs treated with DB00098 displayed increased interleukin - 10 in culture supernatants than those treated with hATG . Furthermore , DB00098 and hATG showed differences in their potential to stimulate P01730 + T cells as examined using different activation markers . Microarray revealed that DB00098 induced markedly different gene - expression patterns in PBMCs , compared with hATG - treated or untreated PBMCs . Our findings indicate that DB00098 expanded Treg , probably through transcriptional regulation by enhanced Q13469 expression , in turn conferring P01730 + CD25 - T cell Q9BZS1 expression and regulatory activity . The therapeutic effects of DB00098 may occur not only because of lymphocyte depletion but also enhanced Treg cell number and function .", "Significance of immune cell function monitoring in renal transplantation after DB00098 induction therapy . Monitoring of immune status in transplant recipients is essential for predicting the risk of rejection or infection . In this study , we assessed the significance of immune cell function in 76 renal allograft recipients after DB00098 induction and initiation of maintenance immunosuppression . Using the Immuknow ( Cylex Inc ) assay , the amount of adenosine triphosphate ( DB00171 ) produced by P01730 + cells in response to phytohemagglutinin ( PHA ) was measured in patients whole blood . In parallel , the frequency and phenotype of P01730 + T cells were determined by flow cytometry . The Immuknow assay yielded paradoxically high DB00171 values during the first 3 months post - transplantation , despite very low P01730 + T cell counts . High DB00171 values were caused by peripheral blood myeloid cells , did not predict rejection , and occurred primarily in transplant recipients who received darbepoietin ( p = 0 . 017 ) . P01730 + T cells displayed predominantly an activated / memory phenotype and comprised a subpopulation of CD25 + Q9BZS1 + cells . Over the first 5 months post - transplantation , mean DB00171 activity gradually decreased , whereas P01730 + T cell counts slowly increased . Low DB00171 values were predictive of infection ( p = 0 . 002 ) . Thus Immuknow results need to be interpreted with caution in patients receiving DB00098 induction therapy . Although low DB00171 levels identify patients at increased risk for infection , high DB00171 values fail to correlate with rejection and do not justify increased immunosuppression .", "Effect of different induction strategies on effector , regulatory and memory lymphocyte sub - populations in clinical islet transplantation . This prospective study assessed lymphocyte subsets in the peripheral blood of 42 islet allograft recipients using flow cytometry from 2 weeks and up to 2 years post - transplantation . Subjects received daclizumab ( n = 16 ) , DB00098 ( n = 12 ) or alemtuzumab ( n = 14 ) . DB00087 was associated with an early ( within 1 month ) and transient ( up to 6 months ) increase in the frequency of CD3 (+) P01730 (+) Foxp3 (+) T cells , while daclizumab induced a near complete loss of these cells ( P < or = 0 . 001 ) . The frequency of memory P01730 (+) T cells was increased following depleting immunosuppression induction with either DB00098 or alemtuzumab ( P < or = 0 . 05 ) , but remained unchanged while using daclizumab . DB00087 induction resulted in a significant loss of memory B lymphocytes when compared with the other induction groups ( P < or = 0 . 001 ) . While the clinical significance of these findings remains to be fully determined , the observed altered balance between effector , regulatory and memory cells suggests that the immune status of patients will be affected according to the induction strategy chosen .", "Preferential increase in memory and regulatory subsets during T - lymphocyte immune reconstitution after DB00098 induction therapy with maintenance sirolimus vs cyclosporine . BACKGROUND : DB00877 maintenance therapy with DB00098 induction is a promising regimen that may preserve renal function . Data are lacking , however , about the immunologic effects of combined DB00098 - sirolimus . METHODS : In a 12 - month , prospective , randomised , open - label , single - centre pilot study , de novo deceased - donor kidney transplant patients were randomised to receive cyclosporine or sirolimus , with DB00098 induction , mycophenolate mofetil and corticosteroids . Flow cytometry analysis of peripheral blood was used to evaluate immune reconstitution . RESULTS : Nineteen patients were recruited ( sirolimus 9 , cyclosporine 10 ) . Reconstitution of the P01730 (+) T - lymphocyte subset was significantly lower with sirolimus versus cyclosporine over year 1 , but CD8 (+) reconstitution did not differ significantly between groups . The proportion of naïve P01730 (+) T - lymphocytes showed an initial decrease with sirolimus versus cyclosporine . Naïve CD8 (+) T - lymphocytes increased versus baseline in the cyclosporine cohort at months 1 and 3 , but remained unchanged with sirolimus . Memory P01730 (+) T - lymphocytes occurred more frequently in sirolimus - versus cyclosporine - treated patients during year 1 . The proportion of memory CD8 (+) T - lymphocytes decreased at months 1 and 3 compared to baseline in the DB00091 arm , but did not change in the sirolimus cohort . By month 12 , the proportion of both naïve and memory P01730 (+) and CD8 (+) T - lymphocytes had become similar with sirolimus or cyclosporine . There were fewer naïve B - lymphocytes in the sirolimus cohort and more P15391 (-) IgD (+/-) P26842 (+) memory B - lymphocytes . CONCLUSIONS : In this small population , homeostatic reconstitution after DB00098 induction showed disproportionately high recovery of memory T - lymphocyte subsets during sirolimus therapy , which may explain the higher rejection rate seen with sirolimus versus cyclosporine following kidney transplantation .", "Q01718 distribution and modulation among murine mononuclear leukocyte populations . Murine mononuclear leukocytes express adrenocorticotropin ( ___MASK17___ ) receptors that were recognized by a monospecific antiserum to the Q01718 on Y - 1 adrenal cells . The antiserum was utilized in an immunofluorescence ( IF ) assay to characterize the distribution of ___MASK17___ receptors on resting murine mononuclear leukocyte populations . Forty - seven percent of spleen cells , 32 % of lymph node cells , and 1 % of thymocytes constitutively expressed ___MASK17___ receptors . Separation of lymphocytes into purified B cell and T cell populations , followed by IF analysis revealed that 47 % of B cells and 23 % of T cells possessed ___MASK17___ receptors . Helper T cells ( P01730 + T cells ) constituted the majority of Q01718 - positive T lymphocytes . Furthermore , 47 % of resident peritoneal macrophages , purified by adherence to plastic , expressed ___MASK17___ receptors . The T - lymphocyte mitogen , concanavalin A , interferon gamma , and ___MASK17___ enhanced Q01718 expression . The differential distribution of Q01718 - positive cells among specific leukocyte populations explains in part why differential cellular responses are observed and implies important regulatory functions for these receptors in the generation or regulation of immune responses .", "Anti - P08575 antibody enhances lipoxygenase pathway of human naïve mononuclear cells and cyclooxygenase pathway of neutrophils . OBJECTIVE AND DESIGN : Anti - P08575 antibody exhibits multiple biological effects on human mononuclear cells ( MNC ) and polymorphonuclear neutrophils ( PMN ) . We intended to determine whether anti - P08575 antibody could affect arachidonic acid metabolism and thereby , the interactions between human naïve MNC and PMN . MATERIALS AND METHODS : Human naïve MNC and PMN were incubated with monoclonal anti - human P08575 IgG F ( ab ')( 2 ) antibody or non - specific IgG F ( ab ')( 2 ) for 30 min . The mRNA expression of cyclooxygenase type 1 ( P23219 ) , type 2 ( P35354 ) , P09917 ( 5 - P28300 ) and leukotriene A ( 4 ) hydrolase ( P01374 ( 4 ) hydrolase ) in both cells was detected by RT - PCR and quantified by densitometric determination . The presence of P23219 and P35354 molecules in the cells was detected by Western blot . The concentration of PGE ( 2 ) and Q06643 ( 4 ) in cultured supernatants was measured by EIA kits . RESULTS : Anti - P08575 IgG F ( ab ')( 2 ) up - regulated P01374 ( 4 ) hydrolase mRNA expression and Q06643 ( 4 ) production , but down - regulated P23219 and P35354 mRNA expression and DB00917 production , of naïve MNC compared to non - specific IgG F ( ab ')( 2 ) . In contrast , a reverse modulation by the specific antibody on PMN was observed including up - regulation of cyclooxygenase pathway and down - regulation of lipoxygenase pathway . CONCLUSIONS : A novel activity of anti - P08575 with reverse modulation on cyclooxygenase / lipoxygenase pathways was found such that the expression of P23219 and P35354 in PMN , and 5 - P28300 and P01374 ( 4 ) hydrolase in MNC were enhanced .", "A proliferation switch for genetically modified cells . Receptor dimerization is the key signaling event for many cytokines , including erythropoietin . A system has been recently developed that permits intracellular protein dimerization to be reversibly activated in response to a lipid - soluble dimeric form of the drug FK506 , called FK1012 . FK1012 is used as a pharmacological mediator of dimerization to bring together FK506 binding domains , taken from the endogenous protein P62942 . In experiments reported herein , FK1012 - induced dimerization of a fusion protein containing the intracellular portion of the erythropoietin receptor allowed cells normally dependent on interleukin 3 to proliferate in its absence . FK506 competitively reversed the proliferative effect of FK1012 but had no influence on the proliferative effect of interleukin 3 . Signaling pathways activated by FK1012 mimicked those activated by erythropoietin , because both O60674 and P42229 were phosphorylated in response to FK1012 . This approach may provide a means to specifically and reversibly stimulate the proliferation of genetically modified cell populations in vitro or in vivo .", "Expression of Th2 - skewed pathology mediators in monocyte - derived type 2 of dendritic cells ( DC2 ) . The information conveyed from dendritic cells ( DCs ) to naïve P01730 (+) T cells has crucial influence on their differentiation toward effector T cells . In an effort to identify DC - derived molecules directly contributing to T cell differentiation , we searched for molecules distinctively expressed between two DC subtypes , which were differentiated from peripheral monocytes by cultivation with GM - P04141 ( for Q9NPG8 ) or P08700 ( for DC2 ) in the presence of P05112 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells , respectively . As the first step to address this issue , we subtracted Q9NPG8 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2 , whose products are known to reside in other than the nucleus . Intriguingly , many of them were molecules involved in Th2 - skewed disease pathologies , such as P02751 , P38570 , Q14956 , Q03405 , P25089 , Q8NHJ6 , P05121 , P16050 , P24557 , P19878 , P10147 , P18510 , P09486 , and Q9NY15 , suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations . We also found that expressions of Q02318 , O14495 , Q8WXG1 , and O15438 were up - regulated in DC2 , implying their significant function in Th2 - deviated states . The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC - derived key molecules for T cell differentiation .", "DB00207 suppresses P01730 (+) T - cell activation by direct modulation of P42345 activity . Advanced macrolides , such as azithromycin ( AZM ) or clarithromycin ( Q5W186 ) , are antibiotics with immunomodulatory properties . Here we have sought to evaluate their in vitro influence on the activation of P01730 (+) T - cells . Isolated P01730 (+) T - cells were stimulated with agonistic anti - CD3 / anti - P10747 monoclonal antibodies in the presence of 0 . 6 mg / L , 2 . 5 mg / L , 10 mg / L or 40 mg / L AZM or Q5W186 . Cell proliferation , cytokine level in supernatants and cell viability was assessed . Intracellular signaling pathways were evaluated using reporter cell lines , FACS analysis , immunoblotting and in vitro kinase assays . AZM inhibited cell proliferation rate and cytokine secretion of P01730 (+) T - cells in a dose - dependent manner . Similarly , high concentrations of Q5W186 ( 40 mg / L ) also suppressed these T - cell functions . Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein , a downstream target of P42345 . This effect was also observed at 40 mg / L Q5W186 . In vitro kinase studies using recombinant P42345 showed that AZM inhibited P42345 activity . In contrast to rapamycin , this inhibition was independent of P62942 . We show for the first time that AZM and to a lesser extent Q5W186 act as immunosuppressive agents on P01730 (+) T - cells by inhibiting P42345 activity . Our results might have implications for the clinical use of macrolides .", "P35354 induction and prostacyclin release by protease - activated receptors in endothelial cells require cooperation between mitogen - activated protein kinase and NF - kappaB pathways . The functional significance of protease - activated receptors ( PARs ) in endothelial cells is largely undefined , and the intracellular consequences of their activation are poorly understood . Here , we show that the serine protease thrombin , a P25116 - selective peptide ( TFLLRN ) , and SLIGKV ( P55085 - selective peptide ) induce cyclooxygenase - 2 ( P35354 ) protein and mRNA expression in human endothelial cells without modifying P23219 expression . P35354 induction was accompanied by sustained production of 6 - keto - PGF1alpha , the stable hydrolysis product of prostacyclin , and this was inhibited by indomethacin and the P35354 - selective inhibitor NS398 . P25116 and P55085 stimulation rapidly activated both P27361 / 2 and p38MAPK , and pharmacological blockade of MEK with either PD98059 or U0126 or of p38MAPK by SB203580 or SB202190 strongly inhibited thrombin - and SLIGKV - induced P35354 expression and 6 - keto - PGF1alpha formation . Thrombin and peptide agonists of P25116 and P55085 increased luciferase activity in human umbilical vein endothelial cells infected with an NF - kappaB - dependent luciferase reporter adenovirus , and this , as well as PAR - induced 6 - keto - PGF1alpha synthesis , was inhibited by co - infection with adenovirus encoding wild - type or mutated ( Y42F ) P25963 . Thrombin - and SLIGKV - induced P35354 expression and 6 - keto - PGF1alpha generation were markedly attenuated by the NF - kappaB inhibitor PG490 and partially inhibited by the proteasome pathway inhibitor MG - 132 . Activation of P25116 or P55085 promoted nuclear translocation and phosphorylation of p65 - NF - kappaB , and thrombin - induced but not P55085 - induced p65 - NF - kappaB phosphorylation was reduced by inhibition of MEK or p38MAPK . Activation of Q96RI0 by AYPGKF increased phosphorylation of P27361 / 2 and p38MAPK without modifying NF - kappaB activation or P35354 induction . Our data show that P25116 and P55085 , but not Q96RI0 , are coupled with P35354 expression and sustained endothelial production of vasculoprotective prostacyclin by mechanisms that depend on P27361 / 2 , p38MAPK , and P25963 - dependent NF - kappaB activation .", "Regulatory T cells in kidney transplant recipients : the effect of induction immunosuppression therapy . BACKGROUND : Regulatory T cells have been suggested to down - regulate the alloimmune response . The aim of this prospective open study was to evaluate the effects of different inductive agents on peripheral blood regulatory T cells in kidney transplant patients and to analyse their association with short - term graft outcome . METHODS : Regulatory and effector T cell numbers in peripheral blood were determined by flow cytometry in 71 prospectively followed kidney transplant recipients at postoperative day 0 , 7 , 14 , 21 , 28 , 60 and 90 . Patients were treated with a calcineurin inhibitor - based triple immunosuppression with polyclonal rabbit anti - thymocyte globulin ( DB00098 , n = 28 ) , basiliximab , the anti - CD25 monoclonal antibody ( n = 18 ) or without induction ( controls , n = 25 ) . Flow cytometry data were correlated to rejection incidence . RESULTS : Compared to controls , P01730 (+) CD25 (+) FoxP3 (+) regulatory T - cell expansion among P01730 (+) T cells was noticed in the DB00098 group at all post - transplant time - points by Day 14 ( P < 0 . 001 ) . A significant decrease in Treg frequency ( P < 0 . 001 ) and concurrently a transient increase of P01730 (+) CD25 ( low /-) FoxP3 (+) population were observed in basiliximab - treated patients 7 - 60 days post - transplantation . Biopsy - proven acute rejection occurred in 16 . 7 % of controls , 10 . 7 % of the DB00098 group and in 11 . 1 % of the basiliximab group . Higher P01730 (+) FoxP3 (+)/ CD8 (+) CD45RA (+) CD62L (-) ratios were observed repeatedly in those patients after basiliximab induction who were rejection free ( P < 0 . 01 ) . CONCLUSIONS : In this study , the DB00098 induction therapy was associated with an expansion of regulatory cells . Sustained high P01730 (+) FoxP3 (+)/ Teff ratios were associated with the absence of rejection after basiliximab induction .", "Rapid T cell repopulation after rabbit anti - thymocyte globulin ( DB00098 ) treatment is driven mainly by cytomegalovirus . Rabbit anti - thymocyte globulin ( DB00098 ) induces a long - lasting lymphocytopenia . P01730 (+) T cells remain depleted for up to 2 years , whereas the CD8 (+) T cell compartment is refilled rapidly by highly differentiated P26842 (-) CD45RA (+) CD57 (+) effector - type cells . Because the presence of these highly differentiated CD8 (+) T cells has been associated with cytomegalovirus ( CMV ) infection , we questioned to what extent restoration of CMV T cell immunity contributes to the re - emergence of T cells following DB00098 treatment . We compared T cell repopulation in six CMV - seropositive patients with CMV reactivation ( reactivating CMV (+) ) to that in three CMV (+) patients without reactivation ( non - reactivating CMV (+) ) , and to that in three CMV - seronegative recipients receiving a kidney from a CMV - seronegative donor ( CMV (-/-) ) . All patients received DB00098 because of acute allograft rejection . Total P01730 and CD8 counts , frequency and phenotype of virus - specific CD8 (+) T cells were determined . In reactivating CMV (+) patients , total CD8 (+) T cells reappeared rapidly , whereas in non - reactivating CMV (+) patients they lagged behind . In CMV (-/-) patients , CD8 (+) T cell counts had not yet reached pretransplant levels after 2 years . CMV reactivation was indeed followed by a progressive accumulation of CMV - specific CD8 (+) T cells . During lymphocytopenia following DB00098 treatment , serum interleukin ( IL ) - 7 levels were elevated . Although this was most prominent in the CMV - seronegative patients , it did not result in an advantage in T cell repopulation in these patients . Repopulated CD8 (+) T cells showed increased skewing in their Vβ repertoire in both CMV (-/-) and reactivating CMV - seropositive patients . We conclude that rapid T cell repopulation following DB00098 treatment is driven mainly by CMV .", "Rabbit anti T - lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells , while hematopoetic stem cells are apoptosis resistant . Polyclonal anti - T - lymphocyte globulins ( ATG ) are used in allogeneic stem cell transplantation ( P09683 ) for the prophylaxis of graft versus host disease ( GVHD ) by in vivo T cell depletion . In this study we investigated the complement independent induction of apoptosis by DB00098 in peripheral blood mononuclear cell ( PBMNC ) compartments and hematopoetic stem cells ( P19526 ) . We also detected antileukemic activity of ATG by measuring apoptosis in myeloid and lymphatic leukemia cell lines and primary leukemia cells . We found ATG to induce apoptosis in T - lymphocytes ( P01730 (+) , CD8 + ) , B - lymphocytes ( P11836 + ) , natural killer ( NK ) - cells ( CD56 (+) ) , and monocytes ( P08571 (+) ) . P19526 , in contrast , were apoptosis resistant and could be growth stimulated by low - dose ATG in the presence of bystander cells . The human leukemia cell lines Jurkat , Daudi , DG - 75 ( lymphoblastic ) , and K562 , HL - 60 , KG1 , and U937 ( myeloblastic ) underwent ATG - induced apoptosis , whereas the NK - cell line YT was resistant . Primary leukemia cells from 6 investigated patients with acute lymphoblastic leukemia , 9 of 10 patients with chronic lymphocytic leukemia , and 4 of 8 patients with acute myeloblastic leukemia underwent ATG - induced apoptosis . We conclude apoptosis induction in all PBMNC compartments contributes to GVHD prophylaxis . ATG might support engraftment . Finally , antileukemic activity of ATG could positively influence the transplantation outcome .", "Expression of cyclooxygenase - 2 ( P35354 ) in tumour and stroma compartments in cervical cancer : clinical implications . This study aims at investigating the relationship between cyclooxygenase - 2 expression in tumour vs stroma inflammatory compartment and its possible clinical role . The study included 99 stage IB - IV cervical cancer patients : immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase - 2 . CD3 , P01730 , CD8 , CD25 , Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours . An inverse relation was found between cyclooxygenase - 2 levels ( cyclooxygenase - 2 IDV ) of tumour vs stroma compartment ( r =- 0 . 44 , P < 0 . 0001 ) . The percentage of cases showing high tumour / stromal cyclooxygenase - 2 IDV ratio was significantly higher in patients who did not respond to treatment ( 93 . 3 % ) with respect to patients with partial ( 60 . 5 % ) , and complete ( 43 . 7 % ) response ( P = 0 . 009 ) . Cases with a high tumour / stroma cyclooxygenase - 2 IDV ratio had a shorter overall survival rate than cases with a low tumour / stroma cyclooxygenase - 2 IDV ( P < 0 . 0001 ) . In the multivariate analysis advanced stage and the status of tumour / stroma cyclooxygenase - 2 IDV ratio retained an independent negative prognostic role . The proportion of CD3 (+) , P01730 (+) , and CD25 (+) cells was significantly lower in tumours with high tumour / stroma cyclooxygenase - 2 IDV ratio , while a higher percentage of mast cells was detected in tumours showing high tumour / stroma cyclooxygenase - 2 IDV ratio . Our study showed the usefulness of assessing cyclooxygenase - 2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis .", "In vivo characterization of rabbit anti - mouse thymocyte globulin : a surrogate for rabbit anti - human thymocyte globulin . BACKGROUND : Polyclonal rabbit anti - human thymocyte globulin ( DB00098 ) is used clinically for immunosuppression in solid organ transplantation ; however , it is difficult to fully characterize the effects of this agent in humans . METHODS : A surrogate rabbit anti - murine thymocyte globulin ( mATG ) was generated analogously to the commercial product DB00098 and in vivo activities were evaluated , including pharmacokinetics , T - cell depletion , dose response and kinetics , depletion / sparing of T - cell subsets or other leukocyte populations , and depletion in different lymphoid organs . RESULTS : Within 1 day , T cells are depleted by mATG in the blood , spleen , lymph node , and bone marrow down to doses of 1 mg / kg . Although mATG binds and depletes thymocytes in vitro , there is no thymocyte depletion in vivo at any dose level , suggesting decreased antibody accessibility to the thymus . After two doses of mATG given 3 days apart , T - cell reconstitution begins as early as day 9 and returns to basal levels by day 21 and 29 for P01730 and CD8 T cells , respectively . There is also preferential depletion of naïve T cells that results in increased ratios of regulatory and memory T cells within 1 day after mATG administration . Depletion of natural killer - T cells , natural killer cells , plasma cells , and plasmablasts occurs , but is modest and more transient compared with T cells . B cells , macrophages , dendritic cells , hematopoetic stem cells , and bone marrow stromal cells seem resistant to mATG depletion . CONCLUSIONS : These studies characterize the depletive effects of mATG in normal mice and provide insight into mechanisms of action of DB00098 .", "Enhancement of the P11362 signaling in the P11362 - P08908 heteroreceptor complex in midbrain raphe 5 - HT neuron systems . Relevance for neuroplasticity and depression . New findings show existence of P11362 - P08908 heteroreceptor complexes in 5 - HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus . Synergistic receptor - receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity . The existence of P11362 - P08908 heteroreceptor complexes also in midbrain raphe 5 - HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5 - HT levels can cause an activation of the P09038 / P11362 mechanism in these nerve cells as well . Therefore , the agonist modulation of the P11362 - P08908 heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5 - HT nerve cells . The combined i . c . v . treatment with P09038 and the P08908 agonist 8 - OHDPAT synergistically increased P11362 and P27361 / 2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells . Cotreatment with P09038 and the P08908 agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5 - HT immunoreactivity . These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the P08908 receptor . Taken together , the P08908 autoreceptors by being part of a P11362 - P08908 heteroreceptor complex in the midbrain raphe 5 - HT nerve cells appears to have also a trophic role in the central 5 - HT neuron systems besides playing a key role in reducing the firing of these neurons .", "Cyclooxygenase inhibitors modulate NK activities that control metastatic disease . Cyclooxygenase ( P36551 ) inhibitors have demonstrated efficacy in models of human cancer but the relevant mechanisms have not all been elucidated . Both Cox - dependent as well as Cox - independent mechanisms have been implicated . Using a syngeneic model of metastatic breast cancer , we have investigated the effect of Cox inhibitors on NK functions that are critical to the control of metastatic disease . NK recognition of target cells is governed by a balance of activating and inhibiting receptors that bind ligands including MHC class I . We now show that treatment of tumor cells with the nonselective P23219 / P35354 inhibitor indomethacin or the selective P35354 inhibitor celecoxib leads to decreased expression of the MHC class I molecules Ld and Kd . Downregulated class I expression is associated with concomitant increased sensitivity to NK cell - mediated lysis . Both P36551 inhibitors limit tumor metastasis and this therapeutic effect is dependent on NK but not T cell function . Antimetastatic activity is also lost in the absence of interferon - gamma ( P01579 ) . Both P36551 inhibitors also suppress local tumor growth of subcutaneously implanted mammary tumor cells in immune competent Balb / cByJ mice . This therapeutic activity is lost in the absence of either P01730 + or CD8 + T cells , but is not compromised by the loss of NK activity . Thus , the mechanism of tumor inhibition differs in the context of local versus metastatic disease . Taken together , these findings are consistent with a mechanism not previously described , whereby P36551 inhibitors may relieve MHC - mediated inhibition of NK cytotoxicity leading to recognition and lysis of metastatic tumor cells .", "Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .", "Ex vivo expansion of human Tregs by DB00098 is dependent on intact P40763 - signaling in CD4 ⁺ T cells and requires the presence of monocytes . The addition of low , nondepleting doses of rabbit antithymocyte globulin ( ATG ) to human peripheral blood mononuclear cells has been shown to expand functional P01730 (+) CD25 (+) FoxP3 (+) regulatory T cells ( Tregs ) in vitro . This report is the first to elucidate the exact cellular mechanisms of ATG - mediated Treg expansion . P01730 (+) T cells require monocytes , but not other antigen presenting cell subsets , to be present in coculture to expand Tregs . However , T cells do not require direct cell - cell contact with monocytes , suggesting the importance of soluble factors . Moreover , ATG initially \" reprograms \" P01730 (+) T cells , but not monocytes , and induces P40763 and P42229 signaling in P01730 (+) cells . These reprogrammed P01730 (+) T cells subsequently secrete GM - P04141 and P22301 only in case of intact P40763 signaling , which in turn promote the generation of tolerogenic P08571 (+) CD11c (+) dendritic cells characterized by enhanced P22301 and decreased IL - 12 production . Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM - P04141 and Bcl - 2 , but not TGF - β , in peripheral blood mononuclear cells . These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram P01730 (+) T cells in a P40763 - dependent but TGF - β - independent manner , leading to the generation of monocyte - derived dendritic cells with a tolerogenic cytokine profile .", "Prolonged lymphocyte depletion by single - dose rabbit anti - thymocyte globulin and alemtuzumab in kidney transplantation . Although antibody induction has gained in popularity , two agents are rarely combined . We retrospectively analyzed peripheral lymphocyte phenotypes of renal transplant recipients who received induction therapy with a different antibody / combination : alemtuzumab ( C1H ) , DB00098 ( DB00098 ) , daclizumab ( Dac ) , DB00098 + C1H , and DB00098 + Dac . P01730 + T - cells were suppressed by C1H and DB00098 + C1H , as well as by DB00098 and DB00098 + Dac but to a lesser extent . The effect lasted for 3 years at around 40 % of baseline values . CD8 + T - cells showed a similar trend but had a more rapid recovery to baseline . P15391 + B - cells were effectively suppressed for 2 months by C1H and DB00098 + C1H , and abruptly returned to baseline afterwards ; suppression by DB00098 ( 7 doses ) was modest but lasted longer . A higher proportion of CD56 + CD16 + Natural Killer cells in C1H treated patients suggested a relatively spared effect of C1H on this cell type . Low CD25 + T - cells by 5 - dose Dac returned to baseline around 6 months , whereas DB00098 + C1H and DB00098 + Dac showed persistent effect . P01730 + CD25hi T - cells were suppressed by both DB00098 + C1H and DB00098 + Dac , but the initial proportion of P01730 + CD25hi T - cells among P01730 + T - cells and P01730 + CD25hi / P01730 + CD25lo ratio were significantly higher in DB00098 + C1H . Overall , with extensive and persistent lymphocyte suppression by a simple administration of agents , single - dose DB00098 + C1H induction can be an alternative in renal transplantation ." ]

[ "___MASK17___", "___MASK28___", "___MASK32___", "___MASK46___", "___MASK59___", "___MASK74___", "___MASK90___", "___MASK92___", "___MASK9___" ]

[ "DB00082 : current and potential novel therapeutic applications . BACKGROUND : DB00082 is a genetically engineered molecule , which exhibits specific growth hormone ( GH ) antagonism by directly interacting with the P10912 . It is currently licensed for the treatment of acromegaly where surgery and medical therapy with somatostatin analogues have failed . OBJECTIVE : To delineate the role of pegvisomant in the treatment of acromegaly and its novel application in other areas of clinical medicine where suppression of GH action may be of therapeutic benefit . METHODS : A literature review from PubMed - and EMBASE - listed publications and the web - sites of licensing organisations for medicinal products . CONCLUSION : DB00082 is currently used as a second line therapy in the management of acromegaly . It is highly effective in suppressing the metabolic effects of elevated GH levels when used alone or in combination with somatostatin analogues . However , its long term efficacy and safety for this indication has yet to be established . Preliminary data indicate that pegvisomant may have a role in management of type 1 diabetes with beneficial effects on insulin sensitivity and in preventing the progression of microvascular complications . Additional roles as an adjunct to cancer chemotherapy regimens and for the diagnosis of GH deficiency have been proposed , but have yet to be confirmed .", "Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK95___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .", "The challenges of reliance on insulin - like growth factor I in monitoring disease activity in patients with acromegaly . Serum insulin - like growth factor I ( P05019 ) is an important marker of disease activity in patients with acromegaly , and epidemiological data indicate control of circulating P05019 in patients with acromegaly restores life expectancy to normal . Improvements in the quality of , and access to , P05019 assays has encouraged monitoring of acromegaly with P05019 , although circulating growth hormone ( GH ) and P05019 values provide different information , so ideally both should be monitored . However , the introduction of the P10912 antagonist pegvisomant poses new challenges . DB00082 binds with high affinity to GH receptors , thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive . This leaves P05019 as the principal marker of disease activity . It is conceptually possible to induce a state of functional GH deficiency ( GHD ) with pegvisomant with P05019 values within the normal range . With the goal of minimizing the risk of over - treatment and GHD , we have provided preliminary guidance on the target range for P05019 in patients receiving pegvisomant based on the gender - and decade - based percentile ranges for P05019 of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database ( KIMS ) .", "A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .", "Insights from growth hormone receptor blockade . DB00082 is a genetically manipulated growth hormone ( GH ) that disables signal transduction through the P10912 and thus functions as a P10912 antagonist . In a series of studies of the metabolic effects of GH in healthy male individuals , pegvisomant has been used to create a model of acute GH deficiency but without the typical alterations in body composition . This review summarizes studies of the effects of P10912 blockade and fasting , either alone or in combination , on determinants of GH release . Based on these and other data we present a model to explain the somatotroph hyperactivity of fasting", "Saw palmetto extract suppresses insulin - like growth factor - I signaling and induces stress - activated protein kinase / c - Jun N - terminal kinase phosphorylation in human prostate epithelial cells . A common alternative therapy for benign prostatic hyperplasia ( BPH ) is the extract from the fruit of saw palmetto ( SPE ) . BPH is caused by nonmalignant growth of epithelial and stromal elements of the prostate . IGF action is important for prostate growth and development , and changes in the IGF system have been documented in BPH tissues . The main signaling pathways activated by the binding of P05019 to the P08069 ( IGF - IR ) are the P29323 arm of the MAPK cascade and the phosphoinositol - 3 - kinase ( PI3K ) / protein kinase B ( P31749 / Akt ) cascade . We tested the hypothesis that SPE suppresses growth and induces apoptosis in the P69 prostate epithelial cell line by inhibiting P05019 signaling . Treatment with 150 microg / ml SPE for 24 h decreased P05019 - induced proliferation of P69 cells and induced cleavage of the enzyme poly ( ADP - ribose ) polymerase ( PARP ) , an index of apoptosis . Treatment of serum - starved P69 cells with 150 microg / ml SPE for 6 h reduced P05019 - induced phosphorylation of Akt ( assessed by Western blot ) and Akt activity ( assessed by an Akt kinase assay ) . Western blot analysis showed that SPE reduced P05019 - induced phosphorylation of the adapter protein insulin receptor substrate - 1 and decreased downstream effects of Akt activation , including increased cyclin D1 levels and phosphorylation of glycogen synthase kinase - 3 and P08133 ( s6k ) . There was no effect on P05019 - induced phosphorylation of MAPK , IGF - IR , or Shc . Treatment of starved cells with SPE alone induced phosphorylation the proapoptotic protein JNK . SPE treatment may relieve symptoms of BPH , in part , by inhibiting specific components of the P05019 signaling pathway and inducing JNK activation , thus mediating antiproliferative and proapoptotic effects on prostate epithelia .", "Management of endocrine disease : GH excess : diagnosis and medical therapy . Acromegaly is predominantly caused by a pituitary adenoma , which secretes an excess of GH resulting in increased IGF1 levels . Most of the GH assays used currently measure only the levels of the 22 kDa form of GH . In theory , the diagnostic sensitivity may be lower compared with the previous assays , which have used polyclonal antibodies . Many GH - secreting adenomas are plurihormonal and may co - secrete prolactin , DB00024 and α - subunit . Hyperprolactinaemia is found in 30 - 40 % of patients with acromegaly , and hyperprolactinaemia may occasionally be diagnosed before acromegaly is apparent . Although trans - sphenoidal surgery of a GH - secreting adenoma remains the first treatment at most centres , the role of somatostatin analogues , octreotide long - acting repeatable and lanreotide Autogel as primary therapy is still the subject of some debate . Although the normalisation of GH and IGF1 levels is the main objective in all patients with acromegaly , GH and IGF1 levels may be discordant , especially during somatostatin analogue therapy . This discordance usually takes the form of high GH levels and an IGF1 level towards the upper limit of the normal range . DB06663 , a new somatostatin analogue , may be more efficacious in some patients , but the drug has not yet been registered for acromegaly . Papers published on pasireotide have reported an increased risk of diabetes mellitus due to a reduction in insulin levels . DB00082 , the P10912 antagonist , is indicated - alone or in combination with a somatostatin analogue - in most patients who fail to enter remission on a somatostatin analogue . Dopamine - D2 - agonists may be effective as monotherapy in a few patients , but it may prove necessary to apply combination therapy involving a somatostatin analogue and / or pegvisomant .", "A pegylated growth hormone receptor antagonist , pegvisomant , does not enter the brain in humans . BACKGROUND : GH receptors exist in the hippocampus , cerebral cortex , and hypothalamus , possibly influencing mood , cortical blood flow , and neuronal growth and mediating negative feedback . RATIONALE : DB00082 is a recombinant mutated GH molecule with high affinity , but little or no activating capability , for the P10912 . It is used clinically as a GH antagonist . HYPOTHESIS : Systemic pegvisomant enters brain interstitial fluid via putative choroid - plexus GH receptors , thereby allowing for antagonism of central actions of GH . SUBJECTS AND LOCATION : Six adults requiring a cerebrospinal fluid ( P04141 ) examination for nonneoplastic and noninflammatory syndromes participated at a tertiary medical center . METHODS : Direct assays were conducted of serum and P04141 pegvisomant concentrations 18 - 24 h after sc injection of pegvisomant ( 20 mg ) . OUTCOMES : Median ( range ) concentrations of pegvisomant in serum were 215 ( 74 - 539 ) microg / liter and in P04141 0 . 035 ( 0 . 010 - 0 . 28 ) microg / liter ( P = 0 . 016 ) . P04141 drug levels were indistinguishable from assay threshold . Corresponding GH values were 0 . 29 ( 0 . 010 - 1 . 3 ) in serum and 0 . 075 microg / liter ( 0 . 01 - 0 . 13 ) in P04141 . The geometric mean ratios of serum / P04141 pegvisomant and GH concentrations were 5116 : 1 and 3 . 5 : 1 , respectively , thus defining a more than 1400 - fold difference between mutated and natural GH . CONCLUSIONS : Based upon P04141 measurements , a pegylated GH - receptor antagonist does not cross the human blood - brain barrier , thereby sparing inhibition of central nervous system GH actions . Thus , the capability of this antagonist to stimulate GH secretion predominantly reflects its actions outside the blood - brain barrier , such as via the median eminence and / or via suppression of P05019 concentrations .", "Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK54___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .", "Human immunodeficiency virus ( HIV ) - induced neurotoxicity : roles for the DB01221 receptor subtypes . Neuronal damage in human immunodeficiency virus type 1 ( HIV - 1 ) infection in the brain is thought to occur at least in part through DB01221 receptor ( NMDAR ) excitation initiated by soluble neurotoxins from HIV - infected brain macrophages . Furthermore , brain regions enriched in NMDAR - 2A ( Q12879 ) and NMDAR - 2B ( Q13224 ) subunits , such as the hippocampus , are particularly vulnerable . Using cultured rat hippocampal cells and HIV - 1 - infected human monocyte - derived macrophages ( HIV / MDM ) , we examined the role of Q12879 and Q13224 in HIV / MDM - induced hippocampal neuronal death . We used the primary HIV - 1 strain Jago derived from the P04141 of an individual with HIV - associated dementia and that robustly replicates in MDM . We found the following : ( 1 ) hippocampal neuronal susceptibility to HIV / MDM excitotoxins varies according to the developmental expression patterns of Q12879 and Q13224 ; ( 2 ) NMDAR activation by HIV / MDM results in neuronal calpain activation , which results in neuronal death ; and ( 3 ) selective antagonists of homomeric Q13224 / Q13224 - and heteromeric Q12879 / Q13224 - containing NMDARs , as well as an inhibitor of calpain activity , afford neuroprotection against HIV / MDM . These studies establish a clear link between macrophage HIV infection , neuronal Q12879 and Q13224 activation , and calpain - mediated hippocampal neuronal death . They further suggest a dominant role for Q12879 and Q13224 in determining neuronal susceptibility in HIV - infected brain . Antagonists of Q12879 and Q13224 subunits as well as inhibitors of calpain activation offer attractive neuroprotective approaches against HIV in both developing and mature brain .", "Cancer and the potential place for growth hormone receptor antagonist therapy . DB00082 is a recombinant protein , structurally similar to natural human growth hormone ( GH ) , which is capable of binding to the P10912 as a competitive antagonist . As well as being evaluated for the treatment of acromegaly , pegvisomant is being investigated as a possible antineoplastic agent , initially in mice . So far , in vitro efficacy against meningioma and in vivo efficacy against colon and breast cancer cell lines have been examined .", "Ligand binding domain of granulocyte colony - stimulating factor receptor . The amino - terminal domain of the cytokine receptor homologous region ( BN domain ; roughly 100 amino acid residues ) in the receptor for murine granulocyte colony - stimulating factor ( DB00099 ) was secreted as a maltose - binding protein fusion into the Escherichia coli periplasm . The murine BN domain ( mBN ) was prepared from the fusion protein by restriction protease Factor Xa digestion and purified to homogeneity . The purified BN domain specifically and stoichiometrically bound DB00099 , with an apparent dissociation constant ( Kd ) of 3 - 8 x 10 (- 8 ) M . The CD spectrum of the mBN domain was similar to that of the extracellular region of the human growth hormone ( GH ) receptor , which is composed of turns and beta - sheets held together by disulfide bonds . Tertiary folding and the beta - sheet of this small domain was confirmed by NMR spectroscopy . Disulfide bonds determined by peptide mapping were in the following locations : Cys107 - Cys118 , Cys153 - Cys162 , and Cys143 - Cys194 . Among them , the first and the second produce small loops ( roughly 10 amino acid residues ) as found in the human P10912 . These results suggested that the mBN domain of the Q99062 expressed by E . coli has a P10912 - like structure . However , the third disulfide bond varied considerably between the G - P04141 and GH receptors . Disruption of these disulfide bonds in the BN domain of the Q99062 suggested that all of them are critical for maintaining a stably folded protein . Our results will facilitate understanding of the biophysical and structural properties of this receptor .", "DB00082 in the treatment of acromegaly . Epidemiological studies have highlighted the need for tight control of growth hormone ( GH ) and insulin - like growth factor I ( P05019 ) in patients with acromegaly . Studies highlighting the events involved in P10912 signaling have allowed the development of a pegylated P10912 antagonist ( pegvisomant ) for use in humans , which has been designed to outcompete GH for the P10912 , but which contains a position 120 amino acid substitution that prevents recruitment of a second P10912 . This process of receptor dimerisation is crucial for signal transduction and P05019 generation . Clinical trials of pegvisomant suggest it is the most effective treatment for acromegaly to date , as this therapy is capable of normalising serum P05019 in up to 97 % of patients when doses of 40 mg per day are used . This paper reviews the development of pegvisomant and the clinical experience in patients with acromegaly to date .", "Role of medical therapy in the management of acromegaly . Medical therapy plays an important role in the management of patients with acromegaly and is commonly used adjunctively after surgical resection of the pituitary tumor . Generally , surgery alone provides a 50 to 70 % rate of cure ; however , the outcome depends on the experience and ability of the surgeon and the characteristics of the tumor . The role of postsurgical medical therapy is to achieve long - term biochemical control of the growth hormone ( GH ) / insulin - like growth factor I ( P05019 ) axis . In some patients , medical therapies may be implemented sooner as primary or preoperative therapy . Somatostatin analogs have been the mainstay of medical therapy for acromegaly . The somatostatin analog octreotide produces normalization of P05019 in approximately 50 % of patients but is associated with gastrointestinal adverse effects , including the development of gallstones . DB00104 requires thrice - daily subcutaneous administration . Long - acting formulations of somatostatin analogs ( octreotide P10586 , lanreotide ) are at least as effective and as well tolerated as short - acting octreotide . Unfortunately , some patients are suboptimally responsive to or become intolerant of these agents . DB00082 belongs to a new class of agents known as GH - receptor antagonists . This novel agent competitively binds to the P10912 , blocking P05019 production . DB00082 is highly effective in achieving normal P05019 concentrations and in reducing signs and symptoms of acromegaly , even in patients resistant to previous treatments . DB00082 has been proved safe and well tolerated and has no effect on gallbladder motility . GH levels remain elevated . Transient elevations in liver enzyme levels require monitoring but rarely necessitate termination of therapy . Normalizing P05019 concentrations with pegvisomant also may have a beneficial effect on carbohydrate metabolism and cardiovascular risk .", "Clinical endocannabinoid deficiency ( CECD ) : can this concept explain therapeutic benefits of cannabis in migraine , fibromyalgia , irritable bowel syndrome and other treatment - resistant conditions ? OBJECTIVES : This study examines the concept of clinical endocannabinoid deficiency ( CECD ) , and the prospect that it could underlie the pathophysiology of migraine , fibromyalgia , irritable bowel syndrome , and other functional conditions alleviated by clinical cannabis . METHODS : Available literature was reviewed , and literature searches pursued via the National Library of Medicine database and other resources . RESULTS : Migraine has numerous relationships to endocannabinoid function . Anandamide ( AEA ) potentiates P08908 and inhibits 5 - Q13049 receptors supporting therapeutic efficacy in acute and preventive migraine treatment . Cannabinoids also demonstrate dopamine - blocking and anti - inflammatory effects . AEA is tonically active in the periaqueductal gray matter , a migraine generator . THC modulates glutamatergic neurotransmission via DB01221 receptors . Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia . Cannabinoids have similarly demonstrated the ability to block spinal , peripheral and gastrointestinal mechanisms that promote pain in headache , fibromyalgia , IBS and related disorders . The past and potential clinical utility of cannabis - based medicines in their treatment is discussed , as are further suggestions for experimental investigation of CECD via P04141 examination and neuro - imaging . CONCLUSION : Migraine , fibromyalgia , IBS and related conditions display common clinical , biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines .", "DB00082 treatment in gigantism caused by a growth hormone - secreting giant pituitary adenoma . BACKGROUND : Gigantism is rare with the majority of cases caused by a growth hormone ( GH ) - secreting pituitary adenoma . Treatment options for GH - secreting pituitary adenomas have been widened with the availability of long - acting dopamine agonists , depot preparations of somatostatin analogues , and recently the P10912 antagonist pegvisomant . CASE REPORT : A 23 - year - old male patient presented with continuous increase in height during the past 6 years due to a GH - secreting giant pituitary adenoma . Because of major intracranial extension and failure of octreotide treatment to shrink the tumour , the tumour was partially resected by a trans - frontal surgical approach . At immunohistochemistry , the tumour showed a marked expression of GH and a sparsely focal expression of prolactin . Somatostatin receptors ( sst ) 1 - 5 were not detected . Tumour tissue weakly expressed dopamine receptor type 2 . The Gs alpha subunit was intact . Conversion from somatostatin analogue to pegvisomant normalized insulin - like - growth - factor - I ( P05019 ) levels and markedly improved glucose tolerance . CONCLUSION : DB00082 is a potent treatment option in patients with pituitary gigantism . In patients who do not respond to somatostatin analogues , knowledge of the P61278 receptor status may shorten the time to initiation of pegvisomant treatment .", "P10912 targeting to lipid rafts requires extracellular subdomain 2 . P10912 ( P10912 ) is a single membrane - spanning glycoprotein dimer that binds GH in its extracellular domain ( O95905 ) . GH activates the P10912 intracellular domain ( ICD ) - associated tyrosine kinase , O60674 , which causes intracellular signaling . We previously found that plasma membrane ( PM ) - associated P10912 was dramatically enriched in the lipid raft ( LR ) component of the membrane and that localization of P10912 within PM regions may regulate GH signaling by influencing the profile of pathway activation . In this study , we examined determinants of LR localization of the P10912 using a reconstitution system which lacks endogenous O60674 and P10912 . By non - detergent extraction and multistep fractionation , we found that P10912 was highly enriched in the LR fraction independent of O60674 expression . Various P10912 mutants were examined in transfectants harboring O60674 . LR concentration was observed for a P10912 in which the native transmembrane domain ( TMD ) is replaced by that of the unrelated P01130 and for a P10912 that lacks its ICD . Thus , LR association requires neither the TMD nor the ICD . Similarly , a P10912 that lacks the O95905 , except for the membrane - proximal O95905 stem region , was only minimally LR - concentrated . Mutants with internal stem deletions in the context of the full - length receptor were LR - concentrated similar to the wild - type . A P10912 lacking O95905 subdomain 1 reached the PM and was LR - concentrated , while one lacking O95905 subdomain 2 , also reached the PM , but was not LR - concentrated . These data suggest LR targeting resides in O95905 subdomain 2 , a region relatively uninvolved in GH binding .", "[ P10912 antagonist in the treatment of acromegaly ] . Exploration of construction , function and interaction of human growth hormone and growth hormone receptor in details resulted in the innovation of the new growth hormone receptor antagonist , pegvisomant . DB00082 with different mechanism of action extended the tools of medical management of acromegaly . Importance of the novel treatment modality is high . In one hand the necessity of the strict control of growth hormone / insulin - like growth factor - I axis has been proven regarding the mortality of the disease . On the other hand , despite the use of all current modes of treatment ( surgery , radiotherapy , dopamine agonists , somatostatin analogs ) , a significant cohort of patients with acromegaly remains inadequately controlled . DB00082 has been registered in 2004 . Since 2006 , it has been used in Hungary for the treatment of acromegaly in patients who have had an inadequate response to surgery and / or radiation therapy and / or other medical therapies , or for whom these therapies are not appropriate . Clinical use of pegvisomant in the treatment of acromegaly is effective , well tolerated , and safe , based on international Acrostudy database . In order to improve the efficacy of therapy clinical trials started with pegvisomant and somatostatin analog combination treatment . Evidence of several further effects of the growth hormone / insulin - like growth factor - I axis suggests other potential uses of growth hormone receptor antagonists .", "Neonatal estrogen exposure disrupts uterine development in the postnatal sheep . Postnatal development of the ovine uterus between birth and postnatal day ( P01160 ) 56 involves budding differentiation of the endometrial glandular epithelium from the luminal epithelium ( LE ) followed by extensive coiling and branching morphogenesis of the tubular glands . To determine the short - and long - term effects of estrogen on neonatal ovine uterine development after P01160 14 , neonatal sheep were randomly assigned at birth ( P01160 0 ) to be treated daily with estradiol - 17beta benzoate ( EB ; 0 , 0 . 01 , 0 . 1 , 1 , or 10 microg / kg body weight . d ) during one of two developmental periods ( P01160 14 - 27 or 42 - 55 ) . All ewes were hemiovariohysterectomized at the end of EB treatment on either P01160 28 or 56 , and the remaining uterine horn and ovary removed on P01160 112 . Immediate responses to EB treatment included dose - and age - dependent increases in uterine wet weight , thickness of the endometrium , myometrium , and LE , but decreases in endometrial glands on P01160 28 and 56 . Transient exposure to EB decreased gland number and thickness of the endometrium and LE on P01160 112 but did not affect extrauterine reproductive tract structures . The mechanism of estrogen inhibition of uterine development did not involve effects on cell proliferation . Real - time PCR analyses found that EB exposure disrupted normal patterns of growth factor ( P05019 , P01344 , fibroblast growth factor - 7 , fibroblast growth factor - 10 , and hepatocyte growth factor ) and receptor mRNA expression in the uterus . Transient exposure of the neonatal ewe to estrogens during critical periods specifically alters growth factor networks that perturb normal development of the uterus , leading to permanent alterations in uterine structure and function .", "Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .", "The use of a P10912 antagonist in patients with acromegaly resistant to somatostatin analogs . DB00082 , a P10912 antagonist , is a new pharmaceutical approach to acromegaly . It enables P05019 levels to return in the age - and sex - reference range in approximately 90 % of patients . This new approach is particularly beneficial in those patients who do not experience control of hormone hypersecretion after surgery and / or medical treatment with somatostatin analogs . In our preliminary experience , out of 16 patients unsuccessfully operated on by transsphenoidal surgery and resistant to 40 - mg octreotide - P10586 or 120 - mg lanreotide for at least 6 months , 13 normalized their P05019 levels within 6 months from treatment beginning . Normalization of P05019 levels was accompanied by a significant decrease of ring size . We did not observe any increase of tumor remnant in this short period of treatment . In two cases we observed a significant increase of liver transaminases levels . In conclusion , more than 80 % of patients with acromegaly unsuccessfully treated by surgery or currently available somatostatin analogs can achieve normal P05019 levels after short - term treatment with pegvisomant .", "DB00082 Pfizer / Sensus . Pfizer ( formerly Pharmacia ) , in collaboration with its wholly owned subsidiary Sensus , has developed and launched pegvisomant , a pegylated , genetically modified human growth hormone ( hGH ) , for the treatment of acromegaly . DB00082 , in contrast to classical somatostatin analogs which lower hGH synthesis , exerts its anti - hGH action by preventing P10912 activation . This drug is now available in the US and Europe for the treatment of acromegaly .", "Bovine somatotropin attenuates phorbol ester - induced prostaglandin F2alpha production in bovine endometrial cells . The recent observation that bovine somatotropin ( bST ) treatment at a timed insemination improves pregnancy rates in lactating dairy cows raises the possibility that growth hormone ( GH ) may modulate the endocrine and biochemical cross talk between the conceptus and maternal uterus at the time of pregnancy establishment in cattle . The objective of this study was to characterize the cellular and molecular mechanisms by which exogenous GH affects phorbol ester - induced prostaglandin F2alpha ( PGF2alpha ) production in cultured bovine endometrial ( BEND ) cells . Serum - deprived BEND cells were incubated with or without recombinant bovine GH ( rbGH ) , insulin - like growth factor ( IGF ) - I , recombinant bovine interferon ( rbIFN ) - tau or a combination of rbGH + rbIFN - tau for 3 h and then treated with phorbol 12 , 13 - dibutyrate ( PDBu ) for an additional 6 h . Exogenous PDBu increased PGF2alpha secretion and steady - state levels of P35354 mRNA within 3 h . Priming of BEND cells with rbGH reduced PGF2alpha response to PDBu , whereas cotreatment with P05019 amplified PDBu induction of PGF2alpha . Preincubation of cell monolayers with rbIFN - tau suppressed PGF2alpha and P35354 mRNA responses to PDBu . Inhibitory effects of rbGH and rbIFN - tau on PDBu - induced PGF2alpha production were additive . Results provide the first direct evidence that supplemental bST may interact with conceptus - secreted IFN - tau to modulate PGF2alpha secretion at the critical time of maternal recognition of pregnancy .", "___MASK14___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK14___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK14___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK14___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK14___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .", "P10912 blocker administration and muscle - tendon collagen synthesis in humans . CONTEXT : The growth hormone ( GH ) / insulin - like growth factor - I ( P05019 ) axis stimulates collagen synthesis in tendon and skeletal muscle , but no studies have investigated the effect of reducing P05019 on collagen synthesis in healthy humans . OBJECTIVE : We hypothesised , that a GH blockade would decrease P05019 and collagen synthesis in the connective tissue of skeletal muscle and tendon . DESIGN : The study was randomised and double blinded . PARTICIPANTS : 20 healthy young males completed the study . INTERVENTION : The participants were randomised to 2 weeks of P10912 blocker supplementation ( pegvisomant , 5 mg / day , n = 9 ) or placebo ( n = 11 ) . MAIN OUTCOME MEASURES : Serum levels of GH , P05019 and P17936 ( P17936 ) were measured before and after pegvisomant / placebo supplementation . Fractional synthesis rates ( FSR ) for collagen and myofibrillar protein were determined with stable isotopes in tendon and muscle , and mRNA for collagen ( P02452 and P02461 ) as well as P05019 isoforms ( Ea and Ec ) were measured in skeletal muscle . RESULTS : DB00082 decreased serum P05019 by 20 % ( p < 0 . 01 ) and serum P17936 by 10 % ( p < 0 . 05 ) . DB00082 supplementation had no effect on collagen synthesis in tendon and skeletal muscle , nor was muscle myofibrillar protein synthesis affected . Similarly , pegvisomant supplementation had no effect on mRNA expression of P05019 and collagen in skeletal muscle . CONCLUSION : P10912 blocker administration in healthy humans resulted in a moderate decrease in serum P05019 . Collagen synthesis in tendon and skeletal muscle , as well as skeletal muscle P05019 and collagen mRNA expression , was unaffected by P10912 blocker supplementation .", "___MASK22___ promotes vascular smooth muscle cell differentiation through insulin receptor substrate - 1 / phosphatidylinositol 3 - kinase / Akt2 feedback signaling . The phenotypic plasticity of mature vascular smooth muscle cells ( VSMCs ) facilitates angiogenesis and wound healing , but VSCM dedifferentiation also contributes to vascular pathologies such as intimal hyperplasia . P01308 / insulin - like growth factor I ( P05019 ) is unique among growth factors in promoting VSMC differentiation via preferential activation of phosphatidylinositol 3 - kinase ( PI3K ) and Akt . We have previously reported that rapamycin promotes VSMC differentiation by inhibiting the mammalian target of rapamycin ( P42345 ) target P23443 . Here , we show that rapamycin activates Akt and induces contractile protein expression in human VSMC in an insulin - like growth factor I - dependent manner , by relieving P23443 - dependent negative regulation of insulin receptor substrate - 1 ( P35568 ) . In skeletal muscle and adipocytes , rapamycin relieves P42345 / P23443 - dependent inhibitory phosphorylation of P35568 , thus preventing P35568 degradation and enhancing PI3K activation . We report that this mechanism is functional in VSMCs and crucial for rapamycin - induced differentiation . ___MASK22___ inhibits P23443 - dependent P35568 serine phosphorylation , increases P35568 protein levels , and promotes association of tyrosine - phosphorylated P35568 with PI3K . A rapamycin - resistant P23443 mutant prevents rapamycin - induced Akt activation and VSMC differentiation . Notably , we find that rapamycin selectively activates only the Akt2 isoform and that Akt2 , but not Akt1 , is sufficient to induce contractile protein expression . Akt2 is required for rapamycin - induced VSMC differentiation , whereas Akt1 appears to oppose contractile protein expression . The anti - restenotic effect of rapamycin in patients may be attributable to this unique pattern of PI3K effector regulation wherein anti - differentiation signals from P23443 are inhibited , but pro - differentiation Akt2 activity is promoted through an P35568 feedback signaling mechanism .", "Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant . CONTEXT : Treatment of pituitary gigantism is complex and the results are usually unsatisfactory . OBJECTIVE : The objective of the study was to describe the results of therapy of three children with pituitary gigantism by a P10912 antagonist , pegvisomant . DESIGN : This was a descriptive case series of up to 3 . 5 yr duration . SETTING : The study was conducted at a university hospital . PATIENTS : Patients included three children ( one female , two males ) with pituitary gigantism whose GH hypersecretion was incompletely controlled by surgery , somatostatin analog , and dopamine agonist . INTERVENTION : The intervention was administration of pegvisomant . MAIN OUTCOME MEASURES : Plasma P05019 and growth velocity were measured . RESULTS : In all three children , pegvisomant rapidly decreased plasma P05019 concentrations . Growth velocity declined to subnormal or normal values . Statural growth fell into lower growth percentiles and acromegalic features resolved . Pituitary tumor size did not change in two children but increased in one boy despite concomitant therapy with a somatostatin analog . CONCLUSIONS : DB00082 may be an effective modality for the therapy of pituitary gigantism in children . Titration of the dose is necessary for optimal efficacy , and regular surveillance of tumor size is mandatory .", "Growth hormone and glucose metabolism : the model of the GH - receptor antagonists . DB00082 is a GH analogue that includes a single amino acid substitution at position 120 that generates the P10912 antagonist . Additional changes include amino acid substitutions within binding site 1 and a further modification by the addition of polyethylene glycol moieties that increase the half - life and reduce the immunogenicity of the molecule . In acromegalics , pegvisomant is the most effective treatment for normalizing the P05019 , and pegvisomant significantly improves insulin sensitivity in patients suffering from acromegaly . However , there are simply no data available that might support a role for pegvisomant treatment in disorders in which glucose metabolism is disturbed and in which reducing GH action would be theoretically beneficial .", "Current therapy for acromegaly . Acromegaly is a disabling disease that is associated with reduced life expectancy . Lowering growth hormone ( GH ) concentrations rapidly improves patient wellbeing . Recent data also indicate that GH concentrations < 2 . 5 micrograms l - 1 are associated with improved mortality , providing a therapeutic goal in the majority of patients . In most cases , initial therapy should be surgical via the transsphenoidal route and conducted by an experienced operator . In such centres of excellence , approximately 60 out of every 100 acromegalic patients should be ' cured ' ( GH < 2 . 5 micrograms l - 1 ) by surgery alone . Effective medical therapies have been introduced in the form of long - acting somatostatin analogues -- octreotide and lanreotide -- and depot preparations of these drugs result in lowering of GH to < 2 . 5 micrograms l - 1 and normalization of P05019 concentrations in 55 - 65 % of cases . Preliminary results are also emerging on DB00082 , a genetically engineered P10912 antagonist , which is clinically and biochemically very effective . It is likely that this drug will be licensed for use in patients with acromegaly in the near future . These effective medical therapies will undoubtedly raise the issue of their use as primary therapy for acromegaly but at present they should be used as an adjunct to surgery and / or radiotherapy .", "Automated 22 - kD growth hormone - specific assay without interference from DB00082 . BACKGROUND : Large variability exists among different growth hormone ( GH ) assays owing to differences in calibration , antibody specificity , isoform recognition , and interference from GH binding protein ( P30043 ) . The P10912 antagonist DB00082 presents a new challenge because DB00082 interferes with many GH assays . A recent consensus conference established criteria for standardization and evaluation of GH assays . Following consensus recommendations , we developed a new GH assay on an automated analyzer ( P22304 - iSYS , Immunodiagnostic Systems ) . METHODS : A monoclonal antibody not cross - reacting with DB00082 was combined with a monoclonal antibody specific for 22 - kD GH . Isoform specificity and interference from P30043 was tested and compared to that seen in 2 existing automated GH assays ( Siemens Immulite , Diasorin Liaison ) . We also compared GH concentrations measured by the 3 assays for healthy volunteers and patients with acromegaly receiving different treatments . Using the iSYS assay , we also established nadir GH values during oral glucose load and analyzed changes in endogenous GH during DB00082 treatment . RESULTS : Analytical and functional sensitivities were 0 . 01 μg / L and 0 . 04 μg / L , with a dynamic range from 0 . 04 to 100 μg / L . Intraassay CVs were 2 % - 4 % , whereas interassay CVs were 5 % - 7 % at GH concentrations between 1 . 7 and 27 . 5 μg / L . The assay was specific for 22 - kD GH and not affected by P30043 . The presence of DB00082 , which leads to a negative bias on the Immulite and dramatic overestimation of GH on the Liaison , had no impact on the iSYS GH assay . CONCLUSIONS : The new assay fulfils recent consensus recommendations and presents a useful new tool for reliable measurement of GH .", "Age - related effects of DB01277 on the DB01221 - , GH - and DB01277 - receptor mRNA transcripts in the rat hippocampus . P01308 - like growth factor - 1 ( DB01277 ) and growth hormone ( GH ) have been suggested to promote memory and cognitive capabilities . In a recent publication we observed that GH increase the proportion of the Q13224 subunit mRNA transcript of the DB01221 receptor in rat hippocampus . Q13224 has been suggested to be essential for spatial learning and long - term potentiation ( LTP ) . This effect of GH might be DB01277 - mediated or a result of a co - ordination with DB01277 . To test this hypothesis further , we examined the effects of 10 daily s . c . injections of DB01277 on DB01221 receptor subunits ( Q9UHB4 , Q12879 , and Q13224 ) , P10912 ( P10912 ) , GH binding protein ( P30043 ) and type 1 IGF receptor ( IGF - 1R ) gene transcripts in the hippocampus . The Q13224 subunit mRNA increased in young ( 11 weeks ) but not in older ( 14 - 16 months ) rats and the expression of the Q12879 mRNA was decreased in both groups . The ratio of Q13224 to Q12879 is suggested to mirror the potential for synaptic plasticity . In both age groups , DB01277 treatment resulted in a significant increase of this ratio at transcription level . The P10912 mRNA increased in young rats , mimicking the effect of GH , while the IGF - 1R mRNA was decreased in the older group of rats after DB01277 treatment . These results suggest that DB01277 in many aspects may mediate the actions earlier shown for GH .", "Long - term treatment of acromegalic patients resistant to somatostatin analogues with the P10912 antagonist pegvisomant : its efficacy in relation to gender and previous radiotherapy . CONTEXT : DB00082 is an effective treatment for somatostatin analogue - resistant acromegaly , but the determinants defining the response to this treatment are largely unknown . OBJECTIVE : To investigate the efficacy of pegvisomant treatment in resistant acromegalic patients ( e . g . serum IGF1 at least 1 . 25 x upper normal limit ) in a clinical setting and the factors conditioning this response . DESIGN AND SETTING : A retrospective cross - sectional study performed in six Spanish University hospitals from 2004 to 2007 . Patients Forty - four acromegalic patients ( 61 . 4 % female , mean age : 49 +/- 14 ) , 95 % of whom had undergone pituitary surgery and 61 % having received pituitary radiotherapy . The mean follow - up was 22 . 7 +/- 11 . 2 months . Main outcome measures IGF1 levels reflected treatment efficacy , and the influence of gender , age , weight , previous radiotherapy and duration of treatment was assessed . RESULTS : IGF1 normalisation was achieved in 84 % of the patients . Male gender ( P < 0 . 05 ) , previous irradiation ( P < 0 . 05 ) and the treatment duration ( r = 0 . 364 , P < 0 . 02 ) were associated with a better response to pegvisomant therapy . There was a significant decrease in HbA1c ( P < 0 . 001 ) and in the mean insulin dose ( P < 0 . 01 ) in acromegalic diabetic patients . Although 25 % of patients experienced mild adverse events , pegvisomant was only withdrawn in four patients due to side effects ( two cases of tumour growth , one liver dysfunction and one headache ) . CONCLUSIONS : Long - term pegvisomant is a very effective therapy in resistant acromegaly . Male gender and prior radiotherapy influence the therapeutic response rate .", "Experience with pegvisomant in the treatment of acromegaly . Established modalities of therapy for acromegaly ( surgical adenomectomy , external beam pituitary irradiation , oral dopamine agonists , and injectable somatostatin analogues ) have as their common goal the lowering of circulating growth hormone ( GH ) levels , with a consequent reduction in serum insulin - like growth factor I ( P05019 ) . DB00082 is a P10912 antagonist that inhibits P10912 dimerization and has a powerful ability to lower serum P05019 levels in patients with active acromegaly . Currently available data suggest that pegvisomant is an effective treatment for acromegaly that is safe , well tolerated , and not associated with expansion of residual pituitary tumour over the time period studied .", "Additional metabolic effects of adding P10912 antagonist to long - acting somatostatin analog in patients with active acromegaly . OBJECTIVE : Somatostatin analogs , dopamine agonists and GH - receptor antagonist -- pegvisomant are used in medical therapy of acromegaly . Since pegvisomant has not antitumor effect , the combination of pegvisomant and somatostatin analog could be an attractive option . Aim of study was to assess the effects of pegvisomant and octreotide P10586 treatment on GH and DB01277 levels , and glucose tolerance in acromegaly , and to assess efficacy and tolerability of rapid ( after 7 days ) pegvisomant dose titration . MATERIAL AND METHODS : Six patients ( 4 men , 2 women ) aged 47 . 5 years ( median ) with active acromegaly , after neurosurgery failed , resistant to maximal doses of octreotide , received daily 10 - 20 mg pegvisomant throughout 2 weeks . They were given octreotide P10586 30 mg monthly for at least 6 months before pegvisomant therapy . Clinical symptoms , GH , DB01277 , fasting glucose and insulin levels were measured on the 0 , 8th and 15th day of pegvisomant therapy . On the 8th day pegvisomant dose was titrated based on serum DB01277 level . RESULTS : DB01277 levels reduced from 739 at the beginning to 418 ng / ml ( medians ) on the 15th day of treatment and normalized in one patient . These changes were associated with improvement of glucose metabolism . One diabetic patient could even stop insulin therapy . CONCLUSIONS : DB00082 is an attractive adjuvant therapy for controlling acromegaly . DB00082 improves insulin sensitivity as well as glucose tolerance . The P10912 antagonist is good option for patients with active acromegaly coexistent with disturbances of glucose metabolism , especially with diabetes mellitus . Rapid pegvisomant dose increasing to efficient or maximal is well tolerated and effective .", "Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK22___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .", "P01308 reverses growth hormone - induced homologous desensitization . Growth hormone ( GH ) is secreted in a pulsatile pattern to promote body growth and metabolism . GH exerts its function by activating several signaling pathways , including O60674 / P35610 and MEK / P29323 . P27361 / 2 activation by GH plays important roles in gene expression , cell proliferation , and growth . We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure , a second GH exposure induces P42229 phosphorylation but not P27361 / 2 phosphorylation ( Ji , S . , Frank , S . J . , and Messina , J . L . ( 2002 ) J . Biol . Chem . 277 , 28384 - 28393 ) . In this study the mechanisms underlying GH - induced homologous desensitization were investigated . A second GH exposure activated the signaling intermediates upstream of MEK / P29323 , including O60674 , Ras , and P04049 . This correlated with recovery of P10912 levels , but was insufficient for GH - induced phosphorylation of Q02750 / 2 and P27361 / 2 . P01308 restored the ability of a second GH exposure to induce phosphorylation of Q02750 / 2 and P27361 / 2 without altering P10912 levels or GH - induced phosphorylation / activation of O60674 and P04049 . GH and insulin synergized in promoting cell proliferation . Further investigation suggested that insulin increased the amount of MEK bound to Q8IVT5 ( kinase suppressor of Ras ) and restored GH - induced tyrosine phosphorylation of Q8IVT5 . Previous GH exposure also induced desensitization of P42224 and P40763 phosphorylation , but this desensitization was not reversed by insulin . Thus , insulin - regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal , physiologic pulse of GH .", "The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF - 7 breast cancer xenograft growth . Mammary gland development is dependent upon the growth hormone ( GH ) / insulin - like growth factor - I ( P05019 ) axis , this same axis has also been implicated in breast cancer progression . In this study we investigated the effect of a GH antagonist , pegvisomant ( Somavert , Pfizer ) , on normal mammary gland development and breast cancer xenograft growth . Intraperitoneal administration of pegvisomant resulted in a 60 % suppression of hepatic P05019 mRNA levels and upto a 70 - 80 % reduction of serum P05019 levels . DB00082 administration to virgin female mice caused a significant delay of mammary ductal outgrowth that was associated with a decrease in the number of terminal end buds and reduced branching and complexity of the gland . This effect of pegvisomant was mediated by a complete inhibition of both GH and IGF - IR - mediated signaling within the gland . In breast cancer xenograft studies , pegvisomant caused shrinkage of MCF - 7 xenografts , with an initial 30 % reduction in tumor volume , which was associated with a 2 - fold reduction in proliferation and a 2 - fold induction of apoptosis . Long - term growth inhibition of MCF - 7 xenografts was noted . In contrast , pegvisomant had no effect on MDA - 231 or MDA - 435 xenografts , consistent with primary growth of these xenografts being unresponsive to P05019 both in vitro and in vivo . In MCF - 7 xenografts that regressed , pegvisomant had only minor effects upon P10912 and IGF - IR signaling . This data supports previous studies indicating a role for GH / IGF in mammary gland development , and suggests that pegvisomant maybe useful for the prevention and / or treatment of estrogen receptor positive breast cancer .", "The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK95___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .", "Optimizing control of acromegaly : integrating a growth hormone receptor antagonist into the treatment algorithm . Acromegaly is associated with significant morbidities and a 2 - to 3 - fold increase in mortality because of the excessive metabolic action of GH and P05019 , a marker of GH output . Reductions in morbidity correspond with decreases in P05019 , and mortality is lowered following normalization of P05019 or GH levels . Therefore , this has become an important end point . Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy , in particular , the place of pegvisomant , a P10912 antagonist . Treatment goals include normalizing biochemical markers , controlling tumor mass , preserving pituitary function , and relieving signs and symptoms . Surgery reduces tumor volume and is considered first - line therapy . Radiation reduces tumor volume and GH and P05019 levels , but the onset of action is slow and hypopituitarism typically develops . Therefore , pharmacotherapy is often used following surgery or as first - line therapy for nonresectable tumors . Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH - prolactin - cosecreting tumors but will not achieve hormone normalization in most patients . Somatostatin analogs effectively suppress GH and P05019 in most patients , but intolerance ( e . g . diarrhea , cramping , gallstones ) can occur . DB00082 , the newest therapeutic option , blocks GH action at peripheral receptors , normalizes P05019 levels , reduces signs and symptoms , and corrects metabolic defects . DB00082 does not appear to affect tumor size and has few adverse effects . DB00082 is the most effective drug treatment for acromegaly in normalizing P05019 and producing a clinical response ; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs .", "Pharmacological therapy for acromegaly : a critical review . The treatment of acromegaly has changed considerably over the last few decades . In the late 1970s , the introduction of the dopamine receptor agonists made it possible to reduce growth hormone ( GH ) secretion by somatotropinomas for the first time . Thereafter , the introduction of the somatostatin analogues in the early 1980s had major implications . Recently , the first data on the use of genetically engineered human P10912 ( P10912 ) antagonists that block GH actions have become available . These P10912 antagonists reduce both the biochemical abnormalities of acromegaly , as well as improve clinical signs and symptomatology . In this article we firstly review available data on dopamine agonists . Currently these compounds should be considered in patients with a mixed GH - prolactin secreting pituitary adenoma and / or those in whom pre - treatment insulin - like growth factor ( IGF ) - I concentrations are below 750 microg / L . We then discuss the somatostatin analogues . These compounds are capable of achieving biochemical control of GH and P05019 in 50 - 60 % of patients and tumour shrinkage in some 30 % . In particular , candidates for treatment with these compounds are those patients who have undergone an unsuccessful transsphenoidal operation or who await the therapeutic effect of external pituitary irradiation . In selected patients primary medical therapy with somatostatin analogues is certainly a feasible option . To date , pegvisomant is the only available member of a new class of drugs that was especially designed to block the P10912 . DB00082 is the most effective treatment for normalising P05019 concentrations and appears to have a good safety profile . However , liver function tests should be regularly monitored and tumour size should be closely followed . Finally , we propose a treatment algorithm for acromegaly .", "P10275 ( AR ) expression in AR - negative prostate cancer cells results in differential effects of ___MASK5___ and P05019 on proliferation and AR activity between localized and metastatic tumors . BACKGROUND : Two features of the progression from organ - confined to metastatic prostate cancer are dysregulation of the androgen receptor ( AR ) and a decrease in insulin - like growth factor - type - I receptor ( IGF - IR ) expression . The purpose of this study was to determine the effect of changes in IGF - IR expression on AR activity . METHODS : M12 human prostate cells were stably transfected with an AR expression construct to produce the M12 - AR parental ( PAR ) cell line . PAR cells were implanted orthotopically into nude mice and M12 - AR primary ( P13489 ) cell lines were derived from intraprostatic tumors and metastatic cell lines ( MET ) were derived from P13489 tumors that had metastasized to diaphragm or lung . RESULTS : Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls . PAR , P13489 , and MET cells expressed equivalent amounts of AR protein ; however , IGF - IR expression was increased significantly in PAR and P13489 cells . IGF - IR expression decreased in MET lines to the levels seen in M12 control cells . P05019 significantly enhanced dihydrotestosterone ( ___MASK5___ ) - stimulated , but not basal , AR transcriptional activity in P13489 cells . In MET cells , P05019 significantly suppressed ___MASK5___ - stimulated transcriptional activity . In MET cells in which the IGF - IR was re - expressed from a retroviral vector , the effects of ___MASK5___ and P05019 on AR activity were similar to those seen in P13489 cells . CONCLUSIONS : This study demonstrates that the changes in IGF - IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo .", "Evaluation of growth hormone ( GH ) action in mice : discovery of P10912 antagonists and clinical indications . The discovery of a growth hormone receptor antagonist ( GHA ) was initially established via expression of mutated GH genes in transgenic mice . Following this discovery , development of the compound resulted in a drug termed pegvisomant , which has been approved for use in patients with acromegaly . DB00082 treatment in a dose dependent manner results in normalization of DB01277 levels in most patients . Thus , it is a very efficacious and safe drug . Since the GH / DB01277 axis has been implicated in the progression of several types of cancers , many have suggested the use of pegvisomant as an anti - cancer therapeutic . In this manuscript , we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions . Additionally , we will describe experiments in which the GHA was discovered , review results of pegvisomant ' s preclinical and clinical trials , and provide data suggesting pegvisomant ' s therapeutic value in selected types of cancer .", "___MASK98___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK98___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .", "P35354 [ corrected ] activation by endotoxin mediates the decrease in IGF1 , but not in P17936 , [ corrected ] gene expression in the liver . The aim of this work was to analyse the role of cyclooxygenase - 2 ( Ptgs2 ) in endotoxin - induced decrease in Igf1 and Igf binding protein - 3 ( Igfbp3 ) . For this purpose , male Wistar rats were injected with lipolysaccharide ( LPS ) and / or the Ptgs2 inhibitor meloxicam . LPS induced a significant decrease ( P < 0 . 01 ) in serum concentrations of Igf1 and Igfbp3 and their mRNAs in the liver . Meloxicam administration prevented the inhibitory effect of LPS injection on serum Igf1 and its liver mRNA . By contrast , meloxicam administration was unable to modify the inhibitory effect of LPS on Igfbp3 . LPS injection also induced a decrease in P10912 ( Ghr ) mRNA in the liver , and meloxicam attenuated this effect . In order to elucidate a direct action of the Ptgs2 inhibitor on the liver cells , the effect of LPS and / or meloxicam was studied in primary cultures of hepatocytes with non - parenchymal cells . LPS decreased Igf1 and Ghr but not Igfbp3 gene expression in liver cells in culture . Meloxicam administration attenuated the inhibitory effect of LPS on Igf1 mRNA , whereas it did not modify the decrease in Ghr mRNA after LPS . The effect of meloxicam on the LPS response does not seem to be mediated by changes in nitric oxide or tumour necrosis factor ( Tnf ) production , since meloxicam did not modify the stimulatory effect of LPS on nitric oxide or Tnfalpha gene expression both in vivo and in vitro . All these data suggest that LPS - induced Ptgs2 activation decreases Igf1 gene expression in liver cells .", "The place of medical treatment of acromegaly : current status and perspectives . INTRODUCTION : Acromegaly is characterized by elevated growth hormone ( GH ) and insulin - like growth factor - I ( P05019 ) levels and by progressive somatic disfigurement and systemic manifestations , which lead to a mortality rate higher than the general population . Therefore , diagnosis and properly treatment should be performed as soon as possible . AREAS COVERED : This article focuses on the state of the art of acromegaly medical treatment . Somatostatin analogs , dopamine agonists and P10912 antagonist were reviewed . Somatostatin analogs , the first - choice pharmacotherapy , can be used as primary or pre - operative treatment or as secondary therapy after failed surgery . Dopamine agonists have been used in patients with slightly elevated hormone levels and / or mixed GH / prolactin adenomas . DB00082 is indicated for resistant to somatostatin analogs / dopamine agonists . Combined treatment is also an option for resistant cases . Other non - conventional therapies and perspectives of treatment were also been discussed . EXPERT OPINION : The control of disease activity in acromegaly is of paramount importance . Medical treatment is an important option for cases in which surgery was unsuccessful or not indicated . Despite the achievements in medical treatment , somatotropic tumor aggressiveness and / or resistance to the drugs currently available remain a concern . Therefore , novel therapy targets based on molecular pathogenesis of GH - secreting tumors are currently in development , aiming at fulfilling this important gap .", "Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK95___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .", "The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK34___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .", "Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44 . 1 ± 72 . 1 days ) were genetically analyzed for P51787 , Q12809 , P15382 - 5 , P63252 , Q14524 , P36382 , and P62158 by using denaturing high - performance liquid chromatography and direct sequencing . Whole - cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 and Q12809 cDNA . In 5 of 7 patients , we identified 4 mutations ( p . N1774D , p . T290fsX53 , p . F1486del and p . N406K ) in Q14524 , and 1 mutation ( p . G628D ) in Q12809 . N1774D , F1486del , and N406K in Q14524 displayed tetrodotoxin - sensitive persistent late Na (+) currents . By contrast , Q14524 - T290fsX53 was nonfunctional . Q12809 - G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 mutations , as well as loss of function associated with the Q12809 mutation .", "Lipodystrophy in patients with acromegaly receiving pegvisomant . CONTEXT : DB00082 , a P10912 antagonist , suppresses serum P05019 levels into the normal range in more than 95 % of patients with acromegaly . Documented side effects in the initial registration studies included headache , injection - site reactions , flu - like syndrome , and reversible elevation of hepatic enzymes . OBJECTIVE : We report seven patients with acromegaly treated with pegvisomant who developed lipodystrophy at the site of injection ( anterior abdominal wall , thigh , buttock , and upper arm ) . This side effect resulted in discontinuation of pegvisomant in four patients , with subsequent regression of lipohypertrophy . SUBJECTS : Six female and one male patient with acromegaly , aged 24 - 59 yr , are reported . All patients had undergone prior transsphenoidal surgery , and four received subsequent radiotherapy . Four patients had been treated with maximal doses of somatostatin analogs with partial suppression of P05019 levels before initiation of pegvisomant therapy . DB00082 suppressed P05019 levels into the normal range in five of seven subjects , before discontinuation of the drug . Two of seven patients received pegvisomant as first - line medical therapy , without prior somatostatin analog treatment , and one received combination therapy with a long - acting somatostatin analog and weekly pegvisomant injections . One patient experienced an erythematous superficial injection - site reaction that responded to application of steroid cream before the onset of lipohypertrophy . CONCLUSIONS : We report seven patients with acromegaly who developed lipohypertrophy at the pegvisomant injection site . DB00082 was discontinued due to dissatisfaction with lipohypertrophy by four patients . Lipohypertrophy regressed in all patients when the medication was discontinued . Lipohypertrophy recurred when two patients were rechallenged with pegvisomant . Patients receiving pegvisomant should undergo frequent examination of injection sites for lipohypertrophy .", "An unusual somatotropin and thyreotropin secreting pituitary adenoma efficiently controlled by DB00104 and DB00082 . We describe the first case of a 36 year - old male patient with a somatotropin and thyreotropin secreting pituitary adenoma , co - treated by a long - acting releasing somatostatin analog ( DB00104 ) and a P10912 antagonist ( DB00082 ) . The patient normalized his biological disease activity reflected by hormone levels but his tumor size remained unchanged as measured by Q9BWK5 . The co - treatment was well tolerated and induced a synergic effect on IGF1 levels that allowed us to use low doses of both therapies .", "Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK99___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .", "[ ___MASK75___ sodium ( Photofrin - II ) ] . ___MASK75___ sodium ( ___MASK75___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK75___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK5___ ) in castrated male and female mice subjected to ___MASK5___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK5___ in mice CPs .", "DB00082 , a growth hormone - specific antagonist , undergoes cellular internalization . GH binding to a receptor ( P10912 ) dimer triggers signaling and internalization of the receptor / ligand complex . DB00082 is a specific GH antagonist developed for the treatment of acromegaly , and the basic molecule is GH with an amino acid substitution that blocks the conformational change necessary to generate functional P10912 dimerization required for signal transduction . DB00082 has additional polyethylene glycol moieties to prolong its half - life in the circulation and improve clinical efficacy through reduced renal clearance . DB00082 has a long plasma half - life , and its mode of clearance has not been established . We have studied pegvisomant internalization and demonstrate that despite its size and prolonged plasma half - life , it is internalized by cells expressing the P10912 . As pegvisomant does not activate intracellular signal transduction systems , our results support the concept that the conformational changes required for P10912 signaling are not essential for the intracellular trafficking of the ligand and establish one potential contributing mechanism for pegvisomant clearance .", "Experience from the Argentine DB00082 Observational Study : preliminary data . The P10912 antagonist pegvisomant is an efficient agent to achieve biochemical control of acromegaly in those cases refractory to surgery and medical therapy with somatostatin analogs . We conducted an observational multicenter study consisting of data collection in accordance with the standard management of patients with acromegaly in everyday practice . We reviewed the medical records of 28 patients , 23 females , who were treated with pegvisomant due to the lack of biochemical response or intolerance to the somatostatin analogs . The objective was to monitor long - term safety and efficacy of the antagonist . 82 % of the patients had previous pituitary surgery , 53 . 6 % radiotherapy and 96 . 4 % received medical therapy for acromegaly . Only 19 . 2 % of the patients had pituitary residual tumor size larger than 1 cm , the remainder harbored a microadenoma or no visible tumor in the pituitary images . In terms of biochemical efficacy , P05019 levels decreased to normal ranges in 45 % and 58 . 8 % of patients after 3 and 6 months of treatment , respectively , the daily mean dose of pegvisomant being 9 . 6 +/- 1 . 1 mg . Adverse events , potentially related to pegvisomant were reported in 6 patients ( 21 . 4 % ) , local injection site reaction and elevated liver enzymes being the most frequent . Tumor size did not show enlargement in the evaluated population ( 15 patients ) during the period of the study . This paper presents preliminary data from a small observational study in Argentina which represents the first database in our country .", "Successful treatment of resistant acromegaly with a growth hormone receptor antagonist . BACKGROUND / OBJECTIVE : DB00082 is a pegylated analogue of human GH and functions as a potent P10912 antagonist . This novel mode of action gives it the potential to achieve biochemical control in patients with acromegaly whose disease activity can not be satisfactorily controlled by conventional therapy . We have documented the clinical details of seven patients with residual active acromegaly after surgery and / or radiation therapy successfully treated with pegvisomant . PATIENTS / METHODS : Seven patients ( four male , mean age 47 years , range 34 - 67 years ) who participated in two separate clinical trials of pegvisomant have completed 2 years ( four patients ) or 1 year ( three patients ) of treatment . All had active acromegaly ( mean serum GH level > 5 mU / l ; serum P05019 elevated for age ) that could not be controlled with standard medical therapy ( dopamine agonist and / or a somatostatin analogue ) following appropriate primary treatment with surgery and / or radiotherapy . RESULTS : On a median dose of 20 mg / day ( range 15 - 40 ) pegvisomant , serum P05019 fell from a mean of 920 +/- 351 ng / ml ( s . d . ) to 258 +/- 91 ng / ml and was normalised in all seven patients . These changes were associated with improvements in soft tissue enlargement and general well being . Treatment was well tolerated and no change in pituitary tumour size was evident on Q9BWK5 scans performed every 6 months . CONCLUSIONS : Treatment with pegvisomant is safe and efficacy is maintained after 2 years . Serum P05019 may be normalised in patients who are refractory to conventional therapy .", "A comparison of the effects of pegvisomant and octreotide on glucose , insulin , gastrin , cholecystokinin , and pancreatic polypeptide responses to oral glucose and a standard mixed meal . Standard medical therapy for patients with acromegaly includes somatostatin analogs . Owing to the widespread expression of somatostatin receptors , these may be associated with unwanted effects , such as altered glucose tolerance and impaired gut hormone release . DB00082 is a novel pegylated GH analog that competes with wild - type GH for GH - receptor binding sites but contains a position 120 , amino acid substitution that prevents functional P10912 dimerization , a known prerequisite for GH signal transduction and generation of P05019 . We have studied the short - term effects of these two therapies ( pegvisomant 20 mg / d for 7 d and octreotide 50 microg thrice daily for 7 d ) on glucose tolerance and stimulated gut hormone release in six healthy male volunteers in an open - label , random - order , cross - over study . Subjects were assessed at baseline ( oral glucose tolerance test and standard mixed meal ) and on d 6 and 7 of each therapy with a minimum washout of 2 wk between treatments . Area under the curve and peak responses were analyzed using one - way repeated - measures Q9UNW9 ( on ranks where appropriate ) . DB00082 had no effect on glucose tolerance or stimulated gut hormone response during an oral glucose tolerance test and a standard meal . In contrast , octreotide significantly increased fasting plasma glucose , lowered fasting plasma insulin , and led to deterioration in glucose tolerance ; three subjects developed impaired glucose tolerance and one diabetes mellitus by World Health Organization criteria . DB00104 significantly impaired stimulated release of cholecystokinin , gastrin , insulin , and pancreatic polypeptide . In conclusion , pegvisomant , unlike octreotide , is not associated with deterioration in glucose tolerance and impairment of stimulated gut hormone release in normal males .", "[ P10912 antagonists : potential indications ] . DB00082 is a mutated human growth hormone molecule , which binds to the growth hormone receptor . This binding , however , does not lead to signal transduction . Therefore , in high concentrations pegvisomant acts as a growth hormone receptor antagonist . In a short term study ( 3 months ) pegvisomant was shown to be an effective treatment for acromegaly . On theoretical grounds decreasing the biological effects of growth hormone in patients with diabetes mellitus could have a favourable impact on the severity of the secondary complications associated with this disease . Animal models for diabetic retino - and nephropathy are in accordance with this concept . Human data are lacking but clinical studies investigating the effect of pegvisomant in diabetes mellitus are in preparation . Growth hormone , either directly or via its downstream effector insulin - like growth factor - I ( P05019 ) has been implicated as an important factor in the growth of malignant tumours . Animal studies in which human colon and breast cancer models were used showed that pegvisomant can powerfully decrease tumour growth . Studies in cancer patients have not yet started .", "Expression of candidate genes for residual feed intake in Angus cattle . Residual feed intake ( RFI ) has been adopted in Australia for the purpose of genetic improvement in feed efficiency in beef cattle . RFI is the difference between the observed feed intake of an animal and the predicted feed intake based on its size and growth rate over a test period . Gene expression of eight candidate genes ( P02765 , P10912 , P09488 , P08476 , Q8TAB3 , P60903 , O75830 and P08294 ) , previously identified as differentially expressed between divergent lines of high - and low - RFI animals , was measured in an unselected population of 60 steers from the Angus Society Elite Progeny Test Program using quantitative real - time PCR . Results showed that the levels of gene expression were significantly correlated with RFI . The genes explain around 33 . 2 % of the phenotypic variance in RFI , and prediction equations using the expression data are reasonably accurate estimators of RFI . The association of these genes with economically important traits , such as other feed efficiency - related traits and fat , growth and carcass traits , was investigated as well . The expression of these candidate genes was significantly correlated with feed conversion ratio and daily feed intake , which are highly associated with RFI , suggesting a functional role for these genes in modulating feed utilisation . The expression of these genes did not show any association with average daily gain , eye muscle area and carcass composition .", "Novel use of endogenous GH - measurement directly after transsphenoidal microsurgery in acromegaly treated with pegvisomant . OBJECTIVE : The P10912 antagonist pegvisomant is increasingly used as therapy in acromegaly . Pituitary surgery might be indicated on pegvisomant treatment , due to side effects , adenoma growth or intention to cure after primary treatment . This study was initiated to clarify if , and when , GH measurement could be useful postoperatively with an assay specific for endogenous GH that does not cross - react with pegvisomant . METHODS : This study was designed as a prospective study in 2006 with the German Pituitary Working Group . Only 2 cases with potentially resectable adenomas from the German DB00082 Observational Study ( GPOS ) had been operated . Now with a post - operative follow - up of more than 5 years in these 2 cases , the usefulness of immediate pre - operative GH measurement shortly after pegvisomant treatment was evaluated . RESULTS : In both patients a steep decline of endogenous GH after transnasal microsurgery could be proven by using the special GH assay after near radical or radical removal , of the GH secreting adenomas respectively . Conventional GH assays showed no effect . GH half - life was more than 20 min in the patient with a small invasive residual adenoma and less than 20 min in the cured patient . Endogenous GH - levels declined to less than 1 ng / ml in the days after surgery in the patient with long - term cure . CONCLUSION : Measurement of endogenous GH in this special subgroup of patients under pegvisomant therapy can be used to decide upon early reoperation . Thus the beneficial effect of pegvisomant on acromegalic symptoms can be kept without interfering with post - operative monitoring of GH levels .", "P10912 antagonists . Growth hormone ( GH ) has profound effects on vertebrate growth and cellular differentiation in diverse tissue types . Sexually dimorphic levels of circulating GH vary during development and throughout the lifespan . The synthesis and secretion of GH by the pituitary gland are precisely controlled . Abnormal levels are pathological ; hyposecretion in children results in dwarfism while hypersecretion results in acromegaly . This review provides an overview of GH and the GH / insulin - like growth factor ( DB01277 ) axis and highlights a P10912 antagonist ( i . e . Somavert ( R ) , pegvisomant ) . This antagonist competes with endogenous GH for the receptor and results in suppression of serum insulin - like growth factor ( DB01277 ) . DB00082 is important for the treatment of acromegaly and may have therapeutic implications for certain types of cancer and end organ damage due to diabetes .", "Increased renal Akt / P42345 and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation . Growth hormone ( GH ) and P05019 have been implicated in the pathogenesis of type I diabetic ( DM ) nephropathy . We investigated renal P10912 ( P10912 ) and IGF - type 1 receptor ( P08069 ) signaling in an animal model of type I DM . Kidney tissue was examined for P10912 and P08069 key signaling molecules . P10912 levels were unchanged and P05019 mRNA levels were decreased in the diabetic group ( D ) . Basal and GH stimulated phosphorylated ( p - ) O60674 and P42229 levels were similar in controls ( C ) and D . The levels of p - P08069 were similar in the two groups at baseline , while pAkt , pGSK3 , p - P42345 , p - rpS6 , p - erk1 / 2 ( Mapk ) , and pSTAT - 3 were increased in D . Following P05019 administration p - Akt , p - rpS6 , p - Mapk , and p - GSK levels increased more pronouncedly in D versus C . In conclusion , the lack of O60674 - P42229 activation and the decrease in kidney P05019 mRNA levels in D argue against a role for the GH activated O60674 - P42229 pathway in the pathogenesis of diabetic nephropathy . On the other hand while P08069 phosphorylation was unchanged , Akt / P42345 and MAPK signaling were hyperactivate in DM , suggesting their involvement . The increase in baseline activated Akt , P42345 , rpS6 , and MAPK can not be explained by activation of the P08069 , but may be triggered by other growth factors and nutrients .", "Lessons from 6 years of P10912 antagonist therapy for acromegaly . DB00082 is a P10912 antagonist and a new agent for the medical management of acromegaly . The clinical efficacy and safety of pegvisomant in the treatment of active acromegaly were demonstrated in a 12 - week , placebo - controlled trial of 112 patients . After a washout period , patients were randomized to a fixed dose of pegvisomant ( 10 , 15 or 20 mg / day ) or placebo given by sc injection . Serum P05019 levels were within the normal age - adjusted reference range in 54 , 81 and 89 % of patients in the 10 - , 15 - and 20 - mg / day groups , respectively . The decrease in serum P05019 levels was accompanied by considerable improvement in the signs and symptoms of active acromegaly . This efficacy profile was maintained in a long - term continuation trial , with normalization of serum P05019 at 12 months occurring in 97 % of patients . DB00082 has been well tolerated with an adverse event profile similar to placebo . Two patients had elevations in liver function tests that resolved after discontinuing treatment with pegvisomant . During treatment with pegvisomant , liver function tests should be monitored on a regular basis . Two patients had an increase in pituitary tumor volume during pegvisomant therapy ; however , the relationship to pegvisomant therapy was not clear . In 131 patients treated for at least 6 months , there was no increase in mean tumor volume , regardless of whether they underwent previous radiotherapy . DB00082 is an effective new treatment for the management of patients with acromegaly . Longer - term data are needed to confirm the safety profile that has been demonstrated in studies up to 18 months ." ]

[ "___MASK14___", "___MASK22___", "___MASK34___", "___MASK54___", "___MASK5___", "___MASK75___", "___MASK95___", "___MASK98___", "___MASK99___" ]

[ "The effect of etanercept on cardiac transplant recipients : a study of TNFalpha antagonism and cardiac allograft hypertrophy . Cardiac allograft hypertrophy is associated with persistent expression of cardiac tumor necrosis factor ( P01375 ) - alpha . We investigated whether TNFalpha antagonism would impact allograft hypertrophy . EFECT ( EFfect of DB00005 on Cardiac Transplantation ) was a randomized , controlled , double - blind trial evaluating the effect of etanercept versus placebo treatment immediately posttransplant . The primary end - point was change in left ventricular ( LV ) mass after 6 months . Secondary endpoints included degree of collagen deposition at 6 months and incidence of adverse events . Forty - nine patients were randomized to either etanercept or placebo . LV mass increased significantly in both arms at 6 months , with a smaller increase in the etanercept group ( 19 % vs . 33 % , P = ns ) . Myocardial collagen content increased in the placebo , but not the etanercept , group ( + 39 . 8 % , P < 0 . 08 vs . - 7 . 0 % , P = NS ) . Allograft hypertrophy develops posttransplant with a corresponding increase in extracellular matrix . DB00005 appeared to decrease LV hypertrophy by decreasing extracellular matrix deposition .", "DB00005 - induced cystic acne . P01375 α antagonists are potent biologics used to treat a variety of autoimmune disorders such as rheumatoid arthritis , ankylosing spondylitis , Crohn disease , psoriasis , and psoriatic arthritis . These medications are known to have many side effects ( eg , infusion reactions , cytopenia , risk for infection , heart failure ) ; however , only a few cases of acne vulgaris have been associated with the use of these biologics , particularly infliximab and adalimumab . We report a rare case of etanercept - induced cystic acne .", "Selective inhibition of P23458 and O60674 is efficacious in rodent models of arthritis : preclinical characterization of INCB028050 . Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis . Kinase inhibitors have shown promising oral disease - modifying antirheumatic drug potential with efficacy similar to anti - P01375 biologics . Direct and indirect inhibition of the JAKs , with small molecule inhibitors like CP - 690 , 550 and ___MASK83___ or neutralizing Abs , such as the anti - P05231 receptor Ab tocilizumab , have demonstrated rapid and sustained improvement in clinical measures of disease , consistent with their respective preclinical experiments . Therefore , it is of interest to identify optimized JAK inhibitors with unique profiles to maximize therapeutic opportunities . INCB028050 is a selective orally bioavailable P23458 / O60674 inhibitor with nanomolar potency against P23458 ( 5 . 9 nM ) and O60674 ( 5 . 7 nM ) . INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including P05231 and IL - 23 at concentrations < 50 nM . Significant efficacy , as assessed by improvements in clinical , histologic and radiographic signs of disease , was achieved in the rat adjuvant arthritis model with doses of INCB028050 providing partial and / or periodic inhibition of P23458 / O60674 and no inhibition of P52333 . Diminution of inflammatory Th1 and Th17 associated cytokine mRNA levels was observed in the draining lymph nodes of treated rats . INCB028050 was also effective in multiple murine models of arthritis , with no evidence of suppression of humoral immunity or adverse hematologic effects . These data suggest that fractional inhibition of P23458 and O60674 is sufficient for significant activity in autoimmune disease models . Clinical evaluation of INCB028050 in RA is ongoing .", "DB00005 induces improvement of arthropathy in chronic infantile neurological cutaneous articular ( CINCA ) syndrome . Chronic infantile neurological cutaneous articular ( CINCA ) syndrome is a rare disorder of unknown aetiology with neonatal onset , characterized by severe arthropathy , persistent skin rash and central nervous system disease . Joint involvement may vary from minimal swelling to destructive arthritis , with inability to stand or walk . The most striking findings of CINCA syndrome are cartilage anomalies with epiphyseal modifications and abnormal ossification , for which a pathogenetic role of tumour necrosis factor - alpha ( P01375 ) is postulated . We describe a 4 - year - old child affected with CINCA syndrome and presenting progressive joint disease , in whom non - steroidal anti - inflammatory drugs ( NSAID ) and systemic corticosteroidal therapy had been ineffective . DB00005 , anti - P01375 therapy , was administered over a 6 - month - period resulting in a dramatic improvement of the arthropathy . This good response to anti - cytokine treatment supports our hypothesis that P01375 might play an important role in the pathogenesis of CINCA syndrome , which needs to be evaluated and confirmed in further studies .", "___MASK96___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK96___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK96___ is a promising pharmacological tool in the treatment of renal edema .", "Pneumococcal meningitis and etanercept -- chance or association ? Rheumatoid arthritis is a severe deforming chronic disease which has major implications for mortality and quality of life . Agents with anti - tumour necrosis factor alpha ( TNFalpha ) activity are a new modality of therapy , which can significantly reduce the acute inflammation in this condition . However , TNFalpha is a cytokine involved in initiating the protective immune response ; consequently , patients receiving this therapy are at increased risk of infection . DB00005 is a recombinant form of the p75 P01375 receptor ( P20333 ) dimerised by fusion with a portion of the human IgG1 Fc tail with anti - TNFalpha activity . We report the first case of a patient with rheumatoid arthritis who developed pneumococcal meningitis whilst on etanercept , suggesting a possible association between etanercept and this severe life threatening infection .", "The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer . It is now well established that cancer cells exhibit a number of genetic defects in the machinery that governs programmed cell death and that sabotage of apoptosis is one of the principal factors aiding in the evolution of the carcinogenic phenotype . A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer , whereby promoter hypermethylation silences genes essential for many processes including apoptosis . To date , studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast , colon and stomach , with only limited data available on prostate cancer . Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer . The most significant advances have involved the discovery of apoptotic gene targets of methylation , including Q6GPH4 , ( fragile histidine triad ( P49789 ) , cellular retinol binding protein 1 ( P09455 ) , decoy receptor 1 ( O14798 ) , decoy receptor 2 ( Q9UBN6 ) , target of methylation - induced silenceing 1 ( Q9ULZ3 ) , P01375 receptor superfamily , member 6 ( FAS ) , Reprimo ( Q9NS64 ) and P08151 pathogenesis - related 1 ( P48060 ) . These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers . We also introduce the concept of an ' apoptotic methylation signature ' for prostate cancer and evaluate its potential in a diagnostic , prognostic and therapeutic setting .", "___MASK38___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK38___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK38___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .", "DB00005 does not impair healing in rat models of tendon or metaphyseal bone injury . BACKGROUND AND PURPOSE : Should blockade of P01375 - α be avoided after orthopedic surgery ? Healing of injuries in soft tissues and bone starts with a brief inflammatory phase . Modulation of inflammatory signaling might therefore interfere with healing . For example , Cox inhibitors impair healing in animal models of tendon , ligament , and bone injury , as well as in fracture patients . P01375 - α is expressed locally at increased levels during early healing of these tissues . We therefore investigated whether blocking of P01375 - α with etanercept influences the healing process in established rat models of injury of tendons and metaphyseal bone . METHODS : Rats were injected with etanercept , 3 . 5 mg / kg 3 times a week . Healing of transected Achilles tendons and bone healing around screws implanted in the tibial metaphysis were estimated by mechanical testing . Tendons were allowed to heal either with or without mechanical loading . Ectopic bone induction following intramuscular P12643 implants has previously been shown to be stimulated by etanercept in rodents . This was now tested as a positive control . RESULTS : Tendon peak force after 10 days was not significantly influenced by etanercept . Changes exceeding 29 % could be excluded with 95 % confidence . Likewise , screw pull - out force was not significantly influenced . More than 25 % decrease or 18 % increase could be excluded with 95 % confidence . However , etanercept treatment increased the amount of bone induced by intramuscular P12643 implants , as estimated by blind histological scoring . INTERPRETATION : DB00005 does not appear to impair tendon or metaphyseal bone healing to any substantial degree .", "DB00005 reduces thermal and mechanical orofacial hyperalgesia following inflammation and neuropathic injury . BACKGROUND : This study evaluated the involvement of tumour necrosis factor α ( P01375 - α ) in orofacial thermal and mechanical hyperalgesia induced by an inflammatory stimulus or by chronic constriction of the infraorbital nerve ( CION ) using etanercept ( Eta ) , a P01375 - receptor fusion protein that inhibits P01375 - α action . METHODS : Animals were treated with Eta ( 0 . 5 and 5 . 0 mg / kg , s . c . ) or dexamethasone ( DB00514 , 0 . 5 , 1 . 0 and 2 . 0 mg / kg , s . c . ) and orofacial thermal ( cold and heat ) and mechanical hyperalgesia induced by an inflammatory stimulus ( carrageenan , Cg 50 and 100 μg / lip ) or by chronic CION , a model of neuropathic pain in the orofacial region was evaluated . Treatments with DB00514 or Eta were carried out before Cg or before or after CION . RESULTS : Eta or DB00514 abolished inflammatory thermal and mechanical hyperalgesia . Also , each drug , when given at the day of the surgery and the subsequent day , was effective to abolish thermal and mechanical hyperalgesia induced by CION , assessed on day 4 and on day 13 after the surgery , respectively . However , Eta , but not DB00514 , given after the CION , abolished thermal and mechanical hyperalgesia and reduced P01375 - α level in the trigeminal ganglion . CONCLUSIONS : These results suggest that P01375 - α has an important role in cold , heat and mechanical hyperalgesia induced by inflammation or neuropathy in the orofacial region and this may contribute for the establishment of new therapeutic strategies to treat orofacial pain .", "Effects of etanercept , a tumour necrosis factor - alpha antagonist , in an experimental model of periodontitis in rats . BACKGROUND AND PURPOSE : DB00005 is a tumour necrosis factor antagonist with anti - inflammatory effects . The aim of our study was to evaluate , for the first time , the therapeutic efficacy of in vivo inhibition of P01375 in an experimental model of periodontitis . EXPERIMENTAL APPROACH : Periodontitis was induced in adult male Sprague - Dawley rats by placing a nylon thread ligature around the lower 1st molars . DB00005 was administered at a dose of 5 mg kg - 1 , s . c . , after placement of the ligature . KEY RESULTS : Periodontitis in rats resulted in an inflammatory process characterized by oedema , neutrophil infiltration and cytokine production that was followed by the recruitment of other inflammatory cells , production of a range of inflammatory mediators , tissue damage , apoptosis and disease . Treatment of the rats with etanercept ( 5 mg kg - 1 , s . c . , after placement of the ligature ) significantly reduced the degree of ( 1 ) periodontitis inflammation and tissue injury ( histological score ) , ( 2 ) infiltration of neutrophils ( P05164 evaluation ) , ( 3 ) P35228 ( the expression of nitrotyrosine and cytokines ( eg P01375 ) ) and ( 4 ) apoptosis ( Bax and Bcl - 2 expression ) . CONCLUSIONS AND IMPLICATIONS : Taken together , our results clearly demonstrate that treatment with etanercept reduces the development of inflammation and tissue injury , events associated with periodontitis .", "Acute hepatitis C in a patient receiving etanercept . According to the literature , the use of tumor necrosis factor ( P01375 ) inhibitors in patients with chronic hepatitis C infection is safe and effective . There have been no reports , however , of primary infection with the hepatitis C virus during treatment with a biologic agent . We report the case of a patient with long - standing moderate to severe psoriasis who developed acute hepatitis C while being treated with etanercept . Biologic therapy was continued and the infection was successfully treated with pegylated interferon , which achieved a sustained virologic response . DB00005 did not have a negative impact on disease outcome or on response to antiviral treatment .", "DB00005 suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of interleukin ( IL ) - 19 , IL - 20 and Q13007 . BACKGROUND : Psoriasis is a Th17 / Th1 - mediated skin disease that often responds to antitumour necrosis factor ( P01375 ) - α therapies , such as etanercept . OBJECTIVES : To better define mechanisms by which etanercept improves psoriasis and to gain insight into disease pathogenesis . METHODS : We investigated the early biochemical and cellular effects of etanercept on skin lesions in responder patients prior to substantial clinical improvement ( ≤ 4 weeks ) . RESULTS : By 1 week , etanercept acutely suppressed gene expression of the interleukin ( IL ) - 20 subfamily of cytokines ( Q9UHD0 , IL - 20 , Q13007 ) , which were found to be predominantly epidermis - derived and which are implicated in stimulating epidermal hyperplasia . Additionally , by 1 week of therapy , suppression of other keratinocyte - derived products ( chemokines , antimicrobial proteins ) occurred , while suppression of epidermal regenerative hyperplasia occurred within 1 - 3 weeks . Th17 elements ( Q9NPF7 , IL - 12p40 , Q16552 , Q9GZX6 ) were suppressed by 3 - 4 weeks . In vitro , P01375 - α and Q16552 coordinately stimulated the expression of the IL - 20 subfamily in normal keratinocytes . CONCLUSIONS : Based on the rapid suppression of regenerative hyperplasia , chemokines and other keratinocyte - derived products , including the IL - 20 subfamily , we propose that epidermal activation is a very early target of etanercept . As many of these keratinocyte markers are stimulated by P01375 - α , their rapid downregulation is likely to reflect etanercept ' s antagonism of P01375 - α . Additionally , decreased epidermal hyperplasia might result specifically from acute suppression of the IL - 20 subfamily , which is also a likely consequence of etanercept ' s antagonism of P01375 - α . Thus , the IL - 20 subfamily has potential importance in the pathogenesis of psoriasis and therapeutic response to etanercept .", "Activation - induced T cell death , and aberrant T cell activation via P19438 and CD95 - P48023 pathway in stable cardiac transplant recipients . Specific blockade by antibodies ( Abs ) utilized in induction therapy may cause activation - induced cell death ( AICD ) in lymphocytes of transplant recipients , preactivated via CD95 and tumour necrosis factor - alpha receptor type 1 ( P19438 ) , and reduce allograft rejection frequency . Amongst 618 heart transplant ( HTX ) patients receiving antithymocytes globulin ( ATG ) therapy , 14 recipients with IVUS - verified freedom of transplant vasculopathy were studied . The control group contained 14 patients awaiting transplantation , classified by the New York Hearth Association heart failure as class IV . From 618 HTX patients 89 % were free of rejection grade ISHLT > or = 2 - 3 within 3 - month post transplantation and 86 % after one year . The death inducing receptors ( P30518 ) such as CD95 , P48023 and soluble P19438 were significantly increased in HTX recipients versus controls , as demonstrated by FACS , immunoblotting or ELISA ( P < 0 . 001 ) . The presence of increased P30518 and in vivo apoptosis in HTX recipients , indicated by annexin - V binding , was further confirmed by the presence of high concentration of histones in the sera of patients . ATG , anti - IL - 2R and OKT - 3 Abs inhibited cell proliferation in a dose - dependent manner . The induction of apoptosis and / or necrosis was demonstrated in cells cultured with these Abs by annexin - V and 7 - aminoactinomycin staining , respectively . Our findings demonstrate that T cells from HTX recipients express high level of CD95 , P48023 and soluble P19438 , and undergo apoptosis and AICD . These cells recognizing donor alloantigens may be selectively eliminated in vivo , and should be responsible for the observed immunological unresponsiveness , indicated by low rejection rates in our patient cohort treated by conventional triple therapy .", "The treatment of established murine collagen - induced arthritis with a P19438 - selective antagonistic mutant P01375 . Blocking the binding of P01375 to P01375 receptor subtype - 1 ( P19438 ) is an important strategy for the treatment of rheumatoid arthritis ( RA ) . We recently succeeded in developing a P19438 - selective antagonistic P01375 mutant , R1antTNF . Here , we report the anti - inflammatory effects of R1antTNF in a murine collagen - induced arthritis model . To improve the in vivo stability of R1antTNF , we first engineered PEG ( polyethylene glycol ) - modified R1antTNF ( PEG - R1antTNF ) . In prophylactic protocols , PEG - R1antTNF clearly improved the incidence , and the clinical score of arthritis due to its long plasma half - life . Although , the effect of PEG - R1antTNF on the incidence and production of IL1 - beta was less than that of the existing P01375 - blocking drug DB00005 , its effect on severity was almost as marked as DB00005 . Interestingly , in therapeutic protocols , PEG - R1antTNF showed greater therapeutic effect than DB00005 . These data suggest that the anti - inflammatory effects of PEG - R1antTNF depend on the stage of arthritis . Recently , there has been much concern over the reactivation of viral infection caused by P01375 blockade . Unlike DB00005 , PEG - R1antTNF did not reactivate viral infection . Together , these results indicate that selective inhibition of P01375 / P19438 could be effective in treating RA and that PEG - R1antTNF could serve as a promising anti - inflammatory drug for this purpose .", "Circulating apoptotic proteins are increased in long - term disease - free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis - related proteins and inflammation markers are increased in long - term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF - receptor ( sTNF - R ) 1 and 2 , sFas , sFas ligand , sTNF - related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High - sensitivity P02741 ( HS - CRP ) , fibrinogen , plasma B - type and N - terminal atrial natriuretic peptide ( NT - P01160 and DB04899 ) were also determined . Thirty - four patients with median 6 . 0 years follow - up and 12 healthy age - matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high - dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high - dose than in the standard - dose group . In conclusion , we observed increased circulating apoptotic protein levels in long - term disease - free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .", "DB00005 ( Enbrel ) : update on therapeutic use . Tumour necrosis factor ( P01375 ) is an important inflammatory disease mediator in a wide spectrum of articular diseases , including adult and juvenile rheumatoid arthritis ( RA , JRA ) . DB00005 ( Enbrel ) , approved in the United States and in Europe for use in patients with RA and JRA , is an effective inhibitor of P01375 that has been shown to provide rapid and sustained improvement in both of these diseases . Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time . To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate , and to examine the effect of etanercept on radiographic progression , a double blind , placebo controlled study was recently conducted , comparing etanercept with methotrexate ( median dose 20 mg per week ) . Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA , and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions . In patients with severe psoriatic arthritis ( PsA ) , a double blind , placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA . DB00005 has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases .", "Immediate neurological recovery following perispinal etanercept years after brain injury . Positron emission tomographic brain imaging and pathological examination have revealed that a chronic , intracerebral neuroinflammatory response lasting for years after a single brain injury may occur in humans . Evidence suggests the immune signaling molecule , tumor necrosis factor ( P01375 ) , is centrally involved in this pathology through its modulation of microglial activation , role in synaptic dysfunction , and induction of depressive symptoms and neuropathic pain . DB00005 is a recombinant P01375 receptor fusion protein and potent P01375 inhibitor that has been found to reduce microglial activation and neuropathic pain in multiple experimental models . We report that a single dose of perispinal etanercept produced an immediate , profound , and sustained improvement in expressive aphasia , speech apraxia , and left hemiparesis in a patient with chronic , intractable , debilitating neurological dysfunction present for more than 3 years after acute brain injury . These results indicate that acute brain injury - induced pathologic levels of P01375 may provide a therapeutic target that can be addressed years after injury . Perispinal administration of etanercept is capable of producing immediate relief from brain injury - mediated neurological dysfunction .", "DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "[ Treatment of psoriatic arthritis with P01375 alpha - antagonists ] . The proinflammatory cytokine P01375 alpha is in the pathogenesis of PsA as important as in RA . P01375 is increased in the psoriatic skin lesion and in the synovium of the inflamed joint . The P01375 alpha blockage has been tested in double blind trials with etanercept and infliximab . All studies proved a significant and durable response in the reduction of synovitis in a comparable extend in both drugs . DB00005 showed after 12 weeks an ACR20 response in 59 % of the patients versus 15 % in the placebo arm . DB00065 had after 14 weeks a 69 % ACR20 response versus 8 % placebo response . The psoriatic skin lesion improved with both drugs . The PASI was reduced by 47 % with etanercept and by 81 % with infliximab . The safety - profile was similar to the RA - trials . For etanercept the one year data have shown a reduction in x - ray progression . DB00005 has been approved in the USA and in Europe .", "Targeting anti - inflammatory treatment can ameliorate injury - induced neuropathic pain . P01375 - α plays important roles in immune system development , immune response regulation , and T - cell - mediated tissue injury . The present study assessed the net value of anti - tumor necrosis factor - α treatment in terms of functional recovery and inhibition of hypersensitivity after peripheral nerve crush injury . We created a right sciatic nerve crush injury model using a Sugita aneurysm clip . Animals were separated into 3 groups : the first group received only a skin incision ; the second group received nerve crush injury and intraperitoneal vehicle injection ; and the third group received nerve crush injury and intraperitoneal etanercept ( 6 mg / kg ) . DB00005 treatment improved recovery of motor nerve conduction velocity , muscle weight loss , and sciatic functional index . Plantar thermal and von Frey mechanical withdrawal thresholds recovered faster in the etanercept group than in the control group . On day 7 after crush injury , the numbers of ED - 1 - positive cells in crushed nerves of the control and etanercept groups were increased compared to that in the sham - treated group . After 21 days , ED - 1 - positive cells had nearly disappeared from the etanercept group . DB00005 reduced expression of interleukin - 6 and monocyte chemotactic and activating factor - 1 at the crushed sciatic nerve . These findings demonstrate the utility of etanercept , in terms of both enhancing functional recovery and suppressing hypersensitivity after nerve crush . DB00005 does not impede the onset or progression of Wallerian degeneration , but optimizes the involvement of macrophages and the secretion of inflammatory mediators .", "Deficient spontaneous in vitro apoptosis and increased tmTNF reverse signaling - induced apoptosis of monocytes predict suboptimal therapeutic response of rheumatoid arthritis to P01375 inhibition . INTRODUCTION : In vitro apoptosis of peripheral monocytes in rheumatoid arthritis ( RA ) is disturbed and influenced by cytokine production and transmembrane P01375 ( tmTNF ) reverse signaling . The goal of the study was the analysis of the predictive value of the rate of in vitro apoptosis for the therapeutic response to anti - P01375 treatment . METHODS : Spontaneous and tmTNF reverse signaling - induced apoptosis were determined in vitro in monocytes from 20 RA patients prior to initiation of therapeutic P01375 inhibition with etanercept , and the subsequent clinical response was monitored . RESULTS : Spontaneous in vitro apoptosis was significantly reduced in RA patients compared to controls . Deficiency in spontaneous apoptosis was associated with an insufficient therapeutic response according to the European League Against Rheumatism ( EULAR ) response criteria and less reduction of the disease activity determined by disease activity score ( DAS ) 28 . High susceptibility to reverse signaling - induced apoptosis was also associated with less efficient reduction in the DAS28 . Of note , a strong negative correlation between the two apoptotic parameters was discernible , possibly indicative of two pathogenetically relevant processes counter - regulating each other . tmTNF reverse signaling induced in vitro production of soluble IL1 - RI and IL - 1RII only in monocytes not deficient in spontaneous apoptosis , and the levels of soluble IL1 - RII were found to be predictive of a good clinical response to DB00005 . CONCLUSION : Although tmTNF reverse signaling is able to induce apoptosis of RA monocytes in vitro , this process appears to occur in vitro preferentially in patients with suboptimal therapeutic response . Resistance to spontaneous in vitro apoptosis , in contrast , is a predictor of insufficient response to treatment .", "DB00005 in the treatment of rheumatoid arthritis . INTRODUCTION : Biologic agents have transformed clinical outcomes in rheumatoid arthritis , and there are now several immune - modulating therapies available . Tumour necrosis factor - α ( P01375 - α ) inhibitors were the first biologic drug class licensed for the treatment of rheumatoid arthritis . DB00005 is a fusion protein composed of two P01375 receptors bound to the constant portion ( Fc ) of human immunoglobulin G ( IgG ) . AREAS COVERED : This article will consider the pharmacological properties of etanercept and the clinical efficacy data presented in clinical trials . Its safety in clinical practice will be reviewed . EXPERT OPINION : There is overwhelming evidence to support the use of etanercept in rheumatoid arthritis . Trial data demonstrate etanercept ' s efficacy in reducing structural damage , improving clinical outcomes and inducing remission . Optimal response to therapy is seen when used in combination with methotrexate and when initiated early . DB00005 is an attractive therapeutic option given the excellent safety profile , reduced immunogenicity and ease of administration .", "Q9GZV9 contributes to diminished bone mineral density in childhood inflammatory bowel disease . BACKGROUND : Diminished bone mineral density ( BMD ) is of significant concern in pediatric inflammatory bowel disease ( Q9UKU7 ) . Exact etiology is debatable . The recognition of fibroblast growth factor 23 ( Q9GZV9 ) , a phosphaturic hormone related to tumor necrosis factor alpha ( P01375 - α ) makes it plausible to hypothesize its possible relation to this pathology . METHODS : In this follow up case control study , BMD as well as serum levels of Q9GZV9 , calcium , phosphorus , alkaline phosphatase , creatinine , parathyroid hormone , 25 hydroxy vitamin D3 and 1 , 25 dihydroxy vitamin D3 were measured in 47 children with Q9UKU7 during flare and reassessed in the next remission . RESULTS : Low BMD was frequent during Q9UKU7 flare ( 87 . 2 % ) with significant improvement after remission ( 44 . 7 % ) . During disease flare , only 21 . 3 % of patients had vitamin D deficiency , which was severe in 12 . 8 % . During remission , all patients had normal vitamin D except for two patients with Crohn ' s disease ( CD ) who remained vitamin D deficient . Mean value of serum Q9GZV9 was significantly higher among patients with Q9UKU7 during flare compared to controls . It showed significant improvement during remission but not to the control values . 1 , 25 dihydroxy vitamin D3 , Q9GZV9 , serum calcium and urinary phosphorus were significant determinants of BMD in Q9UKU7 patients . CONCLUSIONS : We can conclude that diminished BMD in childhood Q9UKU7 is a common multifactorial problem . Elevated Q9GZV9 would be a novel addition to the list of factors affecting bone mineral density in this context . Further molecular studies are warranted to display the exact interplay of these factors .", "DB00005 induced organizing pneumonia in a patient with rheumatoid arthritis . P01375 inhibitors are being used in a rapidly expanding number of rheumatoid arthritis ( RA ) patients due to their effectiveness and acceptable safety profiles . To date , concerns regarding the adverse effects of P01375 inhibitors have focused on infections , hematologic malignancies , and demyelinating disorders . Recently , the development of autoantibodies and other autoimmunity has been increasingly reported . Here , we describe a 36 - year - old RA patient in whom organizing pneumonia and systemic lupus erythematosus were detected during etanercept treatment .", "DB00005 : therapeutic use in patients with rheumatoid arthritis . Tumour necrosis factor ( P01375 ) plays a central part in the pathophysiology of rheumatoid arthritis ( RA ) . P01375 initiates signal transduction by interacting with surface bound P01375 receptors . Soluble tumour necrosis factor receptors ( sTNFRs ) act as natural inhibitors of P01375 activity . DB00005 , recombinant p75 sTNFR : Fc fusion protein , has received approval from the US Food and Drug Administration for patients with RA and juvenile RA ( JRA ) who have failed treatment with at least one other drug . DB00005 has demonstrated excellent safety and efficacy in large scale , randomised , double blind , placebo controlled trials of patients with RA and JRA who are refractory to other disease modifying anti - rheumatic drugs . The therapeutic effects mediated by etanercept are rapid and sustained . Combining etanercept with methotrexate was found to be safe and more effective than treatment with methotrexate alone in the treatment of RA . These clinical findings demonstrate that etanercept can result in symptomatic improvement in patients with RA and JRA . DB00005 is an important new addition to the treatment of these diseases .", "DB00005 causes regression of endometriotic implants in a rat model . OBJECTIVE : To determine the effects of etanercept ( anti - P01375 - α ) on surgically induced endometriosis in a rat model . MATERIALS AND METHODS : This is a prospective , randomized , controlled , experimental study that was carried out at the Experimental Research Center of Yeditepe University ( YUDETAM ) . Thirty female nonpregnant , nulligravid Wistar - Hannover albino rats were used . The summary of the technique : surgical induction of endometriosis , administration of estrogen for 2 weeks , and laparotomy ; administration of etanercept for 2 weeks following the induction of endometriosis and laparotomy ; administration of estrogen for 2 weeks and necropsy . The volume and histopathological scores of the endometriotic foci were evaluated . RESULTS : One - hundred twenty uterine horns were implanted in 30 rats . Endometriosis was completely formatted in 112 lesions ( 93 . 3 % ) . No rats were lost . In the etanercept group , the lesions ' volumes were 83 . 9 ± 13 . 1 , 47 . 2 ± 8 . 4 , and 96 . 7 ± 34 . 8 mm ( 3 ) at the end of the second week ( pretreatment stage ) , at the end of the fourth week ( post - treatment stage ) , and at the end of the sixth week , respectively ( P = 0 . 007 ) . Histopathologic scores were 2 . 3 ± 0 . 2 , 1 . 7 ± 0 . 2 , and 1 . 9 ± 0 . 1 , respectively ( P = 0 . 08 ) . The changes in the other groups were not statistically significant . CONCLUSIONS : DB00005 , a fusion protein consisting of human recombinant soluble P01375 receptor - 2 , neutralizes P01375 activity . Anti - P01375 therapy could be a new non - hormonal therapeutic option for the treatment of endometriosis in humans .", "Intertoe Squamous Cell Carcinoma Developed in a Patient with Rheumatoid Arthritis under DB00005 Therapy . The use of tumor necrosis factor - α ( P01375 - α ) inhibitors in the treatment of various inflammatory conditions has altered the field of medical therapeutics . Squamous cell carcinoma is the second most common cancer of the skin , usually affecting sun - exposed areas of the body . We present here the case of a 75 - year - old woman with rheumatoid arthritis , who developed an intertoe squamous cell carcinoma ( SCC ) of the right foot . According to her history , she received etanercept and methotrexate for 5 years for rheumatoid arthritis . The rare localization of this cancer could suggest a possible linkage of the malignancy to the chronic intake of anti - P01375 - α treatment . This is the first reported case of an interdigital SCC developed under the use of an anti - P01375 - α agent .", "Autosomal - dominant hypophosphatemic rickets ( P30518 ) mutations stabilize Q9GZV9 . BACKGROUND : The gene for the renal phosphate wasting disorder autosomal - dominant hypophosphatemic rickets ( P30518 ) is Q9GZV9 , which encodes a secreted protein related to the fibroblast growth factors ( FGFs ) . We previously detected missense mutations R176Q , R179W , and R179Q in Q9GZV9 from P30518 kindreds . The mutations replace R residues within a subtilisin - like proprotein convertase ( Q969E3 ) cleavage site 176RHTR - 179 ( RXXR motif ) . The goal of these studies was to determine if the P30518 mutations lead to protease resistance of Q9GZV9 . METHODS : The P30518 mutations were introduced into human Q9GZV9 cDNA clones with or without an N - terminal FLAG tag by site - directed mutagenesis and were transiently transfected into HEK293 cells . Protein expression was determined by Western analyses . RESULTS : Antibodies directed toward the C - terminal portion of Q9GZV9 revealed that the native Q9GZV9 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media ; however , the three mutated proteins were detected only as the 32 kD band . An N - terminal FLAG - tagged native Q9GZV9 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody , whereas the R176Q mutant resolved primarily as the 36 kD protein species . Cleavage of Q9GZV9 was not enhanced by extracellular incubation of Q9GZV9 with HEK293 cells . Native and mutant FGF - 23s bound heparin . CONCLUSIONS : Q9GZV9 proteins containing the P30518 mutations are secreted , and produce polypeptides less sensitive to protease cleavage than wild - type Q9GZV9 . Therefore , the P30518 mutations may protect Q9GZV9 from proteolysis , thereby potentially elevating circulating concentrations of Q9GZV9 and leading to phosphate wasting in P30518 patients .", "Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .", "Treatment of pyoderma gangrenosum with etanercept . We describe a patient with pyoderma gangrenosum ( PG ) whose lesions responded to etanercept therapy . This disease has been recognized for diverse underlying pathology and associated immune disturbances . Although the role of cytokines in pathogenesis is not fully understood , tumor necrosis factor alpha ( P01375 ) may facilitate induction and maintenance of the disease . This is supported by the successful use of infliximab , a recombinant anti - P01375 monoclonal antibody , in cases of PG associated with inflammatory bowel disease ( Q9UKU7 ) . DB00005 is a divalent recombinant fusion protein that binds soluble P01375 . To our knowledge , the utility of etanercept for PG has not been reported . A patient with recalcitrant and widespread PG that was unresponsive to systemic corticosteroids was treated with etanercept . Rapid and complete clearing of the skin lesions was observed , and steroid taper to 5 mg / day was sustained for two months . Treatment was well - tolerated with no adverse reactions reported . CONCLUSIONS : DB00005 therapy offered rapid and complete resolution of all PG lesions . Such response supports the use of etanercept as a steroid - sparing agent in recalcitrant disease and suggests the role of P01375 in pathogenesis of PG .", "Pulmonary Mycobacterium kansasii Infection Mimicking Malignancy on the ( 18 ) F - DB09150 PET Scan in a Patient Receiving DB00005 : A Case Report and Literature Review . A 66 - year - old male presented with chest pain , malaise , generalized weakness , and weight loss . He had been receiving etanercept injection for rheumatoid arthritis . Chest X - ray revealed a right upper lobe mass . Chest computed tomography ( CT ) showed a right apical mass , highly suggestive of a Pancoast tumor . The thoracic fluorine - 18 fluoro - deoxy - glucose ( ( 18 ) F - DB09150 ) positron emission tomography ( PET ) scan demonstrated significantly high metabolic pulmonary lesions with the standardized uptake value ( SUV ) of 12 . 5 , consistent with lung cancer . The patient underwent bronchoscopy and bronchoalveolar lavage ( BAL ) . BAL cytology was negative for malignant cells . BAL acid fast bacilli ( AFB ) smears were positive , and Mycobacterium kansasii was eventually isolated . He received a 12 - month course of rifampin , isoniazid , and ethambutol . Interval resolution of pulmonary lesions was noted on follow - up serial CT chest studies . There has been increasing incidence of nontuberculous mycobacterial infections reported in patients treated with the antitumor necrosis factor - alpha ( anti - P01375 ) agents . Infectious foci have an increased glucose metabolism which potentially causes a high DB09150 uptake on the ( 18 ) F - DB09150 PET scan , leading to undue anxiety and cost to the patients . This is the first reported case of pulmonary M . kansasii infection with a positive thoracic ( 18 ) F - DB09150 PET study mimicking malignancy in a patient on etanercept .", "Implementation of the P10323 dose index registry at a large academic institution : early experience . A rising conciousness within both the medical community and in the public has been created by the current levels of radiation exposure from increased use of computed tomography . The concern has prompted the need for more data collection and analysis of hospital and imaging center exam doses . This has spurred the American College of Radiology ( P10323 ) to develop the Dose Index Registry ( P30518 ) , which will allow participating insitutions to compare the radiation dose from their CT exams to aggregate national CT dose data based on exam type and body part . We outline the steps involved in the process of enrolling in the P30518 , the technical requirements , the challenges we encountered , and our solutions to those challenges . A sample of the quaterly report released by the P10323 is presented and discussed . Enrolling in the P10323 dose registry is a team effort with participation from IT , a site physicist , and a site radiologist . Participation in this registry is a great starting point to initiate a QA process for monitoring CT dose if none has been established at an institution . The P10323 has developed an excellent platform for gathering , analyzing , and reporting CT dose data . Even so , each insititutions will have its own unique issues in joining the project .", "A mixed treatment comparison of the efficacy of anti - P01375 agents in rheumatoid arthritis for methotrexate non - responders demonstrates differences between treatments : a Bayesian approach . BACKGROUND : A number of tumour necrosis factor α ( TNFα ) antagonists ( anti - TNFα ) are available to treat rheumatoid arthritis . All of these have demonstrated considerable efficacy in placebo controlled trials , but few head - to - head comparisons exist to date . This work ' s objective is to estimate the relative efficacy among licensed anti - TNFs in patients who have had an inadequate response to methotrexate ( MTX ) . Different outcome measures are used to highlight the advantages of continuous measures in such analyses . METHODS : A systematic review identified randomised controlled trials comparing the efficacy of licensed anti - TNFα agents with placebo at 24 weeks in patients who have had an inadequate response to MTX . Relative efficacy was estimated using Bayesian mixed treatment comparison ( P04629 ) models . Three different outcome measures were used : RR of achieving an American College of Rheumatology ( P10323 ) 20 and ACR50 response and the percentage improvement in Health Assessment Questionnaire ( HAQ ) score . RESULTS : 16 published trials were included in the analysis . All anti - TNFs show considerably improved efficacy over placebo . The P04629 results also provide evidence of some differences in efficacy of the TNFα antagonists . DB00005 appears superior to infliximab and DB06674 , and certolizumab to infliximab and adalimumab . P10323 results indicate improved efficacy of certolizumab over DB06674 . On HAQ analysis , adalimumab , certolizumab , etanercept and DB06674 appear superior to infliximab , and etanercept shows improved efficacy compared with adalimumab . CONCLUSIONS : There are differences in efficacy among the TNFα antagonists . In a P04629 , a continuous outcome measure has more strength to detect such differences than a binomial outcome measure because of its enhanced sensitivity to change .", "P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK80___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Managing moderate - to - severe psoriasis in the elderly . Managing psoriasis in the elderly can be difficult for physicians , who must consider comorbidities , the resulting polypharmacy , and progressive functional impairment of several organs . Indeed , topical agents are the first - line treatment for limited disease . Phototherapy is recommended if topical drugs are not sufficient and the patient has multiple comorbidities and risk factors that make them a poor candidate for an oral or injectable systemic agent . The most important pharmacokinetic alteration in the elderly population is the decreased excretory capacity of the kidney ; thus , cyclosporine should be considered a last resort treatment , and the administered dose of methotrexate should be lowered according to the reduction in estimated creatinine clearance . Acitretin can be used in the absence of severe renal insufficiency , paying attention to lipid profile , treating eventual hyperlipidemia , and closely monitoring liver enzymes . Available data on biological drugs in the elderly are limited . Biologics are associated with a small but significant overall risk of infections . However , there is no convincing evidence that the relative risk of infection with anti - tumor necrosis factor ( P01375 ) - α therapy increases with age . Nevertheless , the package inserts for biologics recommend caution when administering these medications to the geriatric population , due to the high baseline risk of infection in such patients . DB00005 seems to be well tolerated , possibly because of its lower immunosuppressive characteristics compared with other biologics . However , studies with larger sample sizes are needed to confirm its safety .", "DB00005 ( DB01613 ) with methotrexate ( MTX ) is better than DB01613 monotherapy in patients with active rheumatoid arthritis despite MTX therapy : a randomized trial . The superiority of the combination therapy of methotrexate ( MTX ) and anti - tumor necrosis factor ( P01375 ) biological agents over anti - P01375 monotherapy in MTX - naïve patients with rheumatoid arthritis ( RA ) has been demonstrated . We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept ( DB01613 ) in patients with active RA despite MTX therapy . In total , 151 patients with active RA despite treatment with MTX were randomized to either DB01613 25 mg twice a week and MTX 6 - 8 mg / week ( the E + M group ) or DB01613 alone ( the E group ) . Co - primary endpoints included the European League Against Rheumatism ( EULAR ) good response rate and the American College of Rheumatology ( P10323 ) 50 response rate at week 24 . Demographic and clinical features between groups at baseline were similar . The EULAR good response rates were significantly higher in the E + M group ( 52 % ) than in the E group ( 33 % ) at week 24 ( p = 0 . 0001 ) . Although the ACR50 response rate , one of the co - primary endpoints , and the ACR70 response rate at week 24 were not significantly greater in the E + M group ( 64 and 38 % , respectively ) than in the E group ( 48 and 26 % , respectively ) , the ACR20 response rate was significantly greater in the E + M group ( 90 % ) than in the E group ( 64 % ; p = 0 . 0002 ) . Safety profiles were similar for the groups . Thus , MTX should be continued at the commencement of DB01613 therapy , even in RA patients who show an inappropriate response to MTX .", "Recent advances of P01375 antagonists in rheumatoid arthritis and chronic heart failure . P01375 ( P01375 ) - alpha has been thoroughly investigated and established as a pivotal component of the inflammatory cascade . This review encompasses the safety and efficacy of P01375 antagonists in rheumatoid arthritis , the interplay between rheumatoid arthritis and heart failure , as well as presentation of the available preclinical and clinical data discussing the use of anti - P01375 therapy in patients with chronic heart failure . There is well - documented evidence for the role of anti - P01375 in rheumatoid arthritis , in contrast to the controversial role of anti - P01375 in heart failure . In animal models and small - scale clinical trials , anti - P01375 therapy showed some promise in treating chronic heart failure , whereas larger , multicenter , randomized , placebo - controlled clinical trials ( i . e . , RECOVER [ Research into DB00005 Cytokine Antagonism in Ventricular Dysfunction ] and RENAISSANCE [ Randomized DB00005 North American Strategy to Study Antagonism of Cytokines ] ) failed to show a statistically significant difference in composite clinical function score for anti - P01375 therapy versus placebo . Future investigation is needed to determine if individualized dosing of anti - P01375 therapy is necessary and whether or not treating patients with earlier - stage disease will show a benefit .", "Switching to etanercept in patients with rheumatoid arthritis with no response to infliximab . P01375 is thought to play a pivotal role in the initiation and perpetuation of the chronic inflammatory process in rheumatoid arthritis . P01375 blockers such as infliximab and etanercept are currently used in the treatment of active rheumatoid arthritis ( RA ) when traditional DMARDs have failed and are effective in a significant proportion of patients . However , about one third are non - responders to anti - P01375 . The aim of this study was to verify whether rheumatoid patients , after failing infliximab , can benefit from etanercept . We analysed 18 patients with active RA with no response to at least 3 DMARDs and where infliximab therapy had failed . The patients had received infliximab associated with methotrexate : eleven of them did not show any significant response , while seven patients , after a good response , relapsed . DB00005 was then started . EULAR criteria of response were used with calculation of activity index DAS28 at baseline , after 2 weeks , 3 months and every third month until last follow - up . A moderate or good response was achieved with etanercept in 13 out of 18 patients . From our experience , etanercept can be considered as a good alternative choice when infliximab has failed .", "Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK8___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .", "Integrative modeling of transcriptional regulation in response to antirheumatic therapy . BACKGROUND : The investigation of gene regulatory networks is an important issue in molecular systems biology and significant progress has been made by combining different types of biological data . The purpose of this study was to characterize the transcriptional program induced by etanercept therapy in patients with rheumatoid arthritis ( RA ) . DB00005 is known to reduce disease symptoms and progression in RA , but the underlying molecular mechanisms have not been fully elucidated . RESULTS : Using a DNA microarray dataset providing genome - wide expression profiles of 19 RA patients within the first week of therapy we identified significant transcriptional changes in 83 genes . Most of these genes are known to control the human body ' s immune response . A novel algorithm called TILAR was then applied to construct a linear network model of the genes ' regulatory interactions . The inference method derives a model from the data based on the Least Angle Regression while incorporating DNA - binding site information . As a result we obtained a scale - free network that exhibits a self - regulating and highly parallel architecture , and reflects the pleiotropic immunological role of the therapeutic target P01375 . Moreover , we could show that our integrative modeling strategy performs much better than algorithms using gene expression data alone . CONCLUSION : We present TILAR , a method to deduce gene regulatory interactions from gene expression data by integrating information on transcription factor binding sites . The inferred network uncovers gene regulatory effects in response to etanercept and thus provides useful hypotheses about the drug ' s mechanisms of action .", "Blocking Tumor Necrosis Factor α Enhances CD8 T - cell - Dependent Immunity in Experimental Melanoma . P01375 plays a dual , still enigmatic role in melanoma , either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment . Herein , the tumor growth of melanoma cell lines expressing major histocompatibility complex class I molecules at high levels ( MHC - I ( high ) ) was dramatically impaired in P01375 - deficient mice , and this was associated with enhanced tumor - infiltrating CD8 (+) T lymphocytes . Immunodepletion of CD8 T cells fully restored melanoma growth in P01375 (-/-) mice . Systemic administration of DB00005 inhibited MHC - I ( high ) melanoma growth in immunocompetent but not in immunodeficient ( IFNγ (-/-) , nude , or CD8 (-/-) ) mice . MHC - I ( high ) melanoma growth was also reduced in mice lacking P19438 , but not P01375 - R2 . P01375 (-/-) and P19438 (-/-) mice as well as DB00005 - treated WT mice displayed enhanced intratumor content of high endothelial venules surrounded by high CD8 (+) T - cell density . Adoptive transfer of activated P19438 - deficient or - proficient CD8 (+) T cells in CD8 - deficient mice bearing B16K1 tumors demonstrated that P19438 deficiency facilitates the accumulation of live CD8 (+) T cells into the tumors . Moreover , in vitro experiments indicated that P01375 triggered activated CD8 (+) T cell death in a P19438 - dependent manner , likely limiting the accumulation of tumor - infiltrating CD8 (+) T cells in P01375 / P19438 - proficient animals . Collectively , our observations indicate that P19438 - dependent P01375 signaling impairs tumor - infiltrating CD8 (+) T - cell accumulation and may serve as a putative target to favor CD8 (+) T - cell - dependent immune response in melanoma .", "Effectiveness of P01375 inhibitor switch in RA : results from the national Swedish register . BACKGROUND : Switching to a second tumour necrosis factor inhibitor ( TNFi ) after discontinuation of a first in rheumatoid arthritis ( RA ) is a common strategy . The reason for the switch from the first TNFi could potentially influence the response to therapy . Data on direct comparisons between TNFi after switching are limited . METHODS : The national Swedish register was used . RA patients who switched to a second TNFi ( infliximab , etanercept or adalimumab ) after failure of a TNFi as first - ever biologic were identified . Effectiveness of treatment was compared across the three drugs according to the first TNFi used , the reason for discontinuing and the drug survival . Drug survival across TNFi used as second biologic was compared . RESULTS : Half of all patients starting infliximab , adalimumab or etanercept during the period 2005 - 2012 discontinued treatment for various reasons . Of these patients , a third switched within 2 months to a second TNFi ( infliximab , etanercept or adalimumab ) . Around 35 % of all patients achieved low disease activity or remission at 6 months . Regarding the switching strategy , best results were observed among patients who switched from infliximab to etanercept because of ( secondary ) inefficacy . DB00005 as second TNFi was associated with longer drug survival compared with infliximab . CONCLUSIONS : Switching to a second TNFi after the failure of the first may lead to good clinical results . The inter - drug differences in drug survival on the second TNFi mirror those reported previously for the first TNFi , suggesting that these differences are not solely due to channelling bias .", "Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK14___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK14___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK14___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK14___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK14___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK14___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK14___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK14___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK14___ in the treatment of changes in hypervigilance following severe stress .", "DB00005 in rheumatoid arthritis . DB00005 ( Enbrel , Immunex Corporation , Seattle , Washington , USA ) is a new biological disease - modifying antirheumatic drug ( DMARD ) for the treatment of active rheumatoid arthritis ( RA ) . It is one of two P01375 blockers to be licensed for the treatment of active RA and is classified as a recombinant human soluble P01375 receptor . The drug competitively inhibits the binding of P01375 to cell surface receptors and thus renders P01375 biologically inactive . In doing so , etanercept inhibits the pro - inflammatory effects of P01375 and results in a reduction of joint inflammation in patients with RA . DB00005 has shown a statistically significant reduction in swollen and inflamed joint counts , biochemical markers such as erythrocyte sedimentation rate and P02741 and shown significant improvements in quality of life measures ( HAQ and global assessment scores ) in all studies . In early disease , etanercept has shown a reduction in joint space narrowing equal to methotrexate ( MTX ) and a reduction in the appearance of new erosions significantly better than MTX after 1 year of treatment . DB00005 has a rapid onset of action which is significantly faster than standard DMARDs . DB00005 was well - tolerated in clinical trials . The commonest side effects were injection site reactions and upper respiratory tract infections . DB00005 therapy has resulted in serious infections in some patients and should be used with caution in any patient with a history of recurring infections or with disease states that may predispose to infections . In summary , etanercept is an effective and well - tolerated agent that is a significant breakthrough in the treatment of this disabling condition .", "Long term safety of etanercept in elderly subjects with rheumatic diseases . OBJECTIVES : To determine the long term safety profile of the tumour necrosis factor ( P01375 ) antagonist etanercept in subjects with rheumatoid arthritis ( RA ) , psoriatic arthritis ( PsA ) , or ankylosing spondylitis ( AS ) aged > or = 65 years in comparison with subjects aged < 65 years . METHODS : Safety data from an integrated database of 4322 subjects enrolled in 18 RA trials , 2 PsA trials , and 2 AS trials were analysed . Safety end points included subject incidence of all adverse events ( AE ) , serious adverse events ( SAE ) , infectious events ( IE ) , medically important infections ( MII ) , and deaths . Events of particular interest in subjects treated with P01375 modulating biological treatments , including demyelinating diseases , tuberculosis , lymphomas , and cardiovascular diseases , were also evaluated . RESULTS : The incidence of AE , SAE , IE , MII , and malignancies was not significantly raised in elderly subjects in comparison with subjects aged < 65 years . No cases of tuberculosis were reported in the trials . Demyelinating diseases were seen only in subjects aged < 65 years . The incidence and types of death in the elderly subjects were consistent with the expected rates for subjects of comparable age . CONCLUSIONS : DB00005 is a generally safe and well tolerated biological agent for treatment of rheumatological diseases in the elderly , and the risk of AE in these studies was no greater in subjects aged > or = 65 years than in younger subjects .", "[ DB00005 . An effective P01375 alpha - antagonist in the treatment of psoriatic arthritis and chronic plaque psoriasis ] . DB00005 , an inhibitor of P01375 alpha , has been found effective in the treatment of psoriatic arthritis and psoriasis vulgaris . DB00005 is a fusion protein made up of domains of the soluble , fully human p75 - P01375 alpha receptor and the F ( c ) portion of human IgG ( 1 ) . The drug is a protein which must be administered subcutaneously . Several controlled studies have highlighted its efficacy for both skin symptoms and joint involvement . The usual dose is 25 mg s . c . twice weekly . Higher dosages of 50 mg twice weekly may be used in severe cases . Before starting the therapy with etanercept , infections including tuberculosis have to be excluded . DB00563 and other pharmacological immunosuppressive agents can be combined with etanercept , as can all standard topical agents . DB00005 in off - label use has been found to also be useful in several other inflammatory dermatologic conditions . If patients are carefully monitored , etanercept is generally well - tolerated and has a good safety profile . The development of novel biologic agents such as etanercept is one of the most important therapeutic innovations of recent years .", "Tumor - infiltrating macrophages induce apoptosis in activated CD8 (+) T cells by a mechanism requiring cell contact and mediated by both the cell - associated form of P01375 and nitric oxide . We have investigated the ability of different cells present in murine tumors to induce apoptosis of activated CD8 (+) T cells in vitro . Tumor cells do not induce apoptosis of T cells ; however , macrophages that infiltrate tumors are potent inducers of apoptosis . Tumor macrophages express cell surface - associated P01375 , P01375 type I ( CD120a ) and II ( DB00005 ) receptors , and , upon contact with T cells which induces release of P01579 from T cells , secrete nitric oxide . Killing of T cells in vitro is blocked by Abs to P01579 , P01375 , CD120a , or DB00005 , or N - methyl - L - arginine . In concert with that finding , tumor macrophages isolated from either P01375 type I or type II receptor -/- mice are not proapoptotic and do not produce nitric oxide upon contact with activated T cells . Control macrophages do not express P01375 receptors or release nitric oxide . Tumor cells or tumor - derived macrophages do not express P48023 , and blocking Abs to either Fas or P48023 have no effect on macrophage - mediated T cell killing . These results demonstrate that macrophages which infiltrate tumors are highly proapoptotic and may be responsible for elimination of activated antitumor T cells within the tumor bed .", "Central P01375 inhibition results in attenuated neurohumoral excitation in heart failure : a role for superoxide and nitric oxide . This study examined the effect of central tumor necrosis factor - alpha ( P01375 ) blockade on the imbalance between nitric oxide and superoxide production in the paraventricular nucleus ( PVN ) and ventrolateral medulla ( VLM ) , key autonomic regulators , and their contribution to enhanced sympathetic drive in mice with congestive heart failure ( CHF ) . We also used a P01375 gene knockout ( KO ) mouse model to study the involvement of P01375 in body fluid homeostasis and sympathoexcitation in CHF . After implantation of intracerebroventricular ( ICV ) cannulae , myocardial infarction ( MI ) was induced in wild - type ( WT ) and KO mice by coronary artery ligation . Osmotic mini - pumps were implanted into one set of WT + MI / Sham mice for continuous ICV infusion of DB00005 ( DB01613 ) , a P01375 receptor fusion protein , or vehicle ( VEH ) . Gene expressions of neuronal nitric oxide synthase ( NOS ) and angiotensin receptor - type 2 were reduced , while those of inducible NOS , Nox2 homologs , superoxide , peroxynitrite and angiotensin receptor - type 1 were elevated in the brainstem and hypothalamus of MI + VEH . Plasma norepinephrine levels and the number of Fos - positive neurons were also increased in the PVN and VLM in MI + VEH . MI + DB01613 and KO + MI mice exhibited reduced oxidative stress , reduced sympathoexcitation and an improved cardiac function . These changes in WT + MI were associated with increased sodium and fluid retention . These results indicate that elevated P01375 in these autonomic regulatory regions of the brain alter the production of superoxide and nitric oxide , contributing to fluid imbalance and sympathoexcitation in CHF .", "P01375 inhibitors : new options for treating rheumatoid arthritis . There is accumulating evidence that tumor necrosis factor plays a major role in the pathogenesis of rheumatoid arthritis . Recent biotechnological advances have allowed for the development of agents that directly target P01375 , a proinflammatory cytokine . In the last 2 years , the U . S . Food and Drug Administration and the European Union ' s Commission of the European Communities have approved two biological agents for the treatment of refractory RA , etanercept and infliximab . DB00005 is a fusion protein , composed of the Fc portion of immunoglobulin P55008 and the extracellular domain of a P01375 receptor ( p75 ) . DB00065 is a chimeric monoclonal antibody composed of murine variable and human constant regions . In placebo - controlled trials , both agents have proven to be effective and well tolerated in RA patients .", "Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK32___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .", "DB00005 and demyelinating disease in a patient with psoriasis . The tumor necrosis factor - alpha antagonist ( P01375 ) etanercept has been approved for the treatment of rheumatoid arthritis , juvenile rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis , and psoriasis . Earlier reports on the use of etanercept or infliximab in patients with rheumatoid arthritis , psoriatic arthritis , or juvenile rheumatoid arthritis suggested an increased risk of demyelinating disease . It is imperative that dermatologists have a keen awareness of this possible adverse event given the increased use of this class of drugs . We report a case of demyelinating disease occurring in a patient treated for psoriasis . The relation of P01375 antagonist therapy to demyelinating disease / multiple sclerosis is explored . It is recommended that patients be diligently screened before starting P01375 antagonist therapy and that vigilance for symptoms of demyelinating disease / multiple sclerosis be included in follow - up examinations during treatment with these drugs .", "Off - target activity of P01375 inhibitors characterized by protein biochips . P01375 - alpha inhibitors are widely and successfully used to treat rheumatic diseases . However , significant side effects have been reported . To detect the potential off - target activities of such inhibitors we characterized two therapeutic antibodies ( adalimumab , infliximab ) and one receptor fusion protein ( etanercept ) on protein biochips ( UNIchip AV - 400 ) containing a printed serial dilution of tumor necrosis factor - alpha and about 384 different human proteins . DB00005 binds to ten proteins ( affinity : 20 - 33 % of tumor necrosis factor - alpha recognition ) , and six of these proteins are related to ribosomal proteins . Interestingly , adalimumab binds to the same six proteins related to ribosomal proteins ( affinity : 12 - 18 % ) as well as to four proteins crucially involved in ribosomal protein synthesis . Alignment of protein sequences indicates no significant sequence homology between these ten proteins bound by the biological drugs with the highest off - target activities . Taken together , our in vitro results demonstrate that a significant number of proteins are recognized by tumor necrosis factor - alpha inhibitors and are related to ribosome biogenesis .", "P01375 alpha rapidly activates the mitogen - activated protein kinase ( MAPK ) cascade in a MAPK kinase kinase - dependent , c - P04049 - independent fashion in mouse macrophages . P01375 alpha ( P01375 alpha ) is bound by two cell surface receptors , CD120a ( p55 ) and DB00005 ( p75 ) , that belong to the P01375 / nerve growth factor receptor family and whose signaling is initiated by receptor multimerization in the plane of the plasma membrane . The initial signaling events activated by receptor crosslinking are unknown , although activation of the mitogen - activated protein kinase ( MAPK ) cascade occurs shortly after ligand binding to CD120a . In this study , we investigated the upstream kinases that mediate the activation of the 42 - kDa MAPK p42mapk / erk2 following crosslinking of CD120a in mouse macrophages . Exposure of mouse macrophages to P01375 alpha stimulated a time - dependent increase in the activity of MAPK / P29323 kinase ( MEK ) that temporally preceded peak activation of p42mapk / erk2 . MEKs , dual - specificity threonine / tyrosine kinases , act as a convergence point for several signaling pathways including Ras / Raf , MEK kinase ( Q13233 ) , and Mos . Incubation of macrophages with P01375 alpha was found to transiently stimulate a Q13233 that peaked in activity within 30 sec of exposure and progressively declined toward basal levels by 5 min . By contrast , under these conditions , activation of either c - P04049 or Raf - B was not detected . These data suggest that the activation of the MAPK cascade in response to P01375 alpha is mediated by the sequential activation of a Q13233 and a MEK in a c - P04049 - and Raf - B - independent fashion .", "Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK90___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .", "Role of Q12933 in the activation of IgM secretion by P25942 and DB00005 . TNFR - associated factors ( TRAFs ) participate in the signaling of many TNFR family members , including P25942 , CD120a ( P19438 ) , and DB00005 ( P20333 ) . Previously , we found that a dominant - negative TRAF2 molecule inhibits P25942 - mediated Ab secretion by the mouse B cell line CH12 . LX . However , disruption of the TRAF2 binding site in the cytoplasmic domain of P25942 does not diminish the ability of P25942 to stimulate Ab secretion , nor is this mutation able to circumvent the inhibition of Ab secretion by dominant - negative TRAF2 . Here we demonstrate that P25942 - induced P01375 stimulates IgM production through DB00005 and that DB00005 signaling is required for optimal P25942 - induced IgM secretion . Furthermore , although both P25942 and DB00005 can bind TRAF2 , TRAF2 - dependent P25942 signals can not substitute for TRAF2 - dependent DB00005 signals in the activation of IgM secretion . Our results indicate a potentially important role for DB00005 in the activation of IgM secretion and that TRAF2 is used by P25942 and DB00005 in distinct ways .", "Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK36___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .", "Neuroendocrine activation as a target of modern chronic heart failure pharmacotherapy . At present , a constant progress in pathophysiology understanding and treatment of the chronic heart failure ( CHF ) is arising . The current CHF pharmacotherapy is complex , involving factors affecting the renin - angiotensin - aldosterone system ( RAAS ) , beta - blockers , diuretics and vasodilatators . There are also significant efforts to introduce in CHF pharmacology novel therapeutic strategies , based on the other neurohormonal mechanisms activated in CHF . They include vasopressin receptor antagonists ( VRA ; vaptans ) , endothelin receptor antagonists ( ERA ; sentans ) , agents relating to the natriuretic peptides system ( neutral endopeptidase inhibitors ; NEPI and vasopeptidase inhibitors ; VPI ) and anticytokines agents ( anti P01375 immunoglobulin or P01375 scavenger receptor ; DB00005 ) . In this article we briefly describe the modem approach to CHF systemic treatment .", "Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha - neutralizing agents . OBJECTIVE : P01375 alpha ( TNFalpha ) has been implicated in the pathogenesis of certain inflammatory diseases . Two TNFalpha - neutralizing agents are licensed in the US . DB00065 is licensed for the treatment of Crohn ' s disease ( CD ) and , when used with methotrexate , for the treatment of rheumatoid arthritis ( RA ) . DB00005 is licensed for the treatment of RA , including juvenile RA , and , more recently , was licensed for the treatment of psoriatic arthritis . Because of the potential for decreased host resistance to infectious agents due to treatment with anti - TNFalpha agents , we sought to evaluate postlicensure cases of opportunistic infection , including Listeria monocytogenes , in patients treated with these products . METHODS : The FDA Adverse Event Reporting System , a passive monitoring system , was reviewed to identify all reports of adverse events ( through December 2001 ) associated with L monocytogenes infection in patients treated with infliximab or etanercept . RESULTS : Fifteen cases of L monocytogenes infection associated with infliximab or etanercept treatment were identified . In 14 of these cases , patients had received infliximab . The median age of all patients was 69 . 5 years ( range 17 - 80 years ) ; 53 % were female . Six deaths were reported . Among patients for whom an indication for use was reported , there were 9 patients ( 64 % ) with RA and 5 patients ( 36 % ) with CD ( information was not reported for 1 patient ) . All patients for whom information was reported were receiving concurrent immunosuppressant drugs . CONCLUSION : Postlicensure surveillance suggests that L monocytogenes infection may be a serious complication of treatment with TNFalpha - neutralizing agents , particularly infliximab .", "DB00005 therapy in patients with psoriasis and concomitant HCV infection . Treatment of patients with psoriasis and / or psoriatic arthritis and concomitant hepatitis C infection remains difficult . Except for cyclosporine , other drugs have proved unacceptable because of hepatotoxicity in patients with HCV . With the advent of anti - P01375 drugs , including etanercept , new therapeutic options have become available . Our study population was five patients with psoriasis and / or psoriatic arthritis and concomitant chronic HCV infection undergoing etanercept therapy . Serum alanine aminotransferase ( ALT ) , aspartate aminotransferase ( Q9NRA2 ) , and viral load were used as markers for liver damage and disease progression , respectively . The Psoriasis Area Severity Index ( PASI ) was used as a reference parameter for evaluating the therapeutic efficacy of etanercept therapy in improving the clinical skin picture . Q9NRA2 , ALT , viral load and PASI were monitored at 3 - month intervals starting from the beginning of therapy up to two years after initiation of etanercept therapy . In four out of five patients , liver enzyme levels and viral load remained substantially unchanged during the course of therapy . In the one remaining patient , viral load and liver enzyme levels increased during etanercept therapy , and then decreased following the initiation of Peg - IFN / ribavirin in combination with anti - P01375 therapy . PASI scores decreased in all five patients . Our data suggest that etanercept therapy is safe and provides an efficacious therapeutic alternative in patients with psoriasis and concomitant HCV infection .", "DB00005 in arthritis . Tumour necrosis factor - alpha ( P01375 ) is one of the inflammatory cytokines . It is released by activated monocytes , macrophages and T lymphocytes and promotes inflammation . P01375 binds to two receptors ; one of these is the type 2 P01375 receptor ( p75 ) . DB00005 is a soluble P01375 - receptor fusion protein . It consists of two linked dimmers , each with a ligand - binding portion of the higher affinity type 2 P01375 receptor ( p75 ) . This fusion protein binds to P01375 and prevents it from interacting with its receptor . DB00005 is given by subcutaneous administration at a dose of 25 mg twice a week . This dosing reflects its half - life of about 4 days . Clinical trials show etanercept is effective and safe to use in rheumatoid arthritis ( RA ) . It reduces disease activity and limits progressive joint damage in both early and late disease . It can be used as a monotherapy or in combination with methotrexate , and in this , the latter approach appears most effective . It is also effective in psoriatic arthritis and ankylosing spondylitis . Although the biologic appears safe , caution is needed to ensure it does not re - activate tuberculosis . It should not be used in patients with disseminated sclerosis , and there are concerns about a potential relationship to lymphoma . Its high cost means there will be continuing debate about the ideal position of this new biologic within the treatment pathway of RA . At present , it is recommended for use when methotrexate and another disease - modifying drug have failed ." ]

[ "___MASK14___", "___MASK32___", "___MASK36___", "___MASK38___", "___MASK80___", "___MASK83___", "___MASK8___", "___MASK90___", "___MASK96___" ]

[ "Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the Q13639 receptor . OBJECTIVE : Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at Q13639 receptors . The 5 - Q9H205 antagonist tropisetron is thought to act as an antagonist at Q13639 receptors . In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the Q13639 receptor in aldosterone secretion . METHODS : Following a single - blind , random design , ten normal male volunteers received one of the following regimens on three occasions , with at least 2 - week intervals : metoclopramide 10 mg i . v . ; tropisetron 5 mg by slow i . v . i . , or ; tropisetron by slow i . v . i . , followed by 10 mg metoclopramide i . v . RESULTS : In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149 % of basal level and remained significantly elevated for the next 20 min . With tropisetron alone , there was a significant 37 . 8 % drop at 60 min and the aldosterone levels remained low for the duration of the experiment . DB01233 reversed the decline mediated by tropisetron significantly at 30 and 90 min . DB04630 levels after the latter regimen also did not differ significantly from baseline at any time period . CONCLUSION : These results would suggest the existence of a tonic stimulatory influence of 5 - HT via Q13639 receptors on aldosterone secretion , which could be augmented by metoclopramide and blocked by tropisetron . However , the effect of tropisetron per se should be interpreted with caution given the lack of a saline group .", "Systematic meta - analyses and field synopsis of genetic association studies in schizophrenia : the SzGene database . In an effort to pinpoint potential genetic risk factors for schizophrenia , research groups worldwide have published over 1 , 000 genetic association studies with largely inconsistent results . To facilitate the interpretation of these findings , we have created a regularly updated online database of all published genetic association studies for schizophrenia ( ' SzGene ' ) . For all polymorphisms having genotype data available in at least four independent case - control samples , we systematically carried out random - effects meta - analyses using allelic contrasts . Across 118 meta - analyses , a total of 24 genetic variants in 16 different genes ( P02649 , P21964 , DAO , P21728 , P14416 , P21917 , Q96EV8 , P47870 , Q13224 , HP , P01584 , P42898 , O75051 , P31645 , P04637 and P17752 ) showed nominally significant effects with average summary odds ratios of approximately 1 . 23 . Seven of these variants had not been previously meta - analyzed . According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies , four of the significant results can be characterized as showing ' strong ' epidemiological credibility . Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia . As such , it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders .", "Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 , P17643 , P40126 , P21583 , P00533 , P14416 and Q03181 ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 , P17643 and P21583 ) and in Asians ( Q04671 , P40126 , P21583 , P00533 and P14416 ) , whereas signals were scarce in Africans ( P40126 , P00533 and P14416 ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans .", "P14416 mechanisms contribute to age - related cognitive decline : the effects of quinpirole on memory and motor performance in monkeys . The D2 dopamine ( DA ) receptor agonist , quinpirole , was characterized in young adult monkeys , young reserpine - treated monkeys and aged monkeys to assess the contribution of DA to age - related loss of prefrontal cortical ( P27918 ) cognitive function . Monkeys were tested on a delayed response memory task that depends on the P27918 , and a fine motor task that taps the functions of the motor cortex . In young adult monkeys , low quinpirole doses impaired performance of the P27918 and fine motor tasks , while higher doses improved memory performance and induced dyskinesias and \" hallucinatory - like \" behaviors . The pattern of the quinpirole response in reserpine - treated monkeys suggested that the impairments in delayed response and fine motor performance resulted from drug actions at D2 autoreceptors , while the improvement in delayed response performance , dyskinesias and \" hallucinatory - like \" behaviors resulted from actions at postsynaptic receptors . In aged monkeys , low doses of quinpirole continued to impair fine motor performance , but lost their ability to impair delayed response performance . The magnitude of cognitive improvement and the incidence of \" hallucinatory - like \" behaviors were also reduced in the aged animals , suggesting some loss of postsynaptic D2 receptor function . The pattern of results is consistent with the greater loss of DA from the P27918 than from motor areas in aged monkey brain ( Goldman - Rakic and Brown , 1981 ; Wenk et al . , 1989 ) , and indicates that DA depletion contributes significantly to age - related cognitive decline .", "Two - dimensional liquid crystalline growth within a phase - field - crystal model . By using a two - dimensional phase - field - crystal ( P27918 ) model , the liquid crystalline growth of the plastic triangular phase is simulated with emphasis on crystal shape and topological defect formation . The equilibrium shape of a plastic triangular crystal ( PTC ) grown from an isotropic phase is compared with that grown from a columnar or smectic - A ( Q13216 ) phase . While the shape of a PTC nucleus in the isotropic phase is almost identical to that of the classical P27918 model , the shape of a PTC nucleus in Q13216 is affected by the orientation of stripes in the Q13216 phase , and irregular hexagonal , elliptical , octagonal , and rectangular shapes are obtained . Concerning the dynamics of the growth process , we analyze the topological structure of the nematic order , which starts from nucleation of + 1 / 2 and - 1 / 2 disclination pairs at the PTC growth front and evolves into hexagonal cells consisting of + 1 vortices surrounded by six satellite - 1 / 2 disclinations . It is found that the orientational and the positional order do not evolve simultaneously ; the orientational order evolves behind the positional order , leading to a large transition zone , which can span over several lattice spacings .", "Effects of cholinoceptor and 5 - hydroxytryptamine3 receptor antagonism on erythromycin - induced canine intestinal motility disruption and emesis . 1 . Erythromycin administration is associated with gastrointestinal problems , disturbed gastrointestinal motility and emesis . This study in the dog investigates the underlying mechanisms . 2 . Intestinal myoelectrical activity and the occurrence and latency of emesis were recorded in eight conscious dogs . All drugs were administered intravenously . 3 . Erythromycin ( 7 mg kg - 1 ) increased contractions of the proximal small intestine , and caused emesis in all fasted dogs and in 5 dogs after food . Atropine ( 50 mg kg - 1 min - 1 ) and hexamethonium ( 10 mg kg - 1 h - 1 ) partially inhibited the GI motility effects but did not significantly reduce emesis . 4 . DB01233 at a high dose ( 2 mg kg - 1 h - 1 ) reduced the incidence of emesis in the presence of increased intestinal motility , but a low dose ( 150 micrograms kg - 1 h - 1 ) was ineffective . 5 . A 5 - hydroxytryptamine3 ( 5 - Q9H205 ) receptor antagonist , MDL 72222 ( 1 mg kg - 1 ) , reduced emesis when given alone and combined with metoclopramide ( low dose ) . The Q13639 receptor agonist BRL24924 ( DB04917 , 1 mg kg - 1 ) had no effect on emesis either alone in combination with metoclopramide . 6 . In conclusion , erythromycin - induced GI motility disturbances and emesis are not causally related . Whereas the increase in intestinal smooth muscle activity is possibly cholinergically mediated , emesis occurs at least in part via a 5 - hydroxytryptaminergic mechanism , but does not involve the dopamine system .", "Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .", "Effects of enhancement and antagonism of 5 - hydroxytryptamine activity on the influence of metoclopramide on gastric emptying . This study examines the influence of the serotonergic system on the effect of metoclopramide on gastric emptying . Six subjects received the following pretreatments before metoclopramide and paracetamol : fluoxetine ( 5 - HT uptake inhibitor ) ; meterogoline ( 5 - HT1 antagonist ) ; pizotifen ( 5 - HT2 antagonist ) or methysergide ( 5 - HT1 and 5 - HT2 antagonist ) . One regimen consisted of metoclopramide ( 5 - Q9H205 antagonist and Q13639 agonist ) alone . Gastric emptying was measured by the mean cumulative fraction absorbed - time profiles of paracetamol . Methysergide / metoclopramide significantly delayed gastric emptying from 30 min onwards . DB01233 with either metergoline or pizotifen did not retard gastric emptying to the same extent , suggesting a greater influence with simultaneous 5 - HT1 and 5HT2 blockade . DB01233 / fluoxetine caused a significant decrease in the fractional absorption of paracetamol at 5 min when compared to the metoclopramide regimen . It was assumed that the influence of metoclopramide was not optimal at this stage , therefore possibly indicating domination of 5 - Q9H205 over Q13639 effects , resulting in gastric delay . It therefore seems as if all the 5 - HT receptors present in the gut have a role to play in the control of gastric emptying .", "Exposure to an organophosphate ( ___MASK87___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK87___ ( ___MASK87___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK87___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK87___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK87___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .", "Enhanced incentive motivation for sucrose - paired cues in adolescent rats : possible roles for dopamine and opioid systems . Vulnerability to the effects of drugs of abuse during adolescence may be related to altered incentive motivation , a process believed to be important in addiction . Incentive motivation can be seen when a neutral stimulus acquires motivational properties through repeated association with a primary reinforcer . We compared adolescent ( postnatal day ( P01160 ) 24 - 50 ) and adult ( > P01160 70 ) rats on a measure of incentive motivation : responding for a conditioned reinforcer ( CR ) . Rats learned to associate the delivery of 0 . 1 ml of 10 % sucrose with a conditioned stimulus ( CS ; light and tone ) ; 30 pairings per day were given over 14 days . Then , we measured responding on a lever delivering the CS ( now a CR ) after injections of amphetamine ( 0 , 0 . 25 or 0 . 5 mg / kg ) . We also examined responding for CR when the CS and sucrose were paired or unpaired during conditioning , and responding for the primary reinforcer ( 10 % sucrose ) in control experiments . Finally , we examined the effects of D ( 1 ) and P14416 antagonists ( P35240 39166 and eticlopride , respectively ) and an opioid receptor antagonist ( naltrexone ) on responding for a CR in adolescent rats . Adolescents but not adults acquired responding for a CR , but adolescents responded less than adults for the primary reinforcer . Responding for a CR depended upon the pairing of the CS and sucrose during conditioning . Both dopamine and opioid receptor antagonists reduced responding for the CR . Therefore , incentive motivation may be enhanced in adolescents compared with adults , and incentive motivation may be mediated in part by both dopamine and opioid systems .", "Characterization of a novel Q13639 receptor antagonist of the azabicycloalkyl benzimidazolone class : DAU 6285 . Three chemical classes of serotonin Q13639 receptor agonists have been identified so far : 5 - substituted indoles ( e . g . 5 - HT ) , benzamides ( e . g . renzapride ) and benzimidazolones ( e . g . BIMU 8 ) . In a search for Q13639 receptor antagonists , we have discovered that the benzimidazolone derivative DAU 6285 ( for structure see text ) , is 3 - 5 times more potent than tropisetron in blocking 5 - HT , renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons . Schild plot analysis yielded Ki values of 220 , 181 and 255 nmol / l , respectively . In addition , DAU 6285 showed poor activity as a 5 - Q9H205 receptor ligand with respect to tropisetron , as demonstrated by in vitro binding studies ( Ki , 322 vs 2 . 8 nmol / l ) and by its antagonistic activity in the Bezold - Jarisch reflex test ( ID50 , 231 vs 0 . 5 micrograms / kg , i . v . ) . No significant binding ( Ki greater than 10 mumol / l ) of DAU 6285 to serotonergic P08908 , P28222 , P28335 , P28221 , and 5 - HT2 receptors as well as to adrenergic alpha 1 , alpha 2 , dopaminergic D1 , D2 or muscarinic M1 - M3 receptor subtypes was found . The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for Q13639 receptors , a property confirmed in functional tests , and much lower affinity than tropisetron for 5 - Q9H205 receptors . The compound represents a new interesting tool for investigating the pharmacological and physiological properties of Q13639 receptors .", "Molecular genetics of bipolar disorder . Bipolar disorder ( BPD ) is an often devastating illness characterized by extreme mood dysregulation . Although family , twin and adoption studies consistently indicate a strong genetic component , specific genes that contribute to the illness remain unclear . This study gives an overview of linkage studies of BPD , concluding that the regions with the best evidence for linkage include areas on chromosomes 2p , 4p , 4q , 6q , 8q , 11p , 12q , 13q , 16p , 16q , 18p , 18q , 21q , 22q and Xq . Association studies are summarized , which support a possible role for numerous candidate genes in BPD including P21964 , Q01959 , Q13639 , P21917 , P14416 , P28223 , 5 - HTT , the P59103 / G30 complex , Q9NRI5 , Q99572 , P21397 and P23560 . Animal models related to bipolar illness are also reviewed , with special attention paid to those with clear genetic implications . We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness .", "Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .", "Analysis of neurogenic contractions induced by ML - 1035 and other benzamides in the guinea - pig non - stimulated isolated ileum . 4 - Amino - 5 - chloro - substituted benzamides have been shown to increase gastric motility in - vivo and enhance field - stimulated and peristaltic contractions in - vitro . The present experiments examined the contractile response to a series of benzamides in the guinea - pig non - stimulated ileum . Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 microM acetylcholine ( % acetylcholine response = 12 +/- 2 , 19 +/- 3 , 26 +/- 2 , 51 +/- 3 , n = 13 , 8 , 17 , and 21 , with EC50 values of 0 . 85 , 1 . 8 , 5 . 7 , and 14 . 2 microM for cisapride , zacopride , metoclopramide , and ML - 1035 ( 4 - amino - 5 - chloro - 2 -(( 2 - methylsulphinyl )- ethoxy )- N - ( 2 -( diethylamino )- ethyl ) - benzamide hydrochloride ) , respectively ) . ML - 1035 contractions were completely blocked by atropine and tetrodotoxin , while ganglionic blockade with hexamethonium was ineffective . DB01233 has been reported to sensitize postjunctional muscarinic receptors , however , ML - 1035 did not enhance acetylcholine - induced contractions . Tropisetron ( ICS 205 - 930 , 1 microM ) , caused a parallel rightward shift in the concentration - response curve for both ML - 1035 and zacopride ( EC50 = 14 . 2 +/- 1 . 3 and 1 . 8 +/- 0 . 8 microM in the absence , and 26 +/- 2 . 7 and 6 . 9 +/- 2 . 3 microM in the presence of tropisetron for ML - 1035 and zacopride , respectively ) with apparent pKB values of 5 . 9 and 6 . 0 for the respective compounds . 5 - Hydroxytryptaminergic receptor desensitization by 2 - methyl - 5 - hydroxytryptamine ( 5 - Q9H205 ) and 5 - methoxytryptamine ( Q13639 ) , attenuated the response to ML - 1035 . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK27___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .", "The relationship between gastric motility and nausea : gastric prokinetic agents as treatments . Nausea is one of a cluster of symptoms described subjectively by patients with delayed gastric emptying . The mechanisms and treatments are unclear ( anti - emetic drugs are not fully effective against nausea ) . Can nausea be relieved by stimulating gastric emptying ? Physostigmine ( together with atropine ) has been shown experimentally to stimulate gastric motility , relieve nausea and restore normal gastric motility . Is this mimicked by gastric prokinetic drugs ? The answer is complicated by mixed pharmacology . DB01233 increases gastric motility by activating myenteric Q13639 receptors but also directly inhibits vomiting via D2 and 5 - Q9H205 receptor antagonism ; relationships between increased gastric motility and relief from nausea are therefore unclear . Similarly , the D2 receptor antagonist domperidone has direct anti - emetic activity . Nevertheless , more selective Q13639 and motilin receptor agonists ( erythromycin , directly stimulating gastric motility ) inhibit vomiting in animals ; low doses of erythromycin can also relieve symptoms in patients with gastroparesis . Ghrelin stimulates gastric motility and appetite mostly via vagus - dependent pathways , and inhibits vomiting in animals . To date , ghrelin receptor activation has failed to consistently improve gastric emptying or symptoms in patients with gastroparesis . We conclude that nausea can be relieved by gastric prokinetic drugs , but more clinical studies are needed using drugs with selective activity . Other mechanisms ( e . g . ghrelin , vagal and central pathways , influencing a mechanistic continuum between appetite and nausea ) also require exploration . These and other issues will be further explored in a forthcoming special issue of the European Journal of Pharmacology , which focusses on mechanisms of nausea and vomiting .", "[ ___MASK67___ : A new drug of B - cell malignancies ] . ___MASK67___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK67___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK67___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .", "Chronic atrial fibrillation alters the functional properties of If in the human atrium . INTRODUCTION : Despite the evidence that the hyperpolarization - activated current ( If ) is highly modulated in human cardiomyopathies , no definite data exist in chronic atrial fibrillation ( cAF ) . We investigated the expression , function , and modulation of If in human cAF . METHODS AND RESULTS : Right atrial samples were obtained from sinus rhythm ( SR , n = 49 ) or cAF ( duration > 1 year , n = 31 ) patients undergoing corrective cardiac surgery . Among f - channel isoforms expressed in the human atrium ( O60741 , 2 and 4 ) , Q9Y3Q4 mRNA levels measured by RT - PCR were significantly reduced . However , protein expression was preserved in cAF compared to SR ( + 85 % for Q9Y3Q4 ) ; concurrently , miR - 1 expression was significantly reduced . In patch - clamped atrial myocytes , current - specific conductance ( gf ) was significantly increased in cAF at voltages around the threshold for If activation ( - 60 to - 80 mV ) ; accordingly , a 10 - mV rightward shift of the activation curve occurred ( P < 0 . 01 ) . β - Adrenergic and Q13639 receptor stimulation exerted similar effects on If in cAF and SR cells , while the P01160 - mediated effect was significantly reduced ( P < 0 . 02 ) , suggesting downregulation of natriuretic peptide signaling . CONCLUSIONS : In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur , associated with a slight yet significant gain - of - function of If , which may contribute to enhanced atrial ectopy .", "Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .", "___MASK67___ inhibits P11274 and NF - κB signaling and reduces tumor proliferation in tissue - resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue - resident CLL cells show prominent activation of both B - cell receptor ( P11274 ) and NF - κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 ( Q06187 ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway - specific gene signatures , we detected a rapid and sustained downregulation of P11274 and NF - κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . ___MASK67___ reduced phosphorylation of PLCγ2 and P29323 and decreased nuclear protein expression of NF - κB p50 . ___MASK67___ significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on - target effects of Q06187 inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www . clinicaltrials . gov as # NCT01500733 .", "Identification of antithrombin - modulating genes . Role of O95461 , a gene encoding a bifunctional glycosyltransferase , in the secretion of proteins ? The haemostatic relevance of antithrombin together with the low genetic variability of P01008 , and the high heritability of plasma levels encourage the search for modulating genes . We used a hypothesis - free approach to identify these genes , evaluating associations between plasma antithrombin and 307 , 984 polymorphisms in the GAIT study ( 352 individuals from 21 Spanish families ) . Despite no SNP reaching the genome wide significance threshold , we verified milder positive associations in 307 blood donors from a different cohort . This validation study suggested O95461 , a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin - like linear polysaccharides , as a potential modulator of antithrombin based on the significant association of one SNPs , rs762057 , with anti - FXa activity , particularly after adjustment for age , sex and P01008 rs2227589 genotype , all factors influencing antithrombin levels ( p = 0 . 02 ) . Additional results sustained this association . O95461 silencing inHepG2 and P29320 - EBNA cells did not affect P01008 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention . Milder effects were observed on α1 - antitrypsin , prothrombin and transferrin . Our study suggests O95461 as the first known modifier of plasma antithrombin , and proposes a new role for O95461 in modulating extracellular secretion of certain glycoproteins .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .", "Differential radiosensitisation by ZD1839 ( ___MASK88___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK88___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .", "Antidepressant properties of the Q13639 receptor partial agonist , SL65 . 0155 : behavioral and neurochemical studies in rats . This study was undertaken to investigate the potential antidepressant - like properties of SL65 . 0155 , a serotonin 5 - HT ( 4 ) receptor partial agonist , in male rats of the Wistar strain tested in the forced swim test ( P19883 ) , an experimental model widely used to assess antidepressant - like activity . The expression of hippocampal neurotrophic factors , such as the brain - derived neurotrophic factor ( P23560 ) , the phosphorilated DB02527 response element - binding protein ( p - CREB ) , the B cell lymphoma - 2 ( Bcl - 2 ) , the Bax and the vascular endothelium growth factor ( P15692 ) were also evaluated by Western Blot analysis . Different groups of rats received intraperitoneally ( i . p . ) injections of SL65 . 0155 ( 0 . 1 , 0 . 5 and 1 mg / kg ) , clomipramine ( 50 mg / kg ) , citalopram ( 15 mg / kg ) or vehicle , respectively , 24 , 5 and 1 h prior to the P19883 . Compared to the control group , SL65 . 0155 ( 0 . 5 and 1 mg / kg ) , clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the P19883 . Interestingly , this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test . Western blot analysis of hippocampal homogenates showed an enhancement of p - CREB , P23560 Bcl - 2 and P15692 protein levels in SL65 . 0155 treated groups , but not in citalopram or clomipramine treated groups , used here as positive control . No change was found in Bax expression in any treated group . These findings give further support to the hypothesis that the stimulation of serotonin 5 - HT ( 4 ) receptors may be a therapeutic target for depression .", "Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5 - HT ligands . The brominated cyclodipeptides barettin ( cyclo [( 6 - bromo - 8 - entryptophan ) arginine ] ) and 8 , 9 - dihydrobarettin ( cyclo [( 6 - bromotryptophan ) arginine ] ) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose - dependent manner in concentrations ranging from 0 . 5 to 25 microM . To further establish the molecular target and mode of action of these compounds , we investigated their affinity to human serotonin receptors . The tryptophan residue in the barettins resembles that of endogenous serotonin [ 5 - hydroxytryptamine ] . A selection of human serotonin receptors , including representatives from all subfamilies ( 1 - 7 ) , were transfected into P29320 - 293 cells . Barettin selectively interacted with the serotonin receptors 5 - Q13049 , P28335 , and Q13639 at concentrations close to that of endogenous serotonin , with the corresponding Ki values being 1 . 93 , 0 . 34 , and 1 . 91 microM , respectively . 8 , 9 - Dihydrobarettin interacted exclusively with the P28335 receptor with a Ki value of 4 . 63 microM ; it failed to show affinity to 5 - Q13049 and Q13639 , indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins .", "Genetic susceptibility in solvent induced neurobehavioral effects . The aim of this investigation was to study the influence of genetic polymorphisms of biotransformation enzymes and dopamine receptors on neurobehavioral effects in referents ( n = 53 ) , solvent - workers ( n = 144 ) , and chronic toxic encephalopathy ( CTE ) patients ( n = 33 ) . All participants were interviewed for exposure data and confounding factors and underwent a clinical examination . Neurobehavioral complaints ( neurotoxicity symptom checklist - 60 ) and effects [ simple reaction time ( SRT ) , symbol digit substitution ( SDS ) , hand - eye coordination ( O14777 ) , and digit span backwards ( DSB ) ] were evaluated with a computer assisted test battery . The following genotypes were determined : P09488 , P30711 , P09211 , P14416 Taq1A , P14416 Taq1B , and P14416 - 141Cdel . Neurotoxic effects and complaints were significantly higher in CTE patients and were related to both duration and level of exposure . An equal distribution of genotypes was found between all groups . Logistic regression analysis revealed that P30711 was negatively associated with sleep and sensorimotor complaints . P09488 had a protecting influence on the relationship between logDSB and the cumulative exposure index and between logSRT and cumulative exposure index and degree of exposure , respectively . This effect was also found when correcting for age , education level , alcohol consumption , and smoking . P14416 - 141Cdel polymorphisms had a negative influence on the relationship between logSDS and the total exposure time . P30711 might be protective against sleep and sensorimotor complaints , whereas P09488 seems to decrease sustained attention and short - term memory problems in relation to solvent exposure . Individuals possessing P14416 - 141Cdel variant experienced more visuomotor problems .", "DB01233 does not increase gastric muscle contractility in newborn rats . Feeding intolerance resulting from delayed gastric emptying is common in premature neonates . DB01233 ( MCP ) , the most frequently used prokinetic drug in neonates , enhances gastric muscle contractility through inhibition of dopamine receptors . Although its therapeutic benefit is established in adults , limited data are available to support its clinical use in infants . Hypothesizing that developmentally dependent differences are present , we comparatively evaluated the effect of MCP on fundus muscle contractility in newborn , juvenile , and adult rats . The muscle strips were either contracted with electrical field stimulation ( O43281 ) to induce cholinergic nerve - mediated acetylcholine release or carbachol , a cholinergic agonist acting directly on the muscarinic receptor . Although in adult rats MCP increased O43281 - induced contraction by 294 ± 122 % of control ( P < 0 . 01 ) , no significant effect was observed in newborn fundic muscle . MCP had no effect on the magnitude of the carbachol - induced and / or bethanechol - induced gastric muscle contraction at any age . In response to dopamine , an 80 . 7 ± 5 . 3 % relaxation of adult fundic muscle was observed , compared with only a 8 . 4 ± 8 . 7 % response in newborn tissue ( P < 0 . 01 ) . P14416 expression was scant in neonates and significantly increased in adult gastric tissue ( P < 0 . 01 ) . In conclusion , the lack of MCP effect on the newborn fundic muscle contraction potential relates to developmental differences in dopamine D2 receptor expression . To the extent that these novel data can be extrapolated to neonates , the therapeutic value of MCP as a prokinetic agent early in life requires further evaluation .", "Effect of metoclopramide , ondansetron and granisetron on aldosterone secretion in man . The plasma aldosterone response following the administration of drugs with antagonist and agonist activity at Serotonin 3 and 4 ( 5 - Q9H205 & 4 ) receptors has been examined in 9 healthy male volunteers receiving the following four treatments i . v . in a randomised , cross - over sequence : ondansetron 8 mg , granisetron 3 mg , metoclopramide 20 mg , and saline 20 ml . DB01233 significantly increased the mean plasma aldosterone level to 196 % of basal level at 5 min . It rose to 234 % at 15 min and remained at more than 185 % of basal level for the duration of the experiment . The response to ondansetron and granisetron did not differ significantly from placebo . If dopamine antagonism is discounted , the results suggest that metoclopramide - induced aldosterone secretion results from its agonist activity at Q13639 receptors , although slow neuronal depolarization via an unidentified receptor remains a possibility . Antagonism at the 5 - Q9H205 receptor plays no role , as the selective antagonist , granisetron , did not elicit a significant response . It seems unlikely that the Q13639 receptor is the second , low affinity binding site of ondansetron , unless it had no agonist activity at this receptor .", "A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK68___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .", "Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK72___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .", "Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK10___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .", "Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP - PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 , P05556 , P31327 , P07225 , P55259 , Q9UJ96 , Q08499 , Q8N743 , and Q14642 . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 , P05556 , P31327 , P07225 and Q14642 were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 , but there was no significant correlation between loss of P60484 and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes .", "DB01233 stimulates catecholamine - and granin - derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 ( Q13639 ) receptors . The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas . The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 ( 5 - HT ( 4 ) ) receptors in pheochromocytoma tissues . Tissue explants , obtained from 18 pheochromocytomas including the tumor removed from a 46 - year - old female patient who experienced life - threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas ( 9 benign and 8 malignant ) were studied . Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5 - HT ( 4 ) receptor ligands . In addition , total mRNAs were extracted from all the 18 tumors . Catecholamine - and granin - derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays . In addition , expression of 5 - HT ( 4 ) receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase - PCR . RESULTS : DB01233 and the 5 - HT ( 4 ) receptor agonist cisapride were found to activate catecholamine - and granin - derived peptide secretions by cultured tumor cells . DB01233 - and cisapride - evoked catecholamine - and granin - derived peptide productions were inhibited by the 5 - HT ( 4 ) receptor antagonist GR 113808 . 5 - HT ( 4 ) receptor mRNAs were detected in the patient ' s tumor and the series of 17 additional pheochromocytomas . This study shows that pheochromocytomas express functional 5 - HT ( 4 ) receptors that are responsible for the stimulatory action of metoclopramide on catecholamine - and granin - derived peptide secretion . All 5 - HT ( 4 ) receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma .", "DB01454 ( DB01454 ) enhances the release of acetylcholine by Q13639 and D1 receptor mechanisms in the rat prefrontal cortex . DB01454 ( DB01454 ) , an amphetamine analog , has been shown recently to increase the release of acetylcholine ( ACh ) in the prefrontal cortex ( P27918 ) . The present study further characterizes the stimulatory effect of DB01454 on cortical ACh release and examines the role of serotonin ( 5 - HT ) and dopamine ( DA ) receptors in this response . The extracellular concentration of ACh was increased dose - dependently and similarly by the ( + ) and ( - ) enantiomers of DB01454 ( 5 and 20 mg / kg , i . p . ) . The systemic administration of the 5 - HT ( 4 ) antagonist SDZ 205 , 557 ( 1 mg / kg , i . p . ) , but not the 5 - HT ( 2A / 2B / 2C ) antagonist LY - 53 , 857 ( 3 mg / kg , i . p . ) , significantly decreased cortical ACh release induced by DB01454 . The DB01454 - induced increase in the extracellular concentration of ACh also was significantly blunted in rats treated with the D ( 1 ) receptor antagonist P35240 23390 ( 0 . 5 mg / kg , i . p . ) . The extent to which the coadministration of SDZ 205 , 557 and P35240 23390 suppressed the DB01454 - induced release of ACh in the P27918 was no greater than that produced by either antagonist alone . These results suggest that the 5 - HT ( 4 ) and D ( 1 ) receptor subtypes contribute to the mechanism by which DB01454 increases ACh release in the P27918 .", "Fibroblast growth factor - 2 in hyperplastic pituitaries of D2R knockout female mice . P14416 ( D2R ) knockout ( KO ) female mice develop chronic hyperprolactinemia and pituitary hyperplasia . Our objective was to study the expression of the mitogen fibroblast growth factor ( P09038 ) and its receptor , P11362 , comparatively in pituitaries from KO and wild - type ( WT ) female mice . We also evaluated P09038 subcellular localization and P09038 effects on pituitary function . P09038 - induced prolactin release showed a similar response pattern in both genotypes , even though basal and P09038 - stimulated release was higher in KO . P09038 stimulated pituitary cellular proliferation ( MTS assay and [( 3 ) H ] thymidine incorporation ) , with no differences between genotypes . P09038 concentration ( measured by ELISA ) in whole pituitaries or cultured cells was lower in KO ( P < 0 . 00001 and 0 . 00014 ) . Immunofluorescence histochemistry showed less P09038 in pituitaries from KO females and revealed a distinct P09038 localization pattern between genotypes , being predominantly nuclear in KO and cytosolic in WT pituitaries . Finally , P09038 could not be detected in the conditioned media from pituitary cultures of both genotypes . P11362 levels ( Western blot and immunohistochemistry ) were higher in pituitaries of KO . Basal concentration of phosphorylated ERKs was lower in KO cells ( P = 0 . 018 ) . However , when stimulated with P09038 , a significantly higher increment of P29323 phosphorylation was evidenced in KO cells ( P < or = 0 . 02 ) . We conclude that disruption of the D2R caused an overall decrease in pituitary P09038 levels , with an increased distribution in the nucleus , and increased P11362 levels . These results are important in the search for reliable prognostic indicators for patients with pituitary dopamine - resistant prolactinomas , which will make tumor - specific therapy possible .", "Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \" dominant negative \" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .", "___MASK75___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK75___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .", "[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK64___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 ." ]

[ "___MASK10___", "___MASK27___", "___MASK64___", "___MASK67___", "___MASK68___", "___MASK72___", "___MASK75___", "___MASK87___", "___MASK88___" ]

[ "[ Differential gene expression in nasopharyngeal carcinoma cell with reduced and normal expression of 6A8 alpha - mannosidase ] . OBJECTIVE : To detect the differential display of mRNA expression between human nasopharyngeal carcinoma cell CNE - 2L2 with reduced malignancy caused by transduction of a DNA antisense to 6A8 alpha - mannosidase cDNA ( AS cell ) and the wild type cell ( W cell ) . METHODS : Differential display of mRNA expression was analyzed using DNA microarray analysis . The datasets were confirmed by Northern blotting and RT - PCR . RESULTS : Out of the 1069 genes analyzed , 34 genes were up - regulated in AS cells relative to W cells . Conversely , 42 genes were down - regulated . The genes , up - regulation of which might have suppressive effect on tumor malignant behaviors , were P130 mRNA for 130K protein , TGF - betaIIR alpha , Q9UBS5 , P36897 , Q13829 , STANIN , E - CADHERIN , P35221 and 2 , P48378 , TMPO , etc . The genes , down - regulation of which might have suppressive effect on tumor malignant behaviors , were P16070 , Q92597 , P01137 , P46782 , LEGUMAIIN , P35520 , P13987 , P09661 , etc . The microarray datasets were confirmed by Northern blot and RT - PCR analysis . CONCLUSIONS : In comparison to the W cell , AS cell has up - regulation of 34 genes and down - regulation of 42 genes . Changes of the gene expression may play a role in the malignancy reduction of AS cell .", "Molecular identification of the human O75899 : cell surface expression and coupling to adenylyl cyclase in the absence of Q9UBS5 . We have identified a gene encoding a GABAB receptor , the human O75899 , located on chromosome 9q22 . 1 , that is distinct from the recently reported rat Q9UBS5 . O75899 structurally resembles Q9UBS5 ( 35 % identity ) , having seven transmembrane domains and a large extracellular region , but differs in having a longer carboxy - terminal tail . O75899 is localized to the cell surface in transfected COS cells , and negatively couples to adenylyl cyclase in response to GABA , baclofen , and 3 - aminopropyl ( methyl ) phosphinic acid in CHO cells lacking Q9UBS5 . DB00181 action is inhibited by the GABABR antagonist , 2 - hydroxysaclofen . The human O75899 and Q9UBS5 genes are differentially expressed in the nervous system , with the greatest difference being detected in the striatum in which Q9UBS5 but not O75899 mRNA transcripts are detected . O75899 and Q9UBS5 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum . Identification of a functional homomeric O75899 coupled to adenylyl cyclase suggests that the complexity of GABAB pharmacological data is at least in part due to the presence of more than one receptor and opens avenues for future research leading to an understanding of metabotropic GABA receptor signal transduction mechanisms .", "Characterization of the inhibitory effects of erythromycin and clarithromycin on the Q12809 potassium channel . Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans , however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current ( IKr ) encoded by Q12809 ( the human ether - a - go - go - related gene ) at drug concentrations , temperature and ionic conditions mimicking those occurring in human subjects . DB01345 currents in P29320 293 cells stably transfected with Q12809 were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the Q12809 encoded potassium current in a concentration dependent manner with an IC50 of 38 . 9 +/- 1 . 2 microM and Hill Slope factor of 0 . 4 +/- 0 . 1 . ___MASK63___ produced a similar concentration - dependent block with an IC50 of 45 . 7 +/- 1 . 1 microM and Hill Slope factor of 1 . 0 +/- 0 . 1 . Erythromycin ( 25 - 250 microM ) and clarithromycin ( 5 or 25 microM ) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the Q12809 potassium current at clinically relevant concentrations .", "P13987 DX , a double lipoxygenase product of DB01708 , inhibits both ROS production in human neutrophils and cyclooxygenase activities . Neutrophils play a major role in inflammation by releasing large amounts of reactive oxygen species ( ROS ) produced by NADPH oxidase ( NOX ) and myeloperoxidase ( P05164 ) . This ROS overproduction is mediated by phosphorylation of the NOX subunits in an uncontrolled manner . Therefore , targeting neutrophil subunits would represent a promising strategy to moderate NOX activity , lower ROS , and other inflammatory agents , such as cytokines and leukotrienes , produced by neutrophils . For this purpose , we investigated the effects of protectin DX ( DB06813 ) - a docosahexaenoic acid di - hydroxylated product which inhibits blood platelet aggregation - on neutrophil activation in vitro . We found that DB06813 decreases ROS production , inhibits NOX activation and P05164 release from neutrophils . We also confirm , that DB06813 is an anti - aggregatory and anti - inflammatory agent by inhibiting both cyclooxygenase - 1 and - 2 ( P23219 and P35354 , E . C . 1 . 14 . 99 . 1 ) as well as P35354 in lipopolysaccharides - treated human neutrophils . However , DB06813 has no effect on the P09917 pathway that produces the chemotactic agent leukotriene B4 ( LTB4 ) . Taken together , our results suggest that DB06813 could be a protective agent against neutrophil invasion in chronic inflammatory diseases .", "Identification of cell surface targets for HIV - 1 therapeutics using genetic screens . Human immunodeficiency virus ( HIV ) drugs designed to interfere with obligatory utilization of certain host cell factors by virus are less likely to encounter development of resistant strains than drugs directed against viral components . Several cellular genes required for productive infection by HIV were identified by the use of genetic suppressor element ( GSE ) technology as potential targets for anti - HIV drug development . Fragmented cDNA libraries from various pools of human peripheral blood mononuclear cells ( PBMC ) were expressed in vitro in human immunodeficiency virus type 1 ( HIV - 1 ) - susceptible cell lines and subjected to genetic screens to identify GSEs that interfered with viral replication . After three rounds of selection , more than 15000 GSEs were sequenced , and the cognate genes were identified . The GSEs that inhibited the virus were derived from a diverse set of genes including cell surface receptors , cytokines , signaling proteins , transcription factors , as well as genes with unknown function . Approximately 2 . 5 % of the identified genes were previously shown to play a role in the HIV - 1 life cycle ; this finding supports the biological relevance of the assay . GSEs were derived from the following 12 cell surface proteins : P61073 , CCR4 , P32248 , P20702 , P16070 , Q08722 , P34810 , Q07108 , P04233 , Q99062 , Q9UBS5 , and P20333 . Requirement of some of these genes for viral infection was also investigated by using RNA interference ( RNAi ) technology ; accordingly , 10 genes were implicated in early events of the viral life cycle , before viral DNA synthesis . Thus , these cell surface proteins represent novel targets for the development of therapeutics against HIV - 1 infection and AIDS .", "Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK16___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .", "Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .", "Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK38___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK38___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .", "AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK1___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .", "Association study of 45 candidate genes in nicotine dependence in Han Chinese . Numerous genetic linkages , association studies have been performed in different ethnic groups and revealed many susceptibility loci and genes for nicotine dependence . However , limited similar researches were performed in Han Chinese . This study was designed to investigate the association of candidate genes with nicotine dependence in Han Chinese . We genotyped 384 SNPs within 45 candidate genes with nicotine dependence in a Han Chinese population consisting 223 high nicotine dependent subjects and 257 low nicotine dependent subjects by employing GoldenGate genotyping assay ( Illumina ) . Following association analysis was performed using PLINK software . Individual SNP - based association analysis revealed that nine SNPs located in P35462 ( rs2630351 ) , P21918 ( rs1967550 ) , Q9Y6R4 ( rs2314378 ) , DDC ( rs11575461 ) , Q05901 ( rs4954 ) , O75899 ( rs2779562 ) , P14416 ( rs11214613 and rs6589377 ) and P43681 ( rs2236196 ) were significantly associated with FTND after correction for multiple testing with the p values from 2 . 59 × 10 (- 7 ) to 9 . 99 × 10 (- 5 ) . Haplotype - based association analysis revealed haplotype G - A - A formed by rs2630351 , rs167771 and rs324032 and haplotype G - G - G - A formed by rs3773678 , rs2630349 , rs2630351 and rs167771 in P35462 ; haplotype of G - A formed by rs2779562 and rs2808566 in O75899 and haplotype of T - T - A - G - A formed by rs6832644 , rs4057797 , rs9764 , rs4552421 and rs10033119 in P25929 are associated with FTND ( p = 3 . 61 × 10 (- 7 )- 8 . 78 × 10 (- 6 ) ) . Our results provided confirmation of the previous findings that P14416 , P35462 , DDC , Q05901 , O75899 and P43681 are associated with nicotine dependence . Furthermore , we for the first time report a significant association between nicotine dependence and P21918 , Q9Y6R4 and P25929 . These findings need independent replication in the future studies .", "A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK99___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK99___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .", "Complex formation with the Type B gamma - aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium - sensing receptor . Studies with P29320 - 293 cells and neurons . We co - immunoprecipitated the Ca ( 2 +)- sensing receptor ( CaR ) and type B gamma - aminobutyric acid receptor ( GABA - B - R ) from human embryonic kidney ( P29320 ) - 293 cells expressing these receptors and from brain lysates where both receptors are present . CaRs extensively co - localized with the two subunits of the GABA - B - R ( Q96GN5 and R2 ) in P29320 - 293 cell membranes and intracellular organelles . Coexpressing CaRs and GABA - B - R1s in P29320 - 293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [ Ca ( 2 +) ] ( [ Ca ( 2 +)]( e ) ) . In contrast , coexpressing CaRs and GABA - B - R2s enhanced CaR expression and signaling responses to raising [ Ca ( 2 +)]( e ) . The latter effects of the O75899 on the CaR were blunted by coexpressing the Q9UBS5 . Coexpressing the CaR with Q9UBS5 or R2 enhanced the total cellular and cell surface expression of the Q9UBS5 or R2 , respectively . Studies with truncated CaRs indicated that the N - terminal extracellular domain of the CaR participated in the interaction of the CaR with the Q9UBS5 and R2 . In cultured mouse hippocampal neurons , CaRs co - localized with the Q9UBS5 and R2 . CaRs and GABA - B - R1s also co - immunoprecipitated from brain lysates . The expression of the CaR was increased in lysates from Q9UBS5 knock - out mouse brains and in cultured hippocampal neurons with their Q9UBS5 genes deleted in vitro . Thus , CaRs and GABA - B - R subunits can form heteromeric complexes in cells , and their interactions affect cell surface expression and signaling of CaR , which may contribute to extracellular Ca ( 2 +)- dependent receptor activation in target tissues .", "Interaction of early environment , gender and genes of monoamine neurotransmission in the aetiology of depression in a large population - based Finnish birth cohort . Objectives Depression is a worldwide leading cause of morbidity and disability . Genetic studies have recently begun to elucidate its molecular aetiology . The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population - based Northern Finland Birth Cohort 1966 ( 12 058 live births ) . Design The authors ascertained and subdivided the study sample ( n = 5225 ) based on measures of early development and of social environment , and examined candidate genes of monoamine neurotransmission , many of which have shown prior evidence of a gene - environment interaction for affective disorders , namely P31645 , Q8IWU9 , P21964 , P21397 and the dopamine receptor genes P21728 - P21918 . Results and conclusion The authors observed no major genetic effects of the analysed variants on depressiveness . However , when measures of early development and of social environment were considered , some evidence of interaction was observed . Allelic variants of P21964 interacted with high early developmental risk ( p = 0 . 005 for rs2239393 and p = 0 . 02 for rs4680 ) so that the association with depression was detected only in individuals at high developmental risk group ( p = 0 . 0046 and β = 0 . 056 for rs5993883 - rs2239393 - rs4680 risk haplotype CGG including Val158 ) , particularly in males ( p = 0 . 0053 and β = 0 . 083 for the haplotype CGG ) . Rs4274224 from P14416 interacted with gender ( p = 0 . 017 ) showing a significant association with depressiveness in males ( p = 0 . 0006 and β = 0 . 0023 ; p = 0 . 00005 and β = 0 . 069 for rs4648318 - rs4274224 haplotype GG ) . The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex , but not direct major effects of monoaminergic genes in this unselected population .", "Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK11___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .", "___MASK46___ : kinetic and dynamic profile in the treatment of pain . ___MASK46___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK46___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK46___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK46___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .", "___MASK54___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK54___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .", "Immunocytochemical localization of Q9UBS5 receptor subunits in the basolateral amygdala . Gamma - aminobutyric acid B ( GABAB ) receptors ( GBRs ) are G - protein - coupled receptors that mediate a slow , prolonged form of inhibition in the basolateral amygdala ( P00519 ) and other brain areas . Recent studies indicate that this receptor is a heterodimer consisting of Q9UBS5 ( GBR1 ) and O75899 subunits . In the present investigation , antibodies to the Q9UBS5 subunit were used to study the neuronal localization of GBRs in the rat P00519 . GBR immunoreactivity was mainly found in spine - sparse interneurons and astrocytes at the light microscopic level . Very few pyramidal neurons exhibited perikaryal staining . Dual - labeling immunofluorescence analysis indicated that each of the four main subpopulations of interneurons exhibited GBR immunoreactivity . Virtually 100 % of large CCK + neurons in the basolateral and lateral nuclei were GBR + . In the basolateral nucleus 72 % of somatostatin ( Q8TE85 ) , 73 % of parvalbumin ( PV ) and 25 % of P01282 positive interneurons were GBR + . In the lateral nucleus 50 % of somatostatin , 30 % of parvalbumin and 27 % of P01282 positive interneurons were GBR + . Electron microscopic ( EM ) analysis revealed that most of the light neuropil staining seen at the light microscopic level was due to the staining of dendritic shafts and spines , most of which probably belonged to spiny pyramidal cells . Very few axon terminals ( Ats ) were GBR + . In summary , this investigation demonstrates that the distal dendrites of pyramidal cells , and varying percentages of each of the four main subpopulations of interneurons in the P00519 , express GBRs . Because previous studies suggest that GBR - mediated inhibition modulates DB01221 - dependent EPSPs in the P00519 , these receptors may play an important role in neuronal plasticity related to emotional learning .", "Synergism between bosutinib ( ___MASK71___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .", "DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .", "Potent and selective activation of the pancreatic beta - cell type K ( DB00171 ) channel by two novel diazoxide analogues . AIMS / HYPOTHESIS : We investigated the pharmacological properties of two novel DB00171 sensitive potassium ( K ( DB00171 ) ) channel openers , 6 - Chloro - 3 - isopropylamino - 4 H - thieno [ 3 , 2 - e ] - 1 , 2 , 4 - thiadiazine 1 , 1 - dioxide ( NNC 55 - 0118 ) and 6 - chloro - 3 -( 1 - methylcyclopropyl ) amino - 4 H - thieno [ 3 , 2 - e ]- 1 , 2 , 4 - thiadiazine 1 , 1 - dioxide ( NN414 ) , on the cloned cardiac ( Kir6 . 2 / SUR2A ) , smooth muscle ( Kir6 . 2 / SUR2B ) and pancreatic beta cell ( Kir6 . 2 / Q09428 ) types of K ( DB00171 ) channel . METHODS : We studied the effects of these compounds on whole - cell currents through cloned K ( DB00171 ) channels expressed in Xenopus oocytes or mammalian cells ( HEK293 ) . We also used inside - out macropatches excised from Xenopus oocytes . RESULTS : In P29320 293 cells , NNC 55 - 0118 and NN414 activated Kir6 . 2 / Q09428 currents with EC ( 50 ) values of 0 . 33 micromol / l and 0 . 45 micromol / l , respectively , compared with that of 31 micro mol / l for diazoxide . Neither compound activated Kir6 . 2 / SUR2A or Kir6 . 2 / SUR2B channels expressed in oocytes , nor did they activate Kir6 . 2 expressed in the absence of Q09428 . Current activation was dependent on the presence of intracellular MgATP , but was not supported by MgADP . CONCLUSION / INTERPRETATION : Both NNC 55 - 0118 and NN414 selectively stimulate the pancreatic beta - cell type of K ( DB00171 ) channel with a higher potency than diazoxide , by interaction with the Q09428 subunit . The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial ." ]

[ "___MASK11___", "___MASK16___", "___MASK1___", "___MASK38___", "___MASK46___", "___MASK54___", "___MASK63___", "___MASK71___", "___MASK99___" ]

[ "P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK10___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK10___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK10___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK10___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .", "P35367 promotes atherosclerotic lesion formation by increasing vascular permeability for low - density lipoproteins . OBJECTIVE : Enhanced endothelial permeability leading to intimal accumulation of low - density lipoproteins ( LDL ) stimulates the formation of atherosclerotic lesions . DB11320 is known to increase vascular permeability . Whether this affects the formation of atherosclerotic lesions , however , remains elusive . METHODS AND RESULTS : P02649 - null ( ApoE (-/-) ) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40 % fewer atherosclerotic lesions in the aorta than placebo - treated controls . Similarly , genetic deletion of the H1 but not the H2 receptor resulted in a 60 % reduction of lesions compared with ApoE (-/-) controls . The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta , whereas plasma lipoprotein levels remained unaltered . In contrast , the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells . Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells , whereas its presence in bone marrow - derived cells was irrelevant for plaque development . Mice expressing the H1 receptor exhibited higher levels of the chemokine ( C - C motif ) ligand 5 and higher numbers of macrophages and T - helper lymphocytes in plaques , higher numbers of circulating lymphocytes , and larger spleens . CONCLUSION : These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL , which is associated with an enhanced secondary aortic and systemic inflammation . These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease .", "Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK91___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .", "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .", "Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK75___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .", "Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK53___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .", "5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK75___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .", "[ The interconnections of molecular mechanisms of hormone actions and their role in pathogenesis of obesity , insulin resistance , and diabetes mellitus ] . The various hormones , proteins and other compounds related to developing obesity , insulin resistance and type 2 diabetes are analyzed in the paper . 1 ) Leptin , ciliary neurutrophic factor , adiponectin , glucagon - like peptide 1 , peptide YY , neuromedin S , as well as the protein receptors of these hormones decrease the food consumption , increase the energy turnover , and prevent obesity , insulin resistance , and type 2 diabetes development . The mediators of these hormone and receptor actions are melanocyte stimulating hormone ( MSH ) , corticotropin - releasing hormone ( P06850 ) , and the others . 2 ) Ghrelin , endogenose cannabinoides , galanin - like peptide and the mediators of their actions : neuropeptide Y ( P01303 ) and Agouti gene related protein ( O00253 ) increase the appetite and food consumption . Peroxisome proliferation - activated receptor ( Q07869 ) performs the similar action on food intake . The activation of the first group compound functioning decreases the obesity , increases the energy turnover , facilitates the insulin action and prevents the insulin resistance and type 2 diabetes . Increasing the activities of the second group , as well as , decreasing the actions of the first one of substances induce the opposite effects and facilitate obesity , insulin resistance , and type 2 diabetes developments . The interconnections of the molecular mechanisms of so many hormone actions make the very complicated tusk to study the various endocrine disorders including diabetes mellitus as well .", "Kisspeptins : bridging energy homeostasis and reproduction . Body energy reserves and metabolic state are relevant modifiers of puberty onset and fertility ; forms of metabolic stress ranging from persistent energy insufficiency to morbid obesity are frequently linked to reproductive disorders . The mechanisms for such a close connection between energy balance and reproduction have been the subject of considerable attention ; however , our understanding of the neurobiological basis for this phenomenon is still incomplete . In mid 1990s , the adipose - hormone , leptin , was proven as an essential signal for transmitting metabolic information onto the centers governing puberty and reproduction ; yet , the ultimate mode of action of leptin on DB00644 neurons has remained contentious for years . More recently , kisspeptins , a family of neuropeptides encoded by the Kiss1 gene , have emerged as conduits for the metabolic regulation of reproduction and putative effectors of leptin actions on DB00644 neurons . This review recapitulates the experimental evidence obtained to date , mostly in laboratory rodents , supporting the function of kisspeptins in bridging energy balance and reproduction , with special emphasis on recent developments in this field , such as the recognition of P42345 ( mammalian target of rapamycin ) and Crtc1 ( Creb1 - regulated transcription coactivator - 1 ) as putative mediators for leptin regulation of Kiss1 expression , as well as the identification of other potential metabolic modulators of kisspeptin signaling , such as ghrelin , neuropeptide Y ( P01303 ) and melanin - concentrating hormone ( P20382 ) .", "Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin - dependent kinase ( CDK ) inhibitor . Cushing disease caused by adrenocorticotropin ( DB01285 ) - secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes , hypertension , osteoporosis , central obesity , cardiovascular morbidity , and increased mortality . There is no effective pituitary targeted pharmacotherapy for Cushing disease . Here , we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene ( O95997 / securin ) targeted to the adenohypophyseal proopiomelanocortin ( P01189 ) lineage , which recapitulated early features pathognomonic of corticotroph adenomas , including corticotroph expansion and partial glucocorticoid resistance . Adult Tg : Pomc - Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up - regulation , as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease . Early development of corticotroph pathologies in Tg : Pomc - Pttg embryos facilitated drug testing in vivo . We identified a pharmacologic P24941 / cyclin E inhibitor , R - roscovitine ( seliciclib ; CYC202 ) , which specifically reversed corticotroph expansion in live Tg : Pomc - Pttg embryos . We further validated that orally administered R - roscovitine suppresses DB01285 and corticosterone levels , and also restrained tumor growth in a mouse model of DB01285 - secreting pituitary adenomas . Molecular analyses in vitro and in vivo showed that R - roscovitine suppresses DB01285 expression , induces corticotroph tumor cell senescence and cell cycle exit by up - regulating p27 , P38936 and p57 , and downregulates cyclin E expression . The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion .", "Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK25___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .", "P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK63___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .", "DB11320 H3 receptors aggravate cerebral ischaemic injury by histamine - independent mechanisms . The role of the histamine H3 receptor ( Q9Y5N1 ) in cerebral ischaemia / reperfusion ( I / R ) injury remains unknown . Here we show that Q9Y5N1 expression is upregulated after I / R in two mouse models . Q9Y5N1 antagonists and Q9Y5N1 knockout attenuate I / R injury , which is reversed by an Q9Y5N1 - selective agonist . Interestingly , P35367 and P25021 antagonists , a histidine decarboxylase ( HDC ) inhibitor and HDC knockout all fail to compromise the protection by Q9Y5N1 blockade . Q9Y5N1 blockade inhibits P42345 phosphorylation and reinforces autophagy . The neuroprotection by Q9Y5N1 antagonism is reversed by 3 - methyladenine and siRNA for Atg7 , and is diminished in Atg5 ⁻/⁻ mouse embryonic fibroblasts . Furthermore , the peptide Tat - Q9Y5N1 ( CT414 - 436 ) , which blocks Q9Y696 binding with H3Rs , or siRNA for Q9Y696 , further increases I / R - induced autophagy and protects against I / R injury . Therefore , Q9Y5N1 promotes I / R injury while its antagonism protects against ischaemic injury via histamine - independent mechanisms that involve suppressing Q9Y5N1 / Q9Y696 binding - activated autophagy , suggesting that Q9Y5N1 inhibition is a therapeutic target for cerebral ischaemia .", "Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK8___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK8___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK8___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .", "___MASK85___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .", "[ Level of neuropeptide Y in serum of patients with chronic congestive heart failure ] . The purpose of the study was to measure plasma concentrations of neuropeptide Y ( P01303 ) , endothelin - 1 , 2 ( ET - 1 , 2 ) , alpha atrial natriuretic polypeptide ( P01160 ) and noradrenaline ( NA ) in relation to cardiac index ( CI ) and left ventricular ejection fraction ( LVEF ) in patients with congestive heart failure ( CHF ) . There were significant increases in venous blood concentrations of P01303 , Na , ET - 1 , 2 , P01160 in the patients with CHF . Plasma concentrations of P01303 correlated with plasma NA concentrations but plasma noradrenaline concentrations alone correlated with CI and LVEF . In patients with CHF plasma NA concentrations seems to be more sensitive index of cardiac dysfunction then the concentrations of neuropeptide Y .", "A functional role for P29323 in gene induction , but not in neurite outgrowth in differentiating neuroblastoma cells . The human neuroblastoma cell line SH - SY5Y can differentiate into a functional sympathetic neuronal phenotype when treated with low concentrations of the phorbol ester 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) in the presence of serum or defined growth factors . When TrkA is introduced into the cells , P01138 also induces differentiation . In both cases , protein kinase C ( PKC ) is pivotal for induction and maintenance of the differentiated phenotype . We have recently shown that PKC activity is needed to enable the MAPK P29323 to accumulate in the nucleus of SH - SY5Y cells and hence activate transcription . To find out whether this could be one reason for the PKC dependency in the differentiation process we have investigated the role of P29323 during neuronal differentiation of these cells . The results show that P29323 was needed for full upregulation of the neuronal marker genes P01303 and P20936 - 43 . However , P29323 activity was not necessary for TPA - induced neurite formation . Neither was activation of P29323 sufficient to promote neurite outgrowth . The results clearly show that there was no correlation between nuclear P29323 activity , measured as SRE transactivation , and neurite formation in TPA - differentiated SH - SY5Y neuroblastoma cells .", "DB06698 treatment in managing vertigo and improving vestibular compensation : clarification . DB06698 dihydrochloride ( betahistine ) is currently used in the management of vertigo and vestibular pathologies with different aetiologies . The main goal of this review is to clarify the mechanisms of action of this drug , responsible for the symptomatic relief of vertigo and the improvement of vestibular compensation . The review starts with a brief summary recalling the role of histamine as a neuromodulator / neurotransmitter in the control of the vestibular functions , and the role of the histaminergic system in vestibular compensation . Then are presented data recorded in animal models demonstrating that betahistine efficacy can be explained by mechanisms targeting the histamine receptors ( HRs ) at three different levels : the vascular tree , with an increase of cochlear and vestibular blood flow involving the P35367 ; the central nervous system , with an increase of histamine turnover implicating the Q9Y5N1 , and the peripheral labyrinth , with a decrease of vestibular input implying the Q9Y5N1 / Q9H3N8 . Clinical data from vestibular loss patients show the impact of betahistine treatment for the long - term control of vertigo , improvement of balance and quality of life that can be explained by these mechanisms of action . However , two conditions , at least , are required for reaching the betahistine therapeutic effect : the dose and the duration of treatment . Experimental and clinical data supporting these requirements are exposed in the last part of this review .", "The opioid system in alcohol and drug dependence : family - based association study . Opioid receptors and their endogenous peptide ligands play important roles in neurotransmission and neuromodulation in response to addictive drugs such as heroin , cocaine , and alcohol . In an earlier study , we reported that variation in the genes encoding the kappa - opioid receptor ( P41145 ) and its peptide ligand ( P01213 ) were associated with the risk for alcoholism . We continued our investigation of the role of the opioid system in alcohol dependence by analyzing the genes encoding the micro - and delta - opioid receptors and their peptide ligands . We analyzed 18 P35372 SNPs , 18 P41143 SNPs , 7 P01210 SNPs , and 7 P01189 SNPs in a sample of 1923 European Americans from 219 multiplex alcohol dependent families . Employing a family - based test of association , we found no evidence that these four genes were significantly associated with alcohol dependence . We also did not find association between these genes and illicit drug dependence . Secondary analyses employing the narrower phenotype of opioid dependence ( 83 affected individuals ) demonstrated association with SNPs in P01210 and P01189 , but not in P35372 or P41143 . Haplotype analyses provided further support for the association of P01210 and P01189 with opioid dependence . Therefore , our data provide no support for the idea that variations in P35372 , P41143 , P01210 and P01189 are associated with alcohol dependence or general illicit drug dependence , but variations in P01210 and P01189 appear to be associated with the narrower phenotype of opioid dependence in these families .", "Polymorphisms of stress - related genes and the risk of nonsyndromic cleft lip with or without cleft palate . BACKGROUND : Nonsyndromic cleft lip with or without cleft palate ( P19338 / P ) is a common structural malformation with a complex and multifactorial etiology . It has been shown that maternal psychological stress in the periconceptional period can contribute to an increase in the risk of P19338 / P affecting pregnancy . METHODS : Twenty - four single nucleotide polymorphisms of 11 stress - related genes ( P21964 , P34998 , Q13451 , Q16445 , HSD11β2 , P21397 , P01303 , P04150 , P08185 , P31645 , and Q8IWU9 ) were investigated in 220 healthy mothers of children with facial clefts and 210 matched controls using restriction fragment - length polymorphism and high - resolution melting analysis . RESULTS : We found that polymorphisms in P31645 , Q8IWU9 , and P08185 appear to be maternal factors increasing the risk of having a child with facial clefts . The closest correlations with P19338 / P were found for the P31645 rs2020942 and Q8IWU9 rs10879357 gene variants ( odds ratio [ OR ] , 1 . 720 ; 95 % confidence interval [ CI ] , 1 . 158 - 2 . 553 ; p = 0 . 0069 ; p ( trend ) = 0 . 0036 ; and OR , 1 . 837 ; 95 % CI , 1 . 226 - 2 . 753 , p = 0 . 0030 , p ( trend ) = 0 . 0057 ; respectively ) . Moreover , haplotype analysis revealed that several combinations of markers in P31645 , Q8IWU9 , and P08185 might be significantly associated with the risk of P19338 / P affected pregnancies . However , these associations were not statistically significant after correction for multiple testing . CONCLUSION : This study suggests that nucleotide variants of genes encoding components of the hypothalamus - pituitary - adrenal axis and serotoninergic system have a role in the etiology of P19338 / P in the Polish population . P31645 , Q8IWU9 , and P08185 might be novel candidate genes for this common congenital anomaly .", "P35367 mRNA is expressed in capsaicin - insensitive sensory neurons with neuropeptide Y - immunoreactivity in guinea pigs . P35367 mRNA - expressing sensory neurons in guinea pigs are unmyelinated and are not immunoreactive to DB05875 and calcitonin gene - related peptide ( P80511 ) [ Mol . Brain Res . 66 ( 1999 ) 24 ] , which are implicated in the nociceptive transmission of the primary sensory system . In this study , we examined whether these H1 receptor mRNA - expressing neurons are sensitive to capsaicin by using in situ hybridization histochemistry . Of lumbar dorsal root ganglion ( Q86YR7 ) neurons in control animals , 17 % were positive for P80511 . In guinea pigs neonatally treated with capsaicin ( 50 mg / kg ) , few P80511 - immunoreactive neurons were seen in the DRGs . However , the percentages of H1 receptor mRNA - expressing neurons ( 15 - 20 % ) and the intensity of the mRNA signals in these neurons were not affected by neonatal capsaicin treatment . We also revealed the presence of both capsaicin - sensitive and insensitive neuropeptide Y ( P01303 ) - immunoreactive neurons in the DRGs . These neurons were exclusively small . H1 receptor mRNA was expressed in P01303 - immunoreactive neurons in naive guinea pig DRGs . These results suggest that H1 receptor mRNA is expressed in capsaicin - insensitive Q86YR7 neurons with P01303 - immunoreactivity in guinea pigs .", "Stimulation of the histamine 4 receptor with 4 - methylhistamine modulates the effects of chronic stress on the Th1 / Th2 cytokine balance . Alterations to the immune system caused by stress have been considered to markedly increase the risk for immune - related diseases such as cancer and autoimmune disorders . We investigated the potential anti - stress effects of the histamine 4 receptor ( Q9H3N8 ) agonist , 4 - methylhistamine ( 4 - MeH ) , in a murine stress model . Mice were placed in 50ml conical centrifuge tubes for 12h followed by a 12h rest . The effects of treatment with 4 - MeH ( 30mg / kg , i . p . , twice daily ) for 2 days were assessed . At 2 days after physical restraint , mice were sacrificed and tissues harvested . We evaluated the effects of 4 - MeH treatment on P01730 (+) T cell production , and intracellular IFN - γ and P05112 expression in these cells . We also assessed IL - 1β , IFN - γ , P01375 - α , and P05112 mRNA expression as well as IFN - γ , P01375 - α , Q9Y5U5 , Ox40 and P05112 protein expression in the spleen . The results showed that 4 - MeH treatment of stressed mice results in a substantial increase in the P01730 (+) T cells as well as in IFN - γ production by these cells . Compared to both untreated and stressed controls . In contrast , P05112 expression decreased significantly following 4 - MeH treatment of mice . Moreover , stimulation of the Q9H3N8 resulted in up - regulated expression of IL - 1β , IFN - γ and P01375 - α mRNAs and decreased the expression of P05112 . Western blot analysis confirmed decreased protein expression of IFN - γ , P01375 - α , Q9Y5U5 , Ox40 and increased P05112 in the SC group and treatment of mice with 4 - MeH reversed these effects . Our results confirm the significant impact of chronic stress on T cell function and production of Th1 / Th2 mediators Q9H3N8 .", "DB11320 Promotes the Release of P05231 via the P35367 / p38 and NF - κB Pathways in Nasal Fibroblasts . PURPOSE : Based on the close relationship between histamine and interleukin 6 ( P05231 ) , we hypothesized that histamine may regulate the production of cytokines , such as P05231 , during allergic inflammation . Here , we examined the role of histamine in P05231 production and histamine receptor activity in nasal fibroblasts , along with the mechanisms underlying these effects . METHODS : Experiments were performed using nasal fibroblasts from 8 normal patients . RT - PCR was used to identify the major histamine receptors expressed in nasal fibroblasts . Fibroblasts were then treated with histamine with or without histamine - receptor antagonists , and monitored for P05231 production using an ELISA . Four potential downstream signaling molecules , p38 , extracellular signal - regulated kinase ( P29323 ) , c - Jun N - terminal kinase ( JNK ) , and NF - κB , were evaluated by Western blot , and a luciferase reporter assay . RESULTS : Elevated expression was seen for all histamine receptors , with P05231 protein levels increasing significantly following histamine stimulation . Among the histamine - receptor specific antagonists , only the P35367 antagonist significantly decreased P05231 production in histamine - stimulated nasal fibroblasts . DB11320 increased the expression level of phosphorylated p38 ( pp38 ) , pERK , and pJNK , as well as NF - κB induction . The P35367 antagonist actively suppressed pp38 and NF - κB expression in histamine - induced nasal fibroblasts , but not pERK and pJNK . The p38 inhibitor strongly attenuated P05231 production in histamine - stimulated nasal fibroblasts . CONCLUSIONS : The data presented here suggest that antihistamines may be involved in the regulation of cytokines , such as P05231 , due to the role of histamine as an inflammatory mediator in nasal fibroblasts .", "Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease - related and genetic factors contribute to inter - individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four - point categorical scales . In stratified regression models including demographical and disease - related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid - or nausea / vomiting signalling pathways ( P08183 , P35372 , P41145 , P32121 , P42226 , P21964 , P20309 , P08912 , P35367 , P14416 , P35462 , P25103 , P46098 , O95264 , Q8WXA8 , P21554 ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter - individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0 . 01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 ; rs165722 , rs4680 and rs4633 in P21964 ; rs10802789 and rs685550 in P20309 . Only the SNP rs1672717 in O95264 passed the Benjamini - Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 , P21964 and P20309 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .", "FcεRI stimulation promotes the differentiation of histamine receptor 1 - expressing inflammatory macrophages . BACKGROUND : Monocyte differentiation into dendritic cells or macrophages and recruitment to peripheral organs in chronic inflammatory diseases are directed by allergen challenge via FcεRI as well as the nature of soluble factors in the microenvironment . High - affinity receptor for IgE stimulation of effector cells results in the release of histamine , which acts on various histamine receptors ( HR ) 1 - 4 , expressed by immune cells . METHODS : We examined the effect of FcεRI stimulation of human monocytes on P35367 expression and function of differentiating cells . The mRNA levels of P35367 , P25021 and histidine decarboxylase of differentiating cells were detected by quantitative real - time PCR . Expression of CD1c , CD11c , P34810 and Q86VB7 was detected by flow cytometry . Amount of histamine , P05231 and IL - 12p70 in the cell culture was measured with the help of cytometric bead arrays or ELISA assays . Numbers of P35367 - expressing macrophages were evaluated by immunofluorescence double staining of P34810 and P35367 on human skin sections . RESULTS : We demonstrated that FcεRI stimulation promotes the generation of P35367 - expressing macrophage - like cells with enhanced histamine biosynthesis and P35367 - mediated proinflammatory properties . Supporting our in vitro findings , high numbers of P35367 - expressing P34810 ( pos ) macrophages were detected in the dermis of atopic dermatitis ( AD ) skin lesions . CONCLUSION : Our observations point to a close histamine -/ HR - mediated activation of dermal macrophages , leading to modified cell differentiation and responsiveness via P35367 , which might contribute to the aggravation of allergic skin inflammation in AD .", "DB06698 ameliorates olanzapine - induced weight gain through modulation of histaminergic , P01303 and AMPK pathways . Olanzapine is widely used to treat schizophrenia and other disorders , but causes adverse obesity and other metabolic side - effects . Both animal and clinical studies have shown that co - treatment with betahistine ( a histaminergic H1 receptor agonist and H3 receptor antagonist ) is effective for ameliorating olanzapine - induced weight gain / obesity . To reveal the mechanisms underlying these effects , this study investigated the effects of co - treatment of olanzapine and betahistine ( O + B ) on expressions of histaminergic H1 receptor ( P35367 ) , AMP - activated protein kinase ( AMPK ) , neuropeptide Y ( P01303 ) , and proopiomelanocortin ( P01189 ) in the hypothalamus associated with reducing olanzapine - induced weight gain . Olanzapine significantly upregulated the mRNA and protein expressions of P35367 , while O + B co - treatment significantly downregulated the P35367 levels , compared to the olanzapine - only treatment group . The P01303 mRNA expression was significantly enhanced by olanzapine , but it was significantly reversed by O + B co - treatment . The hypothalamic P35367 expression was positively correlated with total food intake , and P01303 expression . Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation ( pAMPKα ) / AMPKα ratio compared with controls , whereas O + B co - treatment decreased the pAMPKα / AMPKα ratio , compared with olanzapine only treatment . The pAMPKα / AMPKα ratio was positively correlated with total food intake and P35367 expression . Although olanzapine administration decreased the P01189 mRNA level , this level was not affected by O + B co - treatment . Therefore , these results suggested that co - treatment with betahistine may reverse olanzapine - induced body weight gain via the P35367 - P01303 and P35367 - pAMPKα pathways .", "Effects of the inhibition of cyclo - oxygenase 1 or 2 or P09917 on the activation of the hypothalamic - pituitary - adrenal axis induced by interleukin - 1beta in the male Rat . The limited entry of interleukin - 1beta ( IL - 1beta ) into the central nervous system has led to the hypothesis that IL - 1beta acts , through IL - 1beta receptors located notably on endothelial cells , on the release of prostaglandins which in turn stimulate the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis . We used cyclo - oxygenase - 1 ( P23219 ) and cyclo - oxygenase - 2 ( P35354 ) and P09917 ( 5 - P28300 ) inhibitors , before the injection of IL - 1beta , to explore the role of arachidonic acid metabolic pathways on Q9Y251 axis activation . Adult male rats were i . m injected 20 min before i . p injection of IL - 1beta , with ( i ) : a P23219 / P35354 inhibitor ( ketoprofen ) ; ( ii ) a P35354 selective inhibitor ( NS 398 ) ; or ( iii ) a 5 - P28300 inhibitor ( BW A4C ) . Following this , rats were killed 90 min after i . p . IL - 1beta injection and analysis for plasma adrenocorticotropic hormone ( DB01285 ) and corticosterone concentrations and determination of anterior pituitary pro - opio melanocortin ( P01189 ) gene transcription was conducted . Administration of the P23219 / P35354 inhibitor led to a complete blockage of DB01285 and corticosterone secretion and P01189 gene transcription . The P35354 inhibitor led to a complete blockade of DB01285 secretion and P01189 gene transcription but had no effect on corticosterone secretion . The 5 - P28300 inhibitor had no significant effect on any parameter . These results demonstrate the crucial role of eicosanoid pathways in mediating the stimulation of the Q9Y251 axis induced by IL - 1beta . Moreover , we found a clear dissociation of the effect of the blockage of COXs upon DB01285 and corticosterone secretion , suggesting that IL - 1beta may act at the brain as well as at the adrenal cortex to stimulate the secretion of corticosterone .", "Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .", "[ Moclobemide ( ___MASK96___ ) , the first P21397 - inhibitor : really something new ? ] .", "Prevention of bleomycin - induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment . Pulmonary fibrosis , a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components , is a major therapeutic challenge for which new therapeutic strategies are warranted . Cyclooxygenase ( P36551 ) inhibitors have been previously utilized to reduce inflammation . Q9H3N8 ( Q9H3N8 ) , largely expressed in hematopoietic cells , has been identified as a novel target for inflammatory and immune disorders . The aim of this study was to evaluate the effect of JNJ7777120 ( 1 -[( 5 - chloro - 1H - indol - 2 - yl ) carbonyl ]- 4 - methylpiperazine ) , a selective Q9H3N8 antagonist , and naproxen , a well known nonsteroidal anti - inflammatory drug , and their combination in a murine model of bleomycin - induced fibrosis . DB00290 ( 0 . 05 IU ) was instilled intratracheally to C57BL / 6 mice , which were then treated by micro - osmotic pump with vehicle , JNJ7777120 ( 40 mg / kg b . wt . ) , naproxen ( 21 mg / kg b . wt . ) , or a combination of both . Airway resistance to inflation , an index of lung stiffness , was assessed , and lung specimens were processed for inflammation , oxidative stress , and fibrosis markers . Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing P35354 and myeloperoxidase expression and activity and thiobarbituric acid - reactive substance and 8 - hydroxy - 2 '- deoxyguanosine production . Lung fibrosis was inhibited , as demonstrated by the reduction of tissue levels of transforming growth factor - β , collagen deposition , relative goblet cell number , and smooth muscle layer thickness . Our results demonstrate that both JNJ7777120 and naproxen exert an anti - inflammatory and antifibrotic effect that is increased by their combination , which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis .", "___MASK91___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK91___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK10___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK10___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK10___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK10___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats ." ]

[ "___MASK10___", "___MASK25___", "___MASK53___", "___MASK63___", "___MASK75___", "___MASK85___", "___MASK8___", "___MASK91___", "___MASK96___" ]

[ "Functional characterisation of a novel mutation affecting the catalytic domain of P08253 in siblings with multicentric osteolysis , nodulosis and arthropathy . Multicentric osteolysis , nodulosis and arthropathy ( MONA ) is a rare autosomal recessive disorder . To date , 13 mutations of the matrix metalloproteinase 2 ( P08253 ) gene have been detected in 26 patients with MONA and other osteolytic syndromes . Here , we describe the molecular and functional analysis of a novel P08253 mutation in two adult Italian siblings with MONA . Both siblings displayed palmar - plantar subcutaneous nodules , tendon retractions , limb arthropathies , osteolysis in the toes and pigmented fibrous skin lesions . Molecular analysis identified a homozygous P08253 missense mutation in exon 8 c . 1228G > C ( p . G410R ) , not detected in 260 controls and predicted by several bioinformatic tools to be pathogenic . By protein modelling , the mutant residue was predicted to affect the main chain conformation of the catalytic domain . Gelatin zymography , the gold standard test for P08253 function , of serum - free conditioned medium from G410R - P08253 - expressing human embryonic kidney ( P29320 ) cells , showed a complete loss of gelatinolytic activity . The novel mutation is located in the catalytic domain , as are 3 ( p . E404K , p . V400del and p . G406D ) of the other 13 P08253 mutations described to date ; however , p . G410R underlies a phenotype that is only partially overlapping that of other P08253 exon 8 mutation carriers . Our results further delineate the complexity of genotype - phenotype correlations in MONA , broaden the repertoire of reported P08253 mutation and enhance the comprehension of the protein motifs crucial for P08253 catalytic activity .", "Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK75___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .", "Endothelial cell - derived nitric oxide enhances aerobic glycolysis in astrocytes via HIF - 1α - mediated target gene activation . Astrocytes exhibit a prominent glycolytic activity , but whether such a metabolic profile is influenced by intercellular communication is unknown . Treatment of primary cultures of mouse cortical astrocytes with the nitric oxide ( NO ) donor DetaNONOate induced a time - dependent enhancement in the expression of genes encoding various glycolytic enzymes as well as transporters for glucose and lactate . Such an effect was shown to be dependent on the hypoxia - inducible factor HIF - 1α , which is stabilized and translocated to the nucleus to exert its transcriptional regulation . NO action was dependent on both the PI3K / Akt / P42345 and MEK signaling pathways and required the activation of P36551 , but was independent of the soluble guanylate cyclase pathway . Furthermore , as a consequence of NO treatment , an enhanced lactate production and release by astrocytes was evidenced , which was prevented by downregulating HIF - 1α . Several brain cell types represent possible sources of NO . It was found that endothelial cells , which express the endothelial NO synthase ( P29474 ) isoform , constitutively produced the largest amount of NO in culture . When astrocytes were cocultured with primary cultures of brain vascular endothelial cells , stabilization of HIF - 1α and an enhancement in glucose transporter - 1 , hexokinase - 2 , and monocarboxylate transporter - 4 expression as well as increased lactate production was found in astrocytes . This effect was inhibited by the NOS inhibitor l - NAME and was not seen when astrocytes were cocultured with primary cultures of cortical neurons . Our findings suggest that endothelial cell - derived NO participates to the maintenance of a high glycolytic activity in astrocytes mediated by astrocytic HIF - 1α activation .", "Endothelial dysfunction in congestive heart failure : P12821 inhibition vs . angiotensin II antagonism . BACKGROUND : Endothelial dysfunction of the vasculature contributes to the elevated peripheral resistance and reduced myocardial perfusion in congestive heart failure ( CHF ) . The present study systematically investigated the effect of angiotensin II ( AT ( 1 ) ) - receptor blockade on vascular superoxide ( O ( 2 )(-) ) production and endothelial dysfunction . METHODS AND RESULTS : Vasodilator responses and O ( 2 )(-) production were determined in aortic rings from Wistar rats with experimental CHF 10 weeks after extensive myocardial infarction and compared with sham - operated animals ( Sham ) . Rats were either treated with placebo ( P ) , with the AT ( 1 )- receptor antagonist Irbesartan ( 50 mg kg (- 1 ) day (- 1 ) ) or with the P12821 inhibitor DB00519 ( 0 . 3 mg kg (- 1 ) day (- 1 ) ) . In CHF - P , endothelium - dependent , acetylcholine - induced relaxation was significantly attenuated compared with Sham - P . Chronic treatment with DB00519 or Irbesartan significantly improved endothelium - dependent relaxation . Aortic O ( 2 )(-) formation was markedly increased in CHF , and was not significantly affected by DB00519 treatment , while it was reduced by Irbesartan . P29474 expression was reduced in CHF and normalised by both treatments . CONCLUSION : Endothelial vasomotor function in CHF rats was normalised by long - term treatment with an P12821 inhibitor or an AT ( 1 )- antagonist . Reduced aortic P29474 expression was normalised by both treatments , whereas aortic superoxide formation was only reduced by the AT ( 1 )- antagonist Irbesartan .", "Lack of direct interaction between enalaprilat and the kinin B1 receptors . It has been recently proposed that the second extracellular loop of the human bradykinin ( BK ) B1 receptor ( P46663 ) contains a conserved HExxH motif also present in peptidases possessing a DB01593 prosthetic group , such as angiotensin converting enzyme ( P12821 ) , and that P12821 inhibitors directly activate P46663 signaling in endothelial cells . However , the binding of P12821 inhibitors to the B1Rs has never been directly evaluated . Information about binding of a radiolabeled inhibitor to natural or recombinant P12821 in intact cells ( physiologic ionic composition ) was also collected . We used the tritiated form of an P12821 inhibitor previously proposed to activate the P46663 , enalaprilat , to address these questions using recombinant human B1Rs and naturally expressed or recombinant P12821 . [ 3H ] Lys - des - Arg9 - BK bound to the human recombinant B1Rs with high affinity ( KD 0 . 35 nM ) in P29320 293a cells . [ 3H ] DB09477 ( 0 . 25 - 10 nM ) did not bind to cells expressing recombinant human P46663 , but bound with a subnanomolar affinity to recombinant P12821 or to naturally expressed P12821 in human umbilical vein endothelial cells . The radioligand was further validated using a binding competition assay that involved unlabeled P12821 inhibitors or their prodrug forms in endothelial cells . Membranes of P29320 293a cells that expressed B1Rs did not hydrolyze hippuryl - glycylglycine ( an P12821 substrate ) . DB09477 did not stimulate calcium signaling in P29320 293a cells that expressed B1Rs . A typical P12821 inhibitor did not bind to nor stimulate the human B1Rs ; nevertheless , several other indirect mechanisms could connect P12821 inhibition to P46663 stimulation in vivo .", "Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK75___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .", "___MASK54___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK54___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "Periadventitial adipose tissue impairs coronary endothelial function via P05771 - dependent phosphorylation of nitric oxide synthase . Endogenous periadventitial adipose - derived factors have been shown to contribute to coronary vascular regulation by impairing endothelial function through a direct inhibition of endothelial nitric oxide synthase ( P29474 ) . However , our understanding of the underlying mechanisms remains uncertain . Accordingly , this study was designed to test the hypothesis that periadventitial adipose tissue releases agents that attenuate coronary endothelial nitric oxide production via a protein kinase C ( PKC ) - beta - dependent mechanism . Isometric tension studies were conducted on isolated canine circumflex coronary arteries with and without natural amounts of periadventitial adipose tissue . Adipose tissue significantly diminished coronary endothelial - dependent vasodilation and nitric oxide production in response to bradykinin and acetylcholine . The selective inhibition of endothelial P05771 with ruboxistaurin ( 1 microM ) abolished the adipose - induced impairment of bradykinin - mediated coronary vasodilation and the endothelial production of nitric oxide . Western blot analysis revealed a significant increase in P29474 phosphorylation at the inhibitory residue DB00156 ( 495 ) in arteries exposed to periadventitial adipose tissue . This site - specific phosphorylation of P29474 was prevented by the inhibition of P05771 . These data demonstrate that periadventitial adipose - derived factors impair coronary endothelial nitric oxide production via a P05771 - dependent , site - specific phosphorylation of P29474 at DB00156 ( 495 ) .", "Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK97___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .", "P00797 status does not predict the anti - hypertensive response to angiotensin - converting enzyme inhibition in African - Americans . DB00519 Multicenter Study Group . The angiotensin - converting enzyme ( P12821 ) inhibitor trandolapril , a non - sulfhydryl prodrug which is hydrolysed into trandolaprilat , was studied in 322 hypertensives of African - American descent using a double - blind , randomised , placebo - controlled , parallel study design . Following 6 weeks of double - blind treatment with placebo or 0 . 25 to 16 mg / day trandolapril , an analysis of drug effect on trough blood pressure ( BP ) stratified by age , gender , weight , pre - treatment plasma renin activity , and trandolaprilat concentration was performed . Two mg was the lowest effective trandolapril dose , whereas doses above 4 mg did not significantly reduce trough BP . Reduction in BP did not correlate with trough plasma trandolaprilat concentration . Pre - treatment plasma renin activity was not a reliable indicator of anti - hypertensive response , as similar reductions in BP occurred even in patients with the lowest renin levels . There were no observable differences based on age , gender or measurements of the renin - angiotensin - aldosterone axis . In conclusion , neither age , gender or plasma renin activity influenced anti - hypertensive response to angiotensin - converting enzyme inhibition in African - Americans .", "eIF4F suppression in breast cancer affects maintenance and progression . Levels of eukaryotic initiation factor 4E ( P06730 ) are frequently elevated in human cancers and in some instances have been associated with poor prognosis and outcome . Here we utilize transgenic and allograft breast cancer models to demonstrate that increased mammalian target of rapamycin ( P42345 ) signalling can be a significant contributor to breast cancer progression in vivo . Suppressing P42345 activity , as well as levels and activity of the downstream translation regulators , P06730 and eIF4A , delayed breast cancer progression , onset of associated pulmonary metastasis in vivo and breast cancer cell invasion and migration in vitro . Translation of vascular endothelial growth factor ( P15692 ) , matrix metallopeptidase 9 ( P14780 ) and cyclin D1 mRNAs , which encode products associated with the metastatic phenotype , is inhibited upon P06730 suppression . Our results indicate that the P42345 / eIF4F axis is an important contributor to tumor maintenance and progression programs in breast cancer . Targeting this pathway may be of therapeutic benefit .", "17β - estradiol inhibits P14780 and Q09428 / TrpM4 expression and activation and thereby attenuates BSCB disruption / hemorrhage after spinal cord injury in male rats . Blood - spinal cord barrier ( BSCB ) disruption and progressive hemorrhage after spinal cord injury ( SCI ) lead to secondary injury and the subsequent apoptosis and / or necrosis of neuron and glia , causing permanent neurological deficits . In this study , we examined the effect of 17β - estradiol ( E2 ) on BSCB breakdown and hemorrhage as well as subsequent inflammation after SCI . After a moderate contusion injury at the 9th thoracic segment of spinal cord , E2 ( 300 μg / kg ) was administered by iv injection immediately after SCI , and the same dose of E2 was then administered 6 and 24 hours after injury . Our data show that E2 attenuated BSCB permeability and hemorrhage and reduced the infiltration of neutrophils and macorphages after SCI . Consistent with this finding , the expression of inflammatory mediators was significantly reduced by E2 . Furthermore , E2 treatment significantly inhibited the expression of sulfonylurea receptor 1 and transient receptor potential melastatin 4 after injury , which are known to mediate hemorrhage at an early stage after SCI . Moreover , the expression and activation of matrix metalloprotease - 9 after injury , which is known to disrupt BSCB , and the degradation of tight junction proteins , such as zona occludens - 1 and occludin , were significantly inhibited by E2 treatment . Furthermore , the protective effects of E2 on BSCB disruption and functional improvement were abolished by an estrogen receptor antagonist , ICI 182780 ( 3 mg / kg ) . Thus , our study provides evidence that the neuroprotective effect of E2 after SCI is , in part , mediated by inhibiting BSCB disruption and hemorrhage through the down - regulation of sulfonylurea receptor 1 / transient receptor potential melastatin 4 and matrix metalloprotease - 9 , which is dependent on estrogen receptor .", "Inhibition of matrix metalloproteinase - 2 enhances radiosensitivity by abrogating radiation - induced FoxM1 - mediated G2 / M arrest in A549 lung cancer cells . P08253 ( P08253 ) , is known to degrade the collagen IV , plays a role in radiation - induced lung injury . We therefore investigated the antitumor effects of combining P08253 inhibition using an adenovirus expressing siRNA against P08253 ( Ad - P08253 - Si ) with radiation therapy ( IR ) on A549 lung cancer cells in vitro and in vivo . IR increased P08253 mRNA , protein and activity in lung cancer cells . P08253 inhibition along with IR enhanced radiosensitivity as determined by clonogenic assay , flow cytometry and TUNEL assay . We show that P08253 inhibition prior to irradiation reduced p53 phosphorylation , with a corresponding reduction in the expression of the p53 downstream target gene P38936 ( Cip1 / Waf1 ) . Irradiated tumor cells induced the FoxM1 - mediated DNA repair gene , P18887 and Checkpoint kinases 2 / 1 , which were abrogated with combined treatment of Ad - P08253 - Si and IR . Further , the combination of Ad - P08253 - Si with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone . Indeed , histological analysis of tumor sections collected from the combination group revealed more apoptotic cells . These studies suggest that P08253 inhibition in combination with radiotherapy abrogates G2 cell cycle arrest leading to apoptosis and provide evidence of the antitumor efficacy of combining P08253 inhibition with irradiation as a new therapeutic strategy for the effective treatment of NSCLC patients .", "Delayed cardioprotective effects of WY - 14643 are associated with inhibition of P08253 and modulation of Bcl - 2 family proteins through Q07869 - α activation in rat hearts subjected to global ischaemia - reperfusion . Peroxisome proliferator - activated receptors ( PPARs ) are ligand - activated transcription factors regulating cardiac lipid metabolism and energy homeostasis . Although the activation of PPARs has been implicated in cardioprotection , the molecular mechanisms are largely unexplored . In this study , we aimed to investigate the effect of the Q07869 - α agonist WY - 14643 ( WY ) , mimicking a delayed effect of preconditioning in rat hearts exposed to acute ischaemia - reperfusion ( I / R ) 24 h later , and to define whether antioxidative and antiapoptotic mechanisms are involved . Treatment with WY markedly attenuated post - ischaemic contractile dysfunction ( as evidenced by the reduced infarct size ) , the higher left ventricular developed pressure ( LVDP ) recovery , and the decreased occurrence of arrhythmias . These effects were abolished in the presence of the Q07869 - α antagonist MK886 . Heme oxygenase - 1 , a key antioxidative enzyme implicated in cytoprotection , was upregulated in response to WY at baseline , but was markedly reduced after I / R , indicating reduced oxidative stress . WY treatment was also associated with decreased mRNA levels and enzymatic activity of matrix metalloproteinase - 2 , and increased ratios of Bcl - 2 : Bax proteins . These results indicate that Q07869 - α activation by its selective ligand WY may confer delayed preconditioning - like protection in rat hearts subjected to I / R by modulating oxidative stress , activation of matrix metalloproteinase - 2 , and expression of Bcl - 2 and Bax .", "Common variants of P29474 and P18887 genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery . PURPOSE : To evaluate the impact of functional polymorphisms in genes related to DNA repair mechanisms ( P18887 , P04637 , P43246 , P20585 , P18074 ) , oxidative stress response ( P09211 , P08263 , P29474 , P04179 ) and fibroblast proliferation ( TGFβ1 ) on the risk of acute skin toxicity in breast cancer patients receiving radiotherapy . MATERIAL AND METHODS : Skin toxicity was scored according to the Radiation Therapy Oncology Group criteria in 286 breast cancer patients who received radiotherapy after breast conserving surgery . Genotyping was conducted by PCR - RFLP analysis and real - time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood . RESULTS : In the multivariate analysis , nominally significant associations , before multiple testing corrections , were found between P18887 T - 77C ( T carriers vs . CC , OR : 2 . 240 , 95 % CI : 1 . 015 - 4 . 941 , P = 0 . 046 ) , P29474 G894T polymorphisms ( TT vs . G carriers , OR : 2 . 473 , 95 % CI : 1 . 220 - 5 . 012 , P = 0 . 012 ) , breast diameter ( OR : 1 . 138 , 95 % CI : 1 . 001 - 1 . 293 , P = 0 . 048 ) , boost dose - fractionation ( 3 Gy vs . no boost , OR : 4 . 902 , 95 % CI : 1 . 458 - 16 . 483 , P = 0 . 010 ) and ≥ grade 2 acute radiation skin toxicity in breast cancer patients . CONCLUSIONS : As our exploratory study suggests that P18887 T - 77C and P29474 G874T may confer an increased risk of acute skin reactions to radiotherapy in breast cancer patients , further confirmatory studies are warranted to determine the clinical significance .", "P49238 receptor is up - regulated in monocytes of coronary artery diseased patients : impact of pre - inflammatory stimuli and renin - angiotensin system modulators . P78423 / P49238 pathway is considered a major modulator of atherosclerosis . In the present study , expression of P49238 on PBMCs / monocytes of healthy individuals and coronary artery diseased patients was initially assessed by flow cytometry . Effects of pre - inflammatory cytokines interferon ( P27352 ) - gamma and tumor necrosis factor ( P01375 ) - alpha on expression of P49238 and a single representative of each major chemokine family ( P51681 and P61073 ) were further assessed in three cell models : THP - 1 monocytes , Jurkat T lymphocytes and primary monocytes isolated from healthy donors . Finally , effects of angiotensin - converting enzyme ( P12821 ) inhibitors captopril , lisinopril and angiotensin receptor blocker ( ARB ) losartan on chemokine receptor expression were evaluated in the same cell models either in a naive or stimulated state . P27352 - gamma significantly affected the chemokine receptor phenotype of THP - 1 cells by increasing the rate of P49238 - positive cells . Pre - treatment with the P12821 inhibitors , captopril and lisinopril , and the ARB , losartan , did not influence these effects . DB01197 and lisinopril similarly had no effect on either stimulated or naive primary monocytes . Yet , a small but repeatable increase in P49238 expression after treatment with losartan was noted . Nevertheless , the latter observation did not retain statistical significance after applying the Bonferroni correction . In conclusion , our data did not indicate any significant effect of the P12821 inhibitors on the chemokine receptor phenotype of monocytes .", "[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .", "Downregulation of the P61073 receptor inhibits cervical carcinoma metastatic behavior in vitro and in vivo . Cervical carcinoma is frequently diagnosed among women , particularly in low and middle income countries . In this study , we investigated the role of the P48061 / P61073 axis during cervical carcinoma growth and progression in vitro and in vivo . Downregulation of P61073 receptor using an RNA interference system led to almost complete inhibition of the receptor expression , activation and function . P61073 receptor silencing led to decreased ability to signal , to induce migration and to form holoclone - like colonies , with no influence on viability / proliferation of the cells . P61073 - deficient cells had also significantly lower levels of P14780 . Interestingly , downregulation of P61073 expression resulted in reduced tumor growth in vivo . Tumors generated by P61073 - deficient cells had also lower expression of the proliferation marker Ki ‑ 67 and decreased ability to engraft into lungs and spleen . Taken together , our results indicate that P61073 receptor may play an important role during cervical carcinoma invasion . In our study P61073 influenced invasive properties of cervical carcinoma cells both in vitro and in vivo .", "Sinusoidal endothelial cells as an early target for hepatic toxicants . Recent studies demonstrate that the hepatic sinusoidal endothelial cells ( SEC ) are a sensitive direct target for early toxicity to acetaminophen ( paracetamol , DB00316 ) and this toxicity is exacerbated following a single and multiple week - end type alcoholic binge ( s ) . SEC become swollen and begin to lose the ability to endocytose FITC - Q2LD37 , a ligand for the scavenger receptor , as early as 30 minutes after the administration of DB00316 . Gaps through the SEC appear to be formed by the destruction and / or coalescence of fenestrae and are seen as early as 2 hrs after the administration of DB00316 which is prior to any evidence of injury to parenchymal cells . The gaps permit red blood cells to penetrate into the Space of Disse . Subsequently , the sinusoid may collapse or disintegrate reducing blood flow . The gaps are larger and more frequent in ethanol binged animals subsequently treated with DB00316 . Similar gaps are seen in the early stages of hepatic venoocclusive disease . Administration of a NO donor or a P08253 and P14780 inhibitor minimizes endothelial injury and red blood cell penetration into the Space of Disse . The injury is exacerbated when an inhibitor of P29474 is administered and minimized when P35228 is inhibited suggesting a protective role for constitutive NO derived from SEC . Both NO and MMPs are known to affect the cytoskeleton of SEC which in turn affects the formation and maintenance of the fenestrae .", "___MASK83___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .", "[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK69___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .", "Role of monoamine oxidases in the exaggerated 5 - hydroxytryptamine - induced tension development of human isolated preeclamptic umbilical artery . We investigated the role ( s ) of monoamine oxidases ( MAOs ) on the altered 5 - hydroxytryptamine ( 5 - HT , serotonin ) - induced tension development of the isolated umbilical artery of preeclamptic pregnancy of Chinese women . An enhanced 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy was observed when compared with that of normal pregnancy . The enhanced component of 5 - HT - induced tension development was eradicated by clorgyline ( a P21397 inhibitor ) . Blockade of P29474 ( endothelial isoform nitric oxide synthase ) ( N ( omega )- nitro - L - arginine methyl ester ) , 5 - HT transporter ( citalopram ) , 5 - HT receptor subtypes ( 5HT2B , SB 204741 ; P28335 , RS 102221 ; P34969 , SB 269970 ) , and endothelium denudation of the umbilical artery of normal pregnancy mimicked the enhanced 5 - HT - induced tension development as observed in the preeclamptic tissues . In contrast , no apparent changes in 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy were observed with the same pharmacological manipulations . A decreased protein expression levels of P21397 and P29474 ( no P35228 and P27338 expression was detected ) and no change in caveolin - 1 and 5 - HT transporter expression were demonstrated in the umbilical artery ( endothelium intact ) lysate of preeclamptic pregnancy , compared to that of the umbilical artery of normal pregnancy . Thus , in the umbilical artery of preeclamptic pregnancy , a decrease of P21397 and P29474 protein expression levels are probably associated with , or responsible for , the exaggerated 5 - HT - induced tension development .", "Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK93___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .", "Combination of P12821 inhibitor with nicorandil provides further protection in chronic kidney disease . An inhibition in the renin - angiotensin system ( DB01367 ) is one of the most widely used therapies to treat chronic kidney disease . However , its effect is occasionally not sufficient and additional treatments may be required . Recently , we reported that nicorandil exhibited renoprotective effects in a mouse model of diabetic nephropathy . Here we examined if nicorandil can provide an additive protection on enalapril in chronic kidney disease . Single treatment with either enalapril or nicorandil significantly ameliorated glomerular and tubulointerstitial injury in the rat remnant kidney while the combination of these two compounds provided additive effects . In addition , an increase in oxidative stress in remnant kidney was also blocked by either enalapril or nicorandil while the combination of the drugs was more potent . A mechanism was likely due for nicorandil to preventing manganase superoxide dismutase ( MnSOD ) and sirtuin ( Sirt ) 3 from being reduced in injured kidneys . A study with cultured podocytes indicated that the antioxidative effect could be mediated through sulfonylurea receptor ( Q09428 ) in the mitochondrial KATP channel since blocking Q09428 with glibenclamide reduced MnSOD and Sirt3 expression in podocytes . In conclusion , nicorandil may synergize with enalapril to provide superior protection in chronic kidney disease .", "Opposite effect of Hsp90α and Hsp90β on P29474 ability to produce nitric oxide or superoxide anion in human embryonic kidney cells . Heat shock protein 90 subfamily is composed by two cytosolic isoforms known as Hsp90α and Hsp90β . Endothelial nitric oxide synthase ( P29474 ) is regulated by Hsp90 , however the specific role of each Hsp90 isoform on NO production has not been established . This study was designed to evaluate the effect of Hsp90α and Hsp90β over - expression on P29474 / NO pathway . Rat Hsp90α and Hsp90β were cloned into pcDNA3 . 1 (+) and transfected in human embryonic kidney cells ( P29320 - 293 ) . Hsp90α and Hsp90β transfection was corroborated by Western blot analysis and their effect on NO production ( NO ( 2 )/ NO ( 3 ) ) , P29474 protein and its phosphorylation at Ser1177 and Thr495 , as well as Akt / P31749 Ser473 phosphorylation was determined . The interaction of Hsp90α and Hsp90β with P29474 and the dimer / monomer ratio of Hsp90 , as well as O ( 2 )(-) generation were also assessed . After transfection , Hsp90α and Hsp90β levels were significantly increased in P29320 - 293 cells . The Hsp90α over - expression induced a significant increase in NO ( 2 )/ NO ( 3 ) levels , an effect that was associated with increased phosphorylation of P29474 DB00133 1177 and Akt / P31749 Ser473 , as well as with a greater Hsp90α dimerization . Noteworthy , pcHsp90β transfection reduced significantly NO ( 2 )/ NO ( 3 ) and increased O ( 2 )(-) generation . These effects were associated with a reduction of P29474 dimeric conformation , increased P29474 Thr495 phosphorylation , reduced Akt / P31749 phosphorylation , and by a greater amount of monomeric Hsp90β conformation . These data show for first time that Hsp90α and Hsp90β differentially modulate NO and O ( 2 )(-) generation by P29474 through promoting changes in P29474 conformation and phosphorylation state .", "DB00563 gamma - hydroxamate derivatives as potential dual target antitumor drugs . A series of new aminopteroyl - based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs . These compounds were designed to target two families of enzymes , matrix metalloproteinases ( MMP ) and a folate enzyme , dihydrofolate reductase ( P00374 ) . These enzymes are the components of two unrelated cellular pathways and they are often over - expressed in metastasizing tumors . In addition to the synthesis and full structural characterization of the hybrid molecules , we describe their inhibitory activities against a series of MMPs ( P08253 , P09237 , P14780 , P50281 ) and P00374 , as well as their antiproliferative activity in three cancer cell lines . The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and P00374 in the micromolar and nanomolar range , respectively . Furthermore , they showed strong antiproliferative activity against A549 cells ( non - small cell lung carcinoma ) , and PPC - 1 and Tsu - Pr1 prostate cancer cell lines . Therefore , based on the present results , these bi - functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development .", "Inhibition of matrix metalloproteinase - 9 activity by trandolapril after middle cerebral artery occlusion in rats . We investigated whether an angiotensin - converting enzyme ( P12821 ) inhibitor could inhibit matrix metalloproteinase ( MMP ) activities in cerebral infarct lesions after middle cerebral artery occlusion ( MCAO ) in rats . After placebo or trandolapril ( 5 mg / kg per day ) was administered orally for 7 days , we permanently occluded the right middle cerebral artery . P12821 activity in extracts from the infarct side of placebo - treated rats was significantly higher than that in extracts from the non - infarct side from 5 days after MCAO , though they did not differ at 1 day . P12821 activities in extracts from both hemispheric segments in the trandolapril - treated group were significantly decreased compared with those in the placebo - treated group before MCAO , and this significant reduction persisted even at 7 days after MCAO . In the placebo - treated group , P14780 and P08253 activities in the infarct side were significantly increased at 12 h and at 1 day after MCAO , respectively . DB00519 treatment significantly reduced P14780 and P08253 activities to 68 . 5 % and 53 . 2 % , respectively . Seven days after MCAO , the ratios of infarct areas to the hemispheric sectional areas in placebo - and trandolapril - treated rats were 55 . 4 +/- 2 . 1 % and 30 . 9 +/- 2 . 9 % , respectively , and this difference was significant . Neurological severity scores were significantly improved from 1 to 7 days after MCAO in trandolapril - treated rats . Cumulative survival in trandolapril - treated rats was significantly increased compared with that in placebo - treated rats . Thus , the inhibition of P14780 by trandolapril might be part of the mechanism that prevents cerebral damage after cerebral ischemia .", "Benzyl isothiocyanate ( BITC ) inhibits migration and invasion of human gastric cancer AGS cells via suppressing P29323 signal pathways . Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases . Benzyl isothiocyanate ( BITC ) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables . BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in humans . Here , the purpose of this study was to investigate the effects of BITC on cell proliferation , migration , invasion and mitogen - activated protein kinase ( MAPK ) pathways of AGS human gastric cancer cells . Wound healing and Boyden chamber ( migration and invasion ) assays demonstrated that BITC exhibited an inhibitory effect on the abilities of migration and invasion in AGS cancer cells . BITC suppressed cell migration and invasion of AGS cells in a dose - dependent manner . Results from Western blotting indicated that BITC exerted an inhibitory effect on the P27361 / 2 , Ras , P62993 , Rho A , P35228 , P35354 for causing the inhibitions of P08253 , - 7 and - 9 then followed by the inhibitions of invasion and migration of AGS cells in vitro . BITC also promoted O14733 , Q99759 , c - jun , P45983 / 2 , P15692 , Sos1 , phosphoinositide 3 - kinase ( PI3K ) , PKC , nuclear factor - kappaB ( NF - κB ) p65 in AGS cells . Results from real - time polymerized chain reaction ( PCR ) showed that BITC inhibited the gene expressions of P08253 ,- 7 - 9 , Q05397 , Q13464 and RhoA after BITC treatment for 24 and 48 hours in AGS cells . Taken together , the finding may provide new mechanisms and functions of BITC , which inhibit migration and invasion of human gastric cancer AGS cells .", "CXC - chemokine receptor 4 antagonist DB06809 promotes cardiac functional recovery after ischemia / reperfusion injury via endothelial nitric oxide synthase - dependent mechanism . BACKGROUND : CXC - chemokine receptor 4 ( P61073 ) regulates the retention of stem / progenitor cells in the bone marrow ( BM ) , and the P61073 antagonist DB06809 improves recovery from coronary ligation injury by mobilizing stem / progenitor cells from the BM to the peripheral blood . Thus , we investigated whether DB06809 also improves recovery from ischemia / reperfusion injury , which more closely mimics myocardial infarction in patients , because blood flow is only temporarily obstructed . METHODS AND RESULTS : Mice were treated with single subcutaneous injections of DB06809 ( 5 mg / kg ) or saline after ischemia / reperfusion injury . Three days later , histological measurements of the ratio of infarct area to area at risk were smaller in DB06809 - treated mice than in mice administered saline , and echocardiographic measurements of left ventricular function were greater in the DB06809 - treated mice at week 4 . P61073 (+) cells were mobilized for just 1 day in both groups , but the mobilization of sca1 (+)/ flk1 (+) cells endured for 7 days in DB06809 - treated mice compared with just 1 day in the saline - treated mice . DB06809 upregulated BM levels of endothelial nitric oxide synthase ( P29474 ) and 2 targets of P29474 signaling , matrix metalloproteinase - 9 and soluble P21583 . Furthermore , the loss of BM P29474 expression abolished the benefit of DB06809 on sca1 (+)/ flk1 (+) cell mobilization without altering the mobilization of P61073 (+) cells , and the cardioprotective effects of DB06809 were retained in P29474 - knockout mice that had been transplanted with BM from wild - type mice but not in wild - type mice with P29474 - knockout BM . CONCLUSIONS : DB06809 prolongs BM progenitor mobilization and improves recovery from ischemia / reperfusion injury , and these benefits appear to occur through a previously unidentified link between DB06809 and BM P29474 expression .", "Endothelial dihydrofolate reductase : critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase . Recent studies demonstrate that oxidative inactivation of tetrahydrobiopterin ( H4B ) may cause uncoupling of endothelial nitric oxide synthase ( P29474 ) to produce superoxide ( O2 *- ) . H4B was found recyclable from its oxidized form by dihydrofolate reductase ( P00374 ) in several cell types . Functionality of the endothelial P00374 , however , remains completely unknown . Here we present findings that specific inhibition of endothelial P00374 by RNA interference markedly reduced endothelial H4B and nitric oxide ( NO . ) bioavailability . Furthermore , angiotensin II ( 100 nmol / liter for 24 h ) caused a H4B deficiency that was mediated by H2O2 - dependent down - regulation of P00374 . This response was associated with a significant increase in endothelial O2 *- production , which was abolished by P29474 inhibitor N - nitro - L - arginine - methyl ester or H2O2 scavenger polyethylene glycol - conjugated catalase , strongly suggesting H2O2 - dependent P29474 uncoupling . Rapid and transient activation of endothelial NAD ( P ) H oxidases was responsible for the initial burst production of O2 * ( Rac1 inhibitor NSC 23766 but not an N - nitro - L - arginine - methyl ester - attenuated P03372 O2 *- signal at 30 min ) in response to angiotensin II , preceding a second peak in O2 *- production at 24 h that predominantly depended on uncoupled P29474 . Overexpression of P00374 restored NO . production and diminished P29474 production of O2 *- in angiotensin II - stimulated cells . In conclusion , these data represent evidence that P00374 is critical for H4B and NO . bioavailability in the endothelium . Endothelial NAD ( P ) H oxidase - derived H2O2 down - regulates P00374 expression in response to angiotensin II , resulting in H4B deficiency and uncoupling of P29474 . This signaling cascade may represent a universal mechanism underlying P29474 dysfunction under pathophysiological conditions associated with oxidant stress .", "Regulation of angiotensin II receptors beyond the classical pathway . The DB01367 ( renin - angiotensin system ) plays a role not only in the cardiovascular system , including blood pressure regulation , but also in the central nervous system . AngII ( angiotensin II ) binds two major receptors : the AT ( 1 ) receptor ( AngII type 1 receptor ) and AT ( 2 ) receptor ( AngII type 2 receptor ) . It has been recognized that AT ( 2 ) receptor activation not only opposes AT ( 1 ) receptor actions , but also has unique effects beyond inhibitory cross - talk with AT ( 1 ) receptor signalling . Novel pathways beyond the classical actions of DB01367 , the P12821 ( angiotensin - converting enzyme ) / AngII / AT ( 1 ) receptor axis , have been highlighted : the Q9BYF1 / Ang -( 1 - 7 ) [ angiotensin -( 1 - 7 ) ] / Mas receptor axis as a new opposing axis against the P12821 / AngII / AT ( 1 ) receptor axis , novel AngII - receptor - interacting proteins and various AngII - receptor - activation mechanisms including dimer formation . Q6RW13 ( AT ( 1 )- receptor - associated protein ) and Q9ULD2 ( AT ( 2 )- receptor - interacting protein ) are well - characterized AngII - receptor - associated proteins . These proteins could regulate the functions of AngII receptors and thereby influence various pathophysiological states . Moreover , the possible cross - talk between Q07869 ( peroxisome - proliferator - activated receptor ) - γ and AngII receptor subtypes is an intriguing issue to be addressed in order to understand the roles of DB01367 in the metabolic syndrome , and interestingly some ARBs ( AT ( 1 )- receptor blockers ) have been reported to have an AT ( 1 )- receptor - blocking action with a partial Q07869 - γ agonistic effect . These emerging concepts concerning the regulation of AngII receptors are discussed in the present review .", "___MASK46___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK46___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK46___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK46___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .", "___MASK94___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .", "Rosiglitazone affects nitric oxide synthases and improves renal outcome in a rat model of severe ischemia / reperfusion injury . Background . DB00435 ( NO ) - signal transduction plays an important role in renal ischemia / reperfusion ( I / R ) injury . NO produced by endothelial NO - synthase ( P29474 ) has protective functions whereas NO from inducible NO - synthase ( P35228 ) induces impairment . Rosiglitazone ( RGZ ) , a peroxisome proliferator - activated receptor ( Q07869 ) - γ agonist exerted beneficial effects after renal I / R injury , so we investigated whether this might be causally linked with NOS imbalance . Methods . RGZ ( 5 mg / kg ) was administered i . p . to SD - rats ( f ) subjected to bilateral renal ischemia ( 60 min ) . Following 24 h of reperfusion , inulin - and PAH - clearance as well as PAH - net secretion were determined . Morphological alterations were graded by histopathological scoring . Plasma NO ( x )- production was measured . P29474 and P35228 expression was analyzed by qPCR . Cleaved caspase 3 ( Q9BUP3 ) was determined as an apoptosis indicator and Q92838 as a marker of macrophage infiltration in renal tissue . Results . RGZ improves renal function after renal I / R injury ( PAH -/ inulin - clearance , PAH - net secretion ) and reduces histomorphological injury . Additionally , RGZ reduces NO ( x ) plasma levels , ED - 1 positive cell infiltration and Q9BUP3 expression . P35228 - mRNA is reduced whereas P29474 - mRNA is increased by RGZ . Conclusion . RGZ has protective properties after severe renal I / R injury . Alterations of the NO pathway regarding P29474 and P35228 could be an explanation of the underlying mechanism of RGZ protection in renal I / R injury .", "Molecular mechanism of imidapril for cardiovascular protection via inhibition of P14780 . To investigate the inhibitory specificity of angiotensin converting enzyme ( P12821 ) inhibitors to matrix metalloproteinase ( MMP ) - 9 , we predicted molecular interactions between an P12821 inhibitor imidapril and P14780 active site based on recent X - ray structural analyses . Two binding modes differing in the orientation of imidapril on the active site were identified , and its hydrophobic group appeared to preferentially interact with the S1 site compared with the S1 ' site . Compared with the lisinopril - P14780 model in our previous study , imidapril was stabilized effectively on the active site with less of molecular distortions . We also measured P12821 and P14780 inhibitory activities of imidapril and lisinopril after myocardial infarction . Imidapril had a stronger inhibitory activity against P14780 than lisinopril . These findings show that imidapril inhibits P14780 directly like lisinopril and its hydrophobic interactions with the S1 site of P14780 would be important for enhancing inhibitory activity .", "Pharmacophore - based virtual screening versus docking - based virtual screening : a benchmark comparison against eight targets . AIM : This study was conducted to compare the efficiencies of two virtual screening approaches , pharmacophore - based virtual screening ( PBVS ) and docking - based virtual screening ( DBVS ) methods . METHODS : All virtual screens were performed on two data sets of small molecules with both actives and decoys against eight structurally diverse protein targets , namely angiotensin converting enzyme ( P12821 ) , acetylcholinesterase ( P22303 ) , androgen receptor ( AR ) , D - alanyl - D - alanine carboxypeptidase ( DacA ) , dihydrofolate reductase ( P00374 ) , estrogen receptors alpha ( ERalpha ) , HIV - 1 protease ( HIV - pr ) , and thymidine kinase ( TK ) . Each pharmacophore model was constructed based on several X - ray structures of protein - ligand complexes . Virtual screens were performed using four screening standards , the program Catalyst for PBVS and three docking programs ( DOCK , GOLD and Glide ) for DBVS . RESULTS : Of the sixteen sets of virtual screens ( one target versus two testing databases ) , the enrichment factors of fourteen cases using the PBVS method were higher than those using DBVS methods . The average hit rates over the eight targets at 2 % and 5 % of the highest ranks of the entire databases for PBVS are much higher than those for DBVS . CONCLUSION : The PBVS method outperformed DBVS methods in retrieving actives from the databases in our tested targets , and is a powerful method in drug discovery .", "Angiotensin converting enzyme inhibition in the postnatal rat results in decreased cell proliferation in the renal outer medulla . 1 . Chronic angiotensin converting enzyme ( P12821 ) inhibition or AT1 antagonism during postnatal development in the rat has been shown to cause renal tubular and vascular damage , particularly in the outer medulla . 2 . The effects of P12821 inhibition were investigated at a stage of development before the renal outer medulla is fully established . 3 . Sprague - Dawley rat pups were given daily i . p . injections of either enalapril or saline from days 3 - 10 . At day 11 , kidneys were perfusion - fixed for either electron microscopy or immunocytochemistry . Sections were incubated in proliferating cell nuclear antigen ( P12004 ) antisera and the avidin - biotin immunoperoxidase method was used to detect an immunoreactive product , indicative of proliferating cells . 4 . Following enalapril treatment , the normal structural arrangement of the outer medulla was disrupted compared with controls . Cell proliferation ( P12004 - positive cells ) in the medullary rays was reduced in enalapril - treated kidneys compared with control kidneys . 5 . Thus , angiotensin II appears to be essential for normal tubular and vascular growth in postnatal renal development in the rat .", "Assessment of the angiotensin - I - converting enzyme ( P12821 - I ) inhibitory and antioxidant activities of hydrolysates of bovine brisket sarcoplasmic proteins produced by papain and characterisation of associated bioactive peptidic fractions . The main objective was to investigate the angiotensin - I - converting enzyme ( P12821 - I ) inhibitory and antioxidant activities of sarcoplasmic proteins isolated from the brisket muscle ( Pectoralis profundus ) of 3 ( Bos taurus ) cattle and hydrolysed with papain for 24 h at 37 ° C . Sarcoplasmic protein hydrolysates were ultra - filtered using molecular weight cut off ( MWCO ) membranes and 10 - kDa and 3 - kDa filtrates were obtained . The total sarcoplasmic protein extracts and the 3 - kDa filtrates were tested for angiotensin I - converting enzyme inhibitory ( P12821 - I ) activities . The total hydrolysates , 10 - kDa and 3 - kDa filtrates were also tested for their associated antioxidant activities using the 2 , 2 - diphenyl - 1 - picrylhydrazyl ( DPPH ) radical scavenging activity assay , the ferric ion reducing antioxidant power ( P42345 ) assay and the Fe ( 2 +) metal chelating ability assay . The peptidic content of the total hydrolysates , the 10 - kDa and the 3 - kDa filtrates were analysed using an ORBITRAP mass spectrometer , and mass spectral data obtained were analysed using TurboSEQUEST . Eleven peptides were characterised from the total hydrolysates , fifteen from the 10 - kDa filtrate fractions , whilst nine peptides were characterised from the 3 - kDa filtrate fractions . Similarities between the amino acid sequences of the peptides identified in this study and previously identified antioxidant and P12821 - I inhibitory peptides detailed in the BIOPEP database were outlined .", "Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK98___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .", "Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples ." ]

[ "___MASK46___", "___MASK54___", "___MASK69___", "___MASK75___", "___MASK83___", "___MASK93___", "___MASK94___", "___MASK97___", "___MASK98___" ]

[ "Dietary conjugated linoleic acid enhances spleen P37231 mRNA expression in broiler chicks . 1 . The anti - inflammatory effects of dietary conjugated linoleic acid ( DB01211 ) on broilers repeatedly challenged with lipopolysaccharide ( LPS ) were investigated . 2 . Day - old broiler chicks were allotted into three treatment groups and fed on a control diet or diets containing 5 . 0 or 10 . 0 g DB01211 / kg diet . Six chicks from each treatment were injected with LPS ( 0 . 25 mg / kg body weight ) at 16 , 18 and 20 d of age . Splenic cyclooxygenase ( P36551 ) and inducible nitric oxide synthase ( P35228 ) activities , and prostaglandin E ( 2 ) ( PGE ( 2 ) ) and nitric oxide ( NO ) production as well as peroxisome proliferator - activated receptor - gamma ( P37231 ) mRNA expression were measured at 21 d of age . 3 . Chicks fed 10 . 0 g DB01211 / kg diet had lower P36551 activities and PGE ( 2 ) production that the controls . Dietary DB01211 ( 10 . 0 g / kg ) did not significantly diminish LPS - induced enhancement of COS - 2 activity , inhibited the subsequent increase in PGE ( 2 ) production . 4 . Regulation of P23219 activity contributed to the difference in PGE ( 2 ) production . 5 . DB01211 did not markedly attenuate the increase of P35228 activity and NO production caused by LPS challenge . Chicks fed DB01211 had lower P35228 activity and NO production than the controls . 6 . Dietary DB01211 activated splenic P37231 mRNA expression and increased P37231 mRNA expression after LPS injection . 7 . These results suggest that dietary DB01211 has immunomodulatory effects in the spleen by restricting basal PGE ( 2 ) and NO to lower levels and enhancing P37231 mRNA expression . During the inflammatory response , dietary DB01211 did not alleviate the increase in P35354 and P35228 activities but enhanced Q06203 - gamma mRNA expression .", "Cognitive and neurological deficits induced by early and prolonged basal forebrain cholinergic hypofunction in rats . In the present study we examined the long - term effects of neonatal lesion of basal forebrain cholinergic neurons induced by intracerebroventricular injections of the immunotoxin 192 IgG saporin . Animals were then characterised behaviourally , electrophysiologically and molecularly . Cognitive effects were evaluated in the social transmission of food preferences , a non - spatial associative memory task . Electrophysiological effects were assessed by recording of cortical electroencephalographic ( EEG ) patterns . In addition , we measured the levels of proteins whose abnormal expression has been associated with neurodegeneration such as amyloid precursor protein ( P05067 ) , presenilin 1 and 2 ( P49768 , P49810 ) , and cyclooxygenases ( P23219 and P35354 ) . In animals lesioned on postnatal day 7 and tested 6 months thereafter , memory impairment in the social transmission of food preferences was evident , as well as a significant reduction of choline acetyltransferase activity in hippocampus and neocortex . Furthermore , similar to what observed in Alzheimer - like dementia , EEG cortical patterns in lesioned rats presented changes in alpha , beta and delta activities . Levels of P05067 protein and mRNA were not affected by the treatment . Levels of hippocampal P35354 protein and mRNA were significantly decreased whereas P23219 remained unaltered . P49768 and P49810 transcripts were reduced in hippocampus and neocortex . These findings indicate that neonatal and permanent basal forebrain cholinergic hypofunction is sufficient to induce behavioural and neuropathological abnormalities . This animal model could represent a valid tool to evaluate the role played by abnormal cholinergic maturation in later vulnerability to neuropathological processes associated with cognitive decline and , possibly , to Alzheimer - like dementia .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK37___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "___MASK41___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK41___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .", "Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK71___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .", "Duodenal mucosal protection by bicarbonate secretion and its mechanisms . Proximal portion of duodenum is exposed to intermittent pulses of gastric H (+) discharged by the stomach . This review summarizes the mechanisms of duodenal mucosal integrity , mainly the role of mucus - alkaline secretion and the mucous barrier protecting surface epithelium against gastric H (+) . The mucous barrier protects the leaky duodenal epithelium against each pulse of gastric H (+) , which penetrates this barrier and diffuses into duodenocytes , but fails to damage them due to ; a ) an enhanced expression of cyclooxygenase - 1 ( P23219 ) , with release of protective prostaglandins ( PG ) and of nitric oxide ( NO ) synthase ( NOS ) with , however , production of NO , stimulating duodenal HCO ( 3 )(-) secretion and b ) the release of several neurotransmitters also stimulating HCO ( 3 )(-) secretion such as vasoactive intestinal peptide ( P01282 ) , pituitary adenylate - cyclase activating polypeptide ( PACAP ) , acetylcholine , melatonin , leptin and ghrelin released by enteric nerves and mucosal cells . At the apical duodenocyte membrane at least two HCO ( 3 )(-)/ Cl (-) anion exchangers operate in response to luminal H (+) to provide adequate extrusion of HCO ( 3 )(-) into duodenal lumen . In the basolateral portion of duodenocyte membrane , both non - electrogenic ( NBC ) and electrogenic ( NBC ( n ) ) Na (+) HCO ( 3 )(-) cotransporters are activated by the exposure to duodenal acidification , causing inward movement of HCO ( 3 )(-) from extracellular fluid to duodenocytes . There are also at least three Na (+)/ H (+) ( P19634 - 3 ) amiloride - sensitive exchangers , eliminating H (+) which diffused into these cells . The Helicobacter pylori ( Hp ) infection and gastric metaplasia in the duodenum with bacterium inoculating metaplastic mucosa and inhibiting HCO ( 3 )(-) secretion by its endogenous inhibitor , asymmetric dimethyl arginine ( DB01686 ) , may result in duodenal ulcerogenesis .", "Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague - Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0 . 02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real - time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .", "The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .", "Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK99___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK99___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .", "Paracrine upregulation of monocyte cyclooxygenase - 2 by mediators produced by T lymphocytes : role of interleukin 17 and interferon - gamma . OBJECTIVE : Cyclooxygenase ( P36551 ) - 2 is an inducible eicosanoid - forming enzyme that is expressed at sites of inflammation . T lymphocytes and monocytes are found in close proximity at sites of inflammation , including synovitis . We investigated whether activated T lymphocytes express P35354 and whether activated T cells upregulate monocyte P35354 expression . METHODS : Human T lymphocytes and monocytes were isolated from fresh buffy coats by density gradient separation followed by passage through either nylon wool columns ( T lymphocytes ) or counter - current elutriation ( monocytes ) . T lymphocytes were stimulated using anti - CD3 and anti - P10747 in a co - culture system with monocytes using transwells , which prevents cell - cell contact , but allows diffusion of soluble mediators . RESULTS : Repeated examination of P36551 isotypes in resting and stimulated T cells revealed P23219 , but not P35354 . Activated T cells produced a soluble mediator ( s ) that upregulated monocyte P35354 . Mediator production was inhibited by cyclosporin A . Activated T cells produced interleukin 17 ( Q16552 ) and interferon - g ( IFN - g ) , and in the co - culture Q16552 - neutralizing antibodies partially reduced monocyte P35354 expression , whereas IFN - g - neutralizing antibodies had the opposite effect . Exogenous Q16552 upregulated monocyte P35354 , although concentrations were high compared with those generated by stimulated T cells . By contrast , monocyte P35354 expression was downregulated when monocytes were treated with IFN - g prior to stimulation with lipopolysaccharide . CONCLUSION : Soluble mediators produced by activated T cells can influence induction of monocyte P35354 , with Q16552 acting as a positive paracrine regulator and IFN - g acting as a negative regulator . In rheumatoid joints , previously observed high concentrations of Q16552 and low concentrations of IFN - g could contribute to T cell - driven upregulation of monocyte P35354 .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "Meloxicam . Meloxicam ( DB00814 trade mark , Boehringer Ingelheim ) is a relatively new oral non - steroidal anti - inflammatory drug ( NSAID ) approved for the treatment of osteoarthritis in the US . It has also been evaluated for the treatment of rheumatoid arthritis , ankylosing spondylitis and acute ' rheumatic ' pain . Meloxicam has been shown to be P35354 preferential , particularly at its lowest therapeutic dose , and is anti - inflammatory by inhibiting prostanoid synthesis in inflammatory cells . Since it is P35354 preferential , it would be expected to have less gastrointestinal toxicity than non - selective NSAIDs . In clinical trials of meloxicam in osteoarthritis , it was found to be as effective as piroxicam , diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations , obstructions and bleeds by meta - analysis . Adverse events , including peripheral oedema and hypertension , occurred at a similar rate as with traditional NSAIDs .", "Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK58___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided .", "Synthetic triterpenoid induces P15428 expression and suppresses inflammation - driven colon carcinogenesis . Colitis - associated colon cancer ( CAC ) develops as a result of inflammation - induced epithelial transformation , which occurs in response to inflammatory cytokine - dependent downregulation of 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) and subsequent suppression of prostaglandin metabolism . Agents that both enhance P15428 expression and suppress cyclooxygenase - 2 ( P35354 ) production may more effectively prevent CAC . Synthetic triterpenoids are a class of small molecules that suppress P35354 as well as inflammatory cytokine signaling . Here , we found that administration of the synthetic triterpenoid 2 - cyano - 3 , 12 - dioxooleana - 1 , 9 ( 11 )- dien - C28 - methyl ester ( CDDO - Me ) suppresses CAC in mice . In a spontaneous , inflammation - driven intestinal neoplasia model , deletion of Q13485 specifically in T cells led to progressive production of inflammatory cytokines , including P01375 - α , IFN - γ , P35228 , P05231 , IL - 1β ; as well as activation of P42224 and P40763 ; along with suppression of P15428 expression . Oral administration of CDDO - Me to mice with Q13485 - deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of P15428 . Induction of P15428 by CDDO - Me was dose dependent in epithelial cells and was abrogated following treatment with TGF - β signaling inhibitors in vitro . Furthermore , CDDO - Me - dependent P15428 induction was not observed in P84022 -/- mice . Similarly , CDDO - Me suppressed azoxymethane plus dextran sodium sulfate - induced carcinogenesis in wild - type animals , highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans .", "Desmopressin ( ___MASK12___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK12___ ) also has strong vasodilatory effects . ___MASK12___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK12___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK12___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK12___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK12___ - induced vasodilation .", "Effect of Electroacupuncture Intervention on Expression of P80511 , SP , P23219 , and DB00917 of Dorsal Portion of the Cervical Spinal Cord in Rats with Neck - Incision Pain . The present study was aimed to determine if cervicospinal DB05875 ( SP ) and its neurokinin - 1 receptor ( P25103 ) , calcitonin gene - related peptide ( P80511 ) , cyclooxygenase - 1 ( P23219 ) , and prostaglandin E2 ( DB00917 ) were involved in electroacupuncture ( EA ) analgesia in neck - incision pain rats . EA intervention was applied to bilateral Futu ( LI18 ) , Hegu ( LI4 ) - Neiguan ( Q92824 ) , and Zusanli ( ST36 ) - Yanglingquan ( GB34 ) for 30 min . Cervicospinal SP and P80511 immunoactivity was detected by immunofluorescence technique , P25103 and P23219 protein and mRNA expression levels were determined using Western blot and real - time PCR , respectively , and DB00917 content was measured using ELISA . Outcomes indicated that EA of EA - LI18 and LI4 - Q92824 ( not ST36 - GB34 ) significantly suppressed neck - incision induced decrease of thermal pain threshold ( P < 0 . 05 ) . EA stimulation of LI18 and LI4 - Q92824 markedly inhibited neck - incision induced upregulation of SP and P80511 immunoactivity , NK - 1 R and P23219 mRNA and protein expression levels , as well as the increase of DB00917 content in the dorsal cervicospinal cord ( P < 0 . 05 ) . These findings showed that LI18 and LI4 - Q92824 EA stimulation - induced downregulation of SP , P80511 , P25103 , P23219 , and DB00917 levels in the dorsal cervicospinal cord may contribute to their effects in relieving neck - incision pain . This study highlights the targets of EA intervention for reducing post - thyroid - surgery pain for the first time .", "Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK58___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK58___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .", "___MASK89___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK89___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK89___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK89___ inhibits activated T cells . We show that in vitro , ___MASK89___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK89___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK89___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK89___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK89___ to treat chronic inflammatory disease .", "Phosphodiesterase - 5 inhibitor sildenafil prevents neuroinflammation , lowers beta - amyloid levels and improves cognitive performance in P05067 / P49768 transgenic mice . Memory deficit is a marker of Alzheimer ' s disease ( AD ) that has been highly associated with the dysfunction of cyclic GMP ( cGMP ) signaling and an ongoing inflammatory process . Phosphodiesterase - 5 ( O76074 ) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement . However , it is still unknown whether inhibition of O76074 reversed β - amyloid peptide ( Aβ ) - induced neuroinflammation in P05067 / P49768 transgenic ( Tg P05067 / P49768 ) mice . The present study evaluated the cognitive behaviors , inflammatory mediators , and cGMP / PKG / pCREB signaling in 15 - month - old Tg P05067 / P49768 mice and age - matched wild - type ( WT ) mice that were treated with O76074 inhibitor sildenafil and the inhibitor of cGMP - dependent protein kinase Rp - 8 - Br - PET - cGMPS . In comparison with WT mice , Tg P05067 / P49768 mice were characterized by impaired cognitive ability , neuroinflammatory response , and down - regulated cGMP signaling . ___MASK31___ reversed these memory deficits and cGMP / PKG / pCREB signaling dysfunction ; it also reduced both the soluble Aβ1 - 40 and Aβ1 - 42 levels in the hippocampus . These effects of sildenafil were prevented by intra - hippocampal infusion of the Rp - 8 - Br - PET - cGMPS . These results suggest that sildenafil could restore cognitive deficits in Tg P05067 / P49768 mice by the regulation of PKG / pCREB signaling , anti - inflammatory response and reduction of Aβ levels .", "___MASK41___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .", "Anti - inflammatory function of Withangulatin A by targeted inhibiting P35354 expression via MAPK and NF - kappaB pathways . Withangulatin A ( WA ) , an active component isolated from Physalis angulata L . , has been reported to possess anti - tumor and trypanocidal activities in model systems via multiple biochemical mechanisms . The aim of this study is to investigate its anti - inflammatory potential and the possible underlying mechanisms . In the current study , WA significantly suppressed mice T lymphocytes proliferation stimulated with LPS in a dose - and time - dependent manner and inhibited pro - inflammation cytokines ( P60568 , P01579 , and P05231 ) dramatically . Moreover , WA targeted inhibited P35354 expression mediated by MAPKs and NF - kappaB nuclear translocation pathways in mice T lymphocytes , and this result was further confirmed by the P23219 / 2 luciferase reporter assay . Intriguingly , administration of WA inhibited the extent of mice ear swelling and decreased pro - inflammatory cytokines production in mice blood serum . Based on these evidences , WA influences the mice T lymphocytes function through targeted inhibiting P35354 expression via MAPKs and NF - kappaB nuclear translocation signaling pathways , and this would make WA a strong candidate for further study as an anti - inflammatory agent .", "[ Meloxicam ( DB00814 ) : a review of its pharmacological and clinical profile ] . Meloxicam ( DB00814 ) is a new nonsteroidal anti - inflammatory drug ( NSAID ) derived from enolic acid , exhibiting selectivity for cyclooxygenase ( P36551 ) - 2 over P23219 . Meloxicam has shown potent anti - inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models . It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat , but also of bone and cartilage destruction . The therapeutic range of meloxicam in the rat , with regard to inhibition of adjuvant arthritis , was several times greater than that of other NSAIDs . Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers . In clinical studies , meloxicam has shown reliable efficacy against rheumatoid arthritis , osteoarthritis , lumbago ( low back pain ) , scapulohumeral periarthritis , and neck - shoulder - arm syndrome with low gastrointestinal toxicity .", "Heart allograft protection with low - dose carbon monoxide inhalation : effects on inflammatory mediators and alloreactive T - cell responses . BACKGROUND : DB11588 ( CO ) , a byproduct of heme catalysis , has lately received considerable attention as a regulatory molecule in cellular and biological processes . CO has been shown to provide potent protection against a variety of tissue injuries . We hypothesized in this study that low concentration CO would be beneficial for organ allografts , which frequently undergo several types of injury such as ischemia / reperfusion , alloimmune reaction , and inflammation METHODS : The efficacy of low - dose CO was examined in a fully allogeneic LEW to BN rat heterotopic heart transplantation ( HHTx ) model . Recipients were kept in air or exposed to low - dose CO ( 20 ppm ) for 14 , 28 , or 100 days after HHTx under short - course tacrolimus RESULTS : CO treatment ( d0 - 28 , 0 - 100 ) was remarkably effective in prolonging heart allograft survival to a median of > 100 from 45 days in the air - control group , with significant reductions of arteritis , fibrosis , and cellular infiltration , including macrophages and T cells . CO inhibited intragraft upregulation of Th1 type cytokines ( P60568 , IFNgamma ) , proinflammatory mediators ( IL - 1beta , TNFalpha , P05231 , P35354 ) , and adhesion molecule . Shorter CO exposure in early ( 0 - 13d ) and late ( 14 - 28d ) posttransplant periods also prolonged graft survival , with a significant inhibition of inflammatory mediators CONCLUSIONS : These results show that low dose CO inhalation protects heart allografts and can considerably prolong their survival . CO appears to function via multiple mechanisms , including direct inhibition of Th1 type cytokine production and regulation of inflammatory responses .", "Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .", "P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK65___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK65___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .", "Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .", "Distinct effects of inflammation on gliosis , osmohomeostasis , and vascular integrity during amyloid beta - induced retinal degeneration . In normal retinas , amyloid - β ( Aβ ) accumulates in the subretinal space , at the interface of the retinal pigment epithelium , and the photoreceptor outer segments . However , the molecular and cellular effects of subretinal Aβ remain inadequately elucidated . We previously showed that subretinal injection of Aβ ( 1 - 42 ) induces retinal inflammation , followed by photoreceptor cell death . The retinal Müller glial ( RMG ) cells , which are the principal retinal glial cells , are metabolically coupled to photoreceptors . Their role in the maintenance of retinal water / potassium and glutamate homeostasis makes them important players in photoreceptor survival . This study investigated the effects of subretinal Aβ ( 1 - 42 ) on RMG cells and of Aβ ( 1 - 42 )- induced inflammation on retinal homeostasis . RMG cell gliosis ( upregulation of P14136 , vimentin , and nestin ) on day 1 postinjection and a proinflammatory phenotype were the first signs of retinal alteration induced by Aβ ( 1 - 42 ) . On day 3 , we detected modifications in the protein expression patterns of cyclooxygenase 2 ( P35354 ) , glutamine synthetase ( GS ) , Kir4 . 1 [ the inwardly rectifying potassium ( Kir ) channel ] , and aquaporin ( AQP ) - 4 water channels in RMG cells and of the photoreceptor - associated P29972 . The integrity of the blood - retina barrier was compromised and retinal edema developed . Aβ ( 1 - 42 ) induced endoplasmic reticulum stress associated with sustained upregulation of the proapoptotic factors of the unfolded protein response and persistent photoreceptor apoptosis . Indomethacin treatment decreased inflammation and reversed the Aβ ( 1 - 42 )- induced gliosis and modifications in the expression patterns of P35354 , Kir4 . 1 , and P29972 , but not of P55087 or GS . Nor did it improve edema . Our study pinpoints the adaptive response to Aβ of specific RMG cell functions .", "Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .", "O76074 inhibitors enhance celecoxib killing in multiple tumor types . The present studies determined whether clinically relevant phosphodiesterase 5 ( O76074 ) inhibitors interacted with a clinically relevant NSAID , celecoxib , to kill tumor cells . Celecoxib and O76074 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types . Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia . Knock down of O76074 recapitulated the effects of O76074 inhibitor treatment ; the nitric oxide synthase inhibitor L - NAME suppressed drug combination toxicity . The effects of celecoxib were P35354 independent . Over - expression of O15519 - s or knock down of CD95 / Q13158 significantly reduced killing by the drug combination . CD95 activation was dependent on nitric oxide and ceramide signaling . CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing . The drug combination inactivated P42345 and increased the levels of autophagy and knock down of Beclin1 or Q9H1Y0 strongly suppressed killing by the drug combination . The drug combination caused an ER stress response ; knock down of IRE1α / P17861 enhanced killing whereas knock down of eIF2α / P18848 / P35638 suppressed killing . ___MASK31___ and celecoxib treatment suppressed the growth of mammary tumors in vivo . Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer .", "A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK12___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .", "Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre - RT ) , at the fourth week of RT ( mid - RT ) , and 1 month after RT completion ( post - RT ) . Two serial punch biopsies were performed at pre - and mid - RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) - 2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre - RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid - RT ( P30518 ) was greater than 0 . 5 , seven ( 100 % , p = 0 . 0515 ) and five ( 71 . 4 % , p = 0 . 3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre - RT were associated with P30518 ( p = 0 . 0782 ) . For the mid - RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0 . 5 ( p = 0 . 2222 ) . CONCLUSION : The poor mid - RT tumor response was associated with the coexpression of P35354 and P00533 .", "Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring . DB03843 ( FA ) is an environmental and occupational pollutant , and its toxic effects on the immune system have been shown . Nevertheless , no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring . In this study , our objective was to investigate the effects of low - dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring . Pregnant Wistar rats were assigned in 3 groups : P ( rats exposed to FA ( 0 . 75 ppm , 1 h / day , 5 days / week , for 21 days ) ) , C ( rats exposed to vehicle of FA ( distillated water ) ) and B ( rats non - manipulated ) . After 30 days of age , the offspring was sensitised with ovalbumin ( OVA ) - alum and challenged with aerosolized OVA ( 1 % , 15 min , 3 days ) . After 24 h the OVA challenge the parameters were evaluated . Our data showed that low - dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis , P05231 and P01375 secretion . Elevated levels of P22301 were found . Any systemic alteration was detected in the exposed pregnant rats , although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated P23219 expression and reduced P29474 and SOD - 2 in the uterus . Therefore , we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment .", "The role of the spinal opioid receptor like1 receptor , the P25103 , and cyclooxygenase - 2 in maintaining postoperative pain in the rat . Postoperative incident pain is not easily treated with opioids . Mechanical hyperalgesia induced by skin incision in rats is one of the animal models of postoperative incident pain . It is thought that mechanical hyperalgesia is maintained by the sensitization of spinal dorsal horn neurons . The P25103 , the opioid receptor like1 ( P41146 ) receptor , and cyclooxygenase ( P36551 ) - 2 reportedly are involved in the development of spinal sensitization . In this study , we clarified the role of the P25103 , the P41146 receptor , and P35354 in the maintenance of mechanical hyperalgesia induced by skin incision . A 1 - cm longitudinal incision was made through skin and fascia of the plantar aspect of the right foot in the rat . Four hours after the skin incision , significant mechanical hyperalgesia developed . An P41146 receptor agonist ( nociceptin ) , P25103 antagonists ( CP - 96 , 345 and FK888 ) , and P35354 inhibitors ( NS398 and JTE522 ) were administered intrathecally 4 h after the skin incision . An P41146 receptor agonist and P25103 antagonists , but not P35354 inhibitors , significantly attenuated the level of mechanical hyperalgesia induced by the skin incision . These findings suggest that the spinal P41146 receptor and the P25103 play an important role in maintaining the mechanical hyperalgesia induced by skin incision . IMPLICATIONS : Intrathecal injection of an P25103 antagonist and an P41146 receptor agonist may be effective for the treatment of postoperative incident pain ." ]

[ "___MASK12___", "___MASK31___", "___MASK37___", "___MASK41___", "___MASK58___", "___MASK65___", "___MASK71___", "___MASK89___", "___MASK99___" ]

[ "Spline - fitting with a genetic algorithm : a method for developing classification structure - activity relationships . Classification methods allow for the development of structure - activity relationship models when the target property is categorical rather than continuous . We describe a classification method which fits descriptor splines to activities , with descriptors selected using a genetic algorithm . This method , which we identify as SFGA , is compared to the well - established techniques of recursive partitioning ( RP ) and soft independent modeling by class analogy ( SIMCA ) using five series of compounds : cyclooxygenase - 2 ( P35354 ) inhibitors , benzodiazepine receptor ( BZR ) ligands , estrogen receptor ( ER ) ligands , dihydrofolate reductase ( P00374 ) inhibitors , and monoamine oxidase ( MAO ) inhibitors . Only 1 - D and 2 - D descriptors were used . Approximately 40 % of compounds in each series were assigned to a test set , \" cherry - picked \" from the complete set such that they lie outside the training set as much as possible . SFGA produced models that were more predictive for all but the P00374 set , for which SIMCA was most predictive . RP gave the least predictive models for all but the MAO set . A similar trend was observed when using training and test sets to which compounds were randomly assigned and when gradually eliminating compounds from the ( designed ) training set . The stability of models was examined for the random and reduced sets , where stability means that classification statistics and the selected descriptors are similar for models derived from different sets . Here , SIMCA produced the most stable models , followed by SFGA and RP . We show that a consensus approach that combines all three methods outperforms the single best model for all data sets .", "Evaluation of the pharmacokinetics , preclinical and clinical efficacy of pralatrexate for the treatment of T - cell lymphoma . INTRODUCTION : Peripheral T - cell lymphomas ( PTCLs ) are a heterogeneous group of T - cell neoplasms . Most patients with PTCL have a poor outcome with conventional therapies and are not cured without stem - cell transplantation . DB06813 , a novel antifolate chemotherapeutic agent , was rationally designed to impede folate metabolism by inhibiting dihydrofolate reductase ( P00374 ) and to be more efficiently internalized into tumor cells . DB06813 is the first drug that is FDA approved for patients with relapsed and refractory PTCL . AREAS COVERED : DB06813 has been used as a single agent and in combination with other agents in clinical trials for non - Hodgkin ' s lymphoma and Hodgkin ' s disease as well as in solid tumors . This review will cover the development of pralatrexate , the pharmacokinetics of pralatrexate , preclinical findings with pralatrexate and clinical studies of pralatrexate in hematologic malignancies . EXPERT OPINION : DB06813 has significant activity in vitro , and in early Phase I / II trials , responses were noted in patients with aggressive T - cell lymphomas . The DB06813 in Patients with Relapsed or Refractory Peripheral T - Cell Lymphoma trial demonstrated the activity of pralatrexate across a spectrum of heavily pretreated patients with different aggressive T - cell lymphoma subtypes , and studies in cutaneous T - cell lymphoma have shown efficacy at different doses and schedules . The most frequent adverse events in these trials were mucositis , reversible thrombocytopenia and fatigue .", "Functional synergy between DP - 1 and Q01094 in the cell cycle - regulating transcription factor Q14186 / E2F . It is widely believed that the cellular transcription factor Q14186 / E2F integrates cell cycle events with the transcription apparatus because during cell cycle progression in mammalian cells it interacts with molecules that are important regulators of cellular proliferation , such as the retinoblastoma tumour suppressor gene product ( P06400 ) , P28749 , cyclins and cyclin - dependent kinases . Thus , P06400 , which negatively regulates early cell cycle progression and is frequently mutated in tumour cells , and the Rb - related protein P28749 , bind to and repress the transcriptional activity of Q14186 / E2F . Viral oncoproteins , such as adenovirus E1a and SV40 large T antigen , overcome such repression by sequestering P06400 and P28749 and in so doing are likely to activate genes regulated by Q14186 / E2F , such as cdc2 , c - myc and P00374 . Two sequence - specific DNA binding proteins , Q01094 and DP - 1 , which bind to the E2F site , contain a small region of similarity . The functional relationship between them has , however , been unclear . We report here that DP - 1 and Q01094 exist in a DNA binding complex in vivo and that they bind efficiently and preferentially as a heterodimer to the E2F site . Moreover , studies in yeast and Drosophila cells indicate that DP - 1 and Q01094 interact synergistically in E2F site - dependent transcriptional activation .", "Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK78___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK78___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK78___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK78___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK78___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK78___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK78___ .", "Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .", "Dermatological adverse events from P15056 inhibitors : a growing problem . The development of targeted therapies has ushered in a new era in the management of melanoma . Inhibitors of the DB01367 - RAF - MEK - P29323 pathway have taken the center stage with development at a rapid pace . ___MASK8___ was recently approved by regulatory agencies , and other agents ( e . g . dabrafenib ) are in various stages of clinical testing . These agents are producing remarkable results for patients , but are also presenting new challenges . Clinical toxicities and drug resistance are topmost issues . Some of the most common and vivid representations of adverse events to these agents are the dermatologic manifestations . Published trials and initial observations reflect a toxicity profile ( e . g . squamous cell carcinomas / keratoacanthomas , maculopapular rashes , hyperkeratosis ) that is distinct from cutaneous toxicities from P00533 and P42345 inhibitors ( acneiform rash , paronychia , xerosis ) . Their management extends beyond conservative treatment and includes specific physical and surgical treatment modalities , skill sets unique to dermatologists . All these pose significant challenges to clinicians , and sound knowledge of such toxicities and their management will likely result in improved patient outcomes and quality of life . In this manuscript , we provide an overview of the emerging scientific literature on dermatological adverse events arising out of P15056 inhibition .", "The growth hormone dependent serine protease inhibitor , Spi 2 . 1 inhibits the des ( 1 - 3 ) insulin - like growth factor - I generating protease . The conversion of insulin - like growth factor - I ( P05019 ) to the biologically more active des ( 1 - 3 ) P05019 variant is catalyzed by a ubiquitous protease . This proteolytic activity is inhibited by human alpha1 - antitrypsin and soy - bean trypsin inhibitor and is up - regulated in serum and tissue extracts of hypophysectomized rats . These observations lead us to investigate whether the growth hormone regulated , serine protease inhibitor , Spi 2 . 1 was able to inhibit the des ( 1 - 3 ) P05019 generating protease . P00374 deficient Chinese hamster ovary ( CHO ( dhfr - ve ) ) cells were transfected with a rat Spi 2 . 1 expression vector containing the dhfr and neomycin resistance gene . Stable transfectants were selected using G418 and amplified using methotrexate . Conditioned medium from Spi 2 . 1 transfected CHO cells potently inhibited proteolytic activity directed against a synthetic hexa - peptide with a sequence identical to the N - terminal of P05019 . In contrast conditioned medium from wild - type CHO cells had little effect . Based upon these observations we suggest that our previous finding of enhanced des ( 1 - 3 ) P05019 generating protease activity in growth hormone deficient rats may be , at least partly explained by reduced levels of Spi 2 . 1 . Furthermore , we propose that the regulation of the generation of des ( 1 - 3 ) P05019 may be an additional potential site of growth hormone regulation of P05019 action .", "[ Presynaptic P08908 receptors in immunomodulation ] . It is shown that a selective agonist of P08908 receptors 8 - OH - DPAT in a low dose ( 0 . 1 mg / kg ) , which is known to affect mainly the presynaptic P08908 receptors increased the immune response at the peak of reactions ( the forth or fifth day after immunization with sheep red blood cells - SRBC ) in CBA mice and Wistar rats . Treatment of the animals with the drug 15 min prior to antigen injection raised the number of plaque - forming cells ( lgM - P27918 ) and rosette - forming cells ( P41440 ) in the spleen . The preliminary blockade of P08908 receptor with a selective antagonist of P08908 receptors WAY - 100635 ( 0 . 1 mg / kg ) prevented the immunostimulating effect of 5 - HT 1A receptors agonist 8 - OH - DPAT , whereas WAY - 100635 administration alone in the same dose did n ' t change the immune response . Activation of P08908 receptors under conditions of electrical lesion of 5 - HTergic neurons of the nucleus raphe was unable to enhance the immune reactions , as it did in sham - operated rats . The data obtained indicate that the somatodendric P08908 autoreceptors are involved in immunomodulation .", "Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK16___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .", "P05121 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma . The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma ( SCC ) often reflects increased autocrine / paracrine TGF - beta synthesis and epidermal growth factor receptor ( P00533 ) amplification . Cooperative TGF - beta / P00533 signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype . In one physiologically relevant model of human cutaneous SCC progression , TGF - beta1 + P01133 stimulation increases the production of several matrix metalloproteinases ( MMPs ) , among the most prominent of which is P09238 - an MMP known to be elevated in SCC in situ . Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity . Paradoxically , P05121 , the major physiological inhibitor of plasmin generation , is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC . One testable hypothesis proposes that TGF - beta1 + P01133 - dependent P09238 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion . Increased P05121 expression serves to temporally and spatially modulate plasmin - initiated pericellular proteolysis , further facilitating epithelial invasive potential . Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK28___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK38___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .", "Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK47___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .", "DB06813 : a novel synthetic antifolate for relapsed or refractory peripheral T - cell lymphoma and other potential uses . PURPOSE : The pharmacology , pharmacokinetics , clinical trials , adverse effects , dosage , and economic considerations of pralatrexate ( DB06813 ) are reviewed . SUMMARY : Peripheral T - cell lymphoma ( PTCL ) comprises approximately 15 - 20 % of all aggressive lymphomas and 5 - 10 % of all non - Hodgkin ' s lymphomas . Advanced PTCL is often refractory to traditional first - line chemotherapy regimens . DB06813 was developed as a synthetic folate analog antimetabolite that competitively inhibits dihydrofolate reductase ( P00374 ) . This results in the depletion of thymidine , leading to interference with deoxyribonucleic acid synthesis and cancer cell death . DB06813 has a higher potency than methotrexate and edatrexate ( EDX ) . The efficacy and safety of DB06813 have been demonstrated in the PROPEL trial , a prospective phase II trial in patients with relapsed or refractory PTCL . Patients with prior stem cell transplantation receiving DB06813 also had similar response rates ( RRs ) . DB06813 was investigated on the treatment of relapsed or refractory cutaneous T - cell lymphoma , previously treated advanced non - small cell lung cancer and other solid malignancies . DB06813 has similar side effects to other P00374 inhibitors . The most common side effect of DB06813 is mucositis . The recommended dose of DB06813 is 30 mg / m ( 2 ) weekly once for 6 weeks in 7 - week cycle until disease progresses or unacceptable toxicity for PTCL and may require dose reduction or discontinuation . Patients should be supplemented with oral folic acid and intramuscular vitamin B ( 12 ) injections . CONCLUSION : DB06813 provides clinical benefit to patients with relapsed or refractory PTCL with durable complete and partial responses in patients who had not responded to multiple prior treatment regimens .", "Clonal selection and in vivo quantitation of protein interactions with protein - fragment complementation assays . Two strategies are described for detecting constitutive or induced protein - protein interactions in intact mammalian cells ; these strategies are based on oligomerization domain - assisted complementation of rationally designed fragments of the murine enzyme dihydrofolate reductase ( P00374 ; EC 1 . 5 . 1 . 3 ) . We describe a dominant clonal - selection assay of stably transfected cells expressing partner proteins FKBP ( FK506 binding protein ) and P42345 ( FKBP - rapamycin binding protein ) fused to P00374 fragments and show a rapamycin dose - dependent survival of clones that requires approximately 25 molecules of reconstituted P00374 per cell . A fluorescence assay also is described , based on stoichiometric binding of fluorescein - methotrexate to reconstituted P00374 in vivo . Formation of the FKBP - rapamycin - P42345 complex is detected in stably and transiently transfected cells . Quantitative rapamycin dose - dependence of this complex is shown to be consistent with in vitro binding and distinguishable from a known constitutive interaction of FKBP and P42345 . We also show that this strategy can be applied to study membrane protein receptors , demonstrating dose - dependent activation of the erythropoietin receptor by ligands . The combination of these clonal - selection and fluorescence assays in intact mammalian cells makes possible selection by simple survival , flow cytometry , or both . High - throughput drug screening and quantitative analysis of induction or disruption of protein - protein interactions are also made possible .", "Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK47___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .", "The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .", "Inhibitory effects of a luteinizing hormone - releasing hormone agonist on basal and epidermal growth factor - induced cell proliferation and metastasis - associated properties in human epidermoid carcinoma A431 cells . The purpose of this study was to investigate the effects of a potent P01148 agonist , [ D - DB00150 ( 6 )] P01148 on the basal and P01133 - induced cell proliferation and the metastasis - associated properties in A431 human epidermoid carcinoma . [ D - DB00150 ( 6 )] P01148 time - dependently inhibited the basal and P01133 - stimulated growth of A431 cancer cells . It is assumed that phosphorylation / dephosphorylation of cellular proteins is highly related to cell growth . This study demonstrates that [ D - DB00150 ( 6 )] P01148 decreased the basal and P01133 - induced total cellular kinase activity , particularly the tyrosine phosphorylation of several cellular proteins including the P00533 . In contrast , [ D - DB00150 ( 6 )] P01148 did not cause detectable changes in basal and P01133 - stimulated serine / threonine phosphorylation of A431 cellular proteins . The inhibitory effect of [ D - DB00150 ( 6 )] P01148 on A431 cell proliferation was associated with apoptosis as evidenced by the cell morphology and DNA integrity ( ladder pattern ) , the expression of interleukin 1beta - converting enzyme ( ICE ) and activation of caspase . Furthermore , P01133 could rescue the remaining attached A431 cells following [ D - DB00150 ( 6 )] P01148 treatment for 48 hr , which suggests that limited exposure to [ D - DB00150 ( 6 )] P01148 did not channel all cells to irreversible apoptotic process . We also determined the effects of [ D - DB00150 ( 6 )] P01148 on metastasis - associated properties in A431 cells . [ D - DB00150 ( 6 )] P01148 reduced both basal and P01133 - stimulated secretion of P14780 and P08253 . In addition , [ D - DB00150 ( 6 )] P01148 suppressed the basal and P01133 - induced invasive activity of A431 cells based on an in vitro invasion assay . In conclusion , this study indicates that [ D - DB00150 ( 6 )] P01148 may act partly through activating tyrosine phosphatase activity to inhibit cell proliferation and the metastasis - associated properties of A431 cancer cells . Our work suggests that [ D - DB00150 ( 6 )] P01148 may be therapeutically useful in limiting the tumor growth and metastasis of some neoplasms .", "A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and / or metastatic head and neck squamous cell cancer . BACKGROUND : DB06813 ( Fotolyn ( TM ) ; Allos Therapeutics Inc . ) is an antifolate dihydrofolate reductase ( P00374 ) inhibitor . We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and / or metastatic head and neck squamous cell cancer ( R / M HNSCC ) . PATIENTS AND METHODS : This was a single - arm , Simon optimal two stage phase II study . Patients with R / M HNSCC previously treated with chemotherapy were eligible . The study was initiated with a dosing schedule of pralatrexate 190 mg / m ( 2 ) biweekly on a 4 - week cycle with vitamin supplementation . Due to toxicity concerns , the dosing was modified to 30 mg / m ( 2 ) weekly for 3 weeks in a 4 - week cycle with vitamin supplementation . Radiologic imaging was to be obtained about every 2 cycles . RESULTS : Thirteen subjects were enrolled ; 12 were treated . Seven of the twelve patients had previously received ≥ 2 lines of chemotherapy . The most common grade 3 toxicity was mucositis ( 3 patients ) . Seven patients did not complete two cycles of therapy due to progression of disease ( 4 ) , toxicity ( 1 ) , death ( 1 ) , and withdrawal of consent ( 1 ) . Two deaths occurred : one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate . No clinical activity was observed . The median overall survival was 3 . 1 months . The study was closed early due to lack of efficacy . CONCLUSIONS : DB06813 does not possess clinical activity against previously treated R / M HNSCC . Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted .", "Functional network reconstruction reveals somatic stemness genetic maps and dedifferentiation - like transcriptome reprogramming induced by P23769 . Somatic stem cell transplantation holds great promise in regenerative medicine . The best - characterized adult stem cells are DB05914 ( MSCs ) , neural stem cells ( NSCs ) , and CD133 (+) hematopoietic stem cells ( HSCs ) . The applications of HSCs are hampered since these cells are difficult to maintain in an undifferentiated state in vitro . Understanding genes responsible for stem cell properties and their interactions will help on this issue . The construction of stem cell genetic networks will also help to develop rational strategies to revert somatic cells back to a stem - like state . We performed a systemic study on human CD133 (+) HSCs , NSCs , MSCs , and embryonic stem cells and two different progenies of CD133 (+) HSCs , microvascular endothelial cells ( MVECs ) and peripheral blood mononuclear cells . Genes abundant in each or in all three somatic stem cells were identified . We also observed complex genetic networks functioning in postnatal stem cells , in which several genes , such as Q06124 and P00374 , acted as hubs to maintain the stability and connectivity of the whole genetic network . Eighty - seven P19526 genes , including Q15389 and P23769 , were independently identified by comparing P28906 (+) P20138 (-) P28907 (-) hematopoietic stem cells with P28906 (+) precursors and various matured progenies . Introducing P23769 into MVECs resulted in dedifferentiation - like transcriptome reprogramming , with P19526 genes ( such as Q15389 ) being up and endothelial genes ( such as P29323 ) being down . This study provides a foundation for a more detailed understanding of human somatic stem cells . Expressing the newly discovered stem cell genes in matured cells might lead to a global reversion of somatic transcriptome to a stem - like status .", "Single nucleotide polymorphisms in P11597 , Q96NT5 , P41440 , P16671 , Q9HAY6 , Q6Q788 , and O95477 are significant predictors of plasma HDL in healthy adults . BACKGROUND : In a marker - trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms ( SNP ) in 23 candidate genes on HDL levels of two independent Caucasian populations . Each population consisted of men and women and their HDL levels were adjusted for gender and body weight . We used a linear regression model . Selected genes corresponded to folate metabolism , vitamins B - 12 , A , and E , and cholesterol pathways or lipid metabolism . METHODS : Extracted DNA from both the Sacramento and Beltsville populations was analyzed using an allele discrimination assay with a MALDI - TOF mass spectrometry platform . The adjusted phenotype , y , was HDL levels adjusted for gender and body weight only statistical analyses were performed using the genotype association and regression modules from the SNP Variation Suite v7 . RESULTS : Statistically significant SNP ( where P values were adjusted for false discovery rate ) included : P11597 ( rs7499892 and rs5882 ) ; Q96NT5 ( rs37514694 ; rs739439 ) ; P41440 ( rs3788199 ) ; P16671 ( rs3211956 ) ; Q9HAY6 ( rs6564851 ) , Q6Q788 ( rs662799 ) , and O95477 ( rs4149267 ) . Many prior association trends of the SNP with HDL were replicated in our cross - validation study . Significantly , the association of SNP in folate transporters ( Q96NT5 rs37514694 and rs739439 ; P41440 rs3788199 ) with HDL was identified in our study . CONCLUSIONS : Given recent literature on the role of niacin in the biogenesis of HDL , focus on status and metabolism of B - vitamins and metabolites of eccentric cleavage of β - carotene with lipid metabolism is exciting for future study .", "No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK98___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK98___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK98___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK98___ among adults with ADHD .", "Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .", "Botulinum neurotoxin type D enables cytosolic delivery of enzymatically active cargo proteins to neurones via unfolded translocation intermediates . Multi - domain bacterial protein toxins are being explored as potential carriers for targeted delivery of biomolecules . Previous approaches employing isolated receptor binding subunits disallow entry into the cytosol . Strategies in which catalytic domains are replaced with cargo molecules are presumably inefficient due to co - operation of domains during the endosomal translocation step . Here , we characterize a novel transport vehicle in which cargo proteins are attached to the amino terminus of the full - length botulinum neurotoxin type D ( BoNT / D ) . The intrinsic enzymatic activity of the neurotoxin allowed quantification of the efficacy of cargo delivery to the cytosol . P00374 and BoNT type A ( DB00083 ) light chain ( LC ) were efficiently conveyed into the cytosol , whereas attachment of firefly luciferase or green fluorescent protein drastically reduced the toxicity . Luciferase and DB00083 LC retained their catalytic activity as evidenced by luciferin conversion or P60880 hydrolysis in the cytosol of synaptosomes , respectively . Conformationally stabilized dihydrofolate reductase as cargo considerably decreased the toxicity indicative for the requirement of partial unfolding of cargo protein and catalytic domain as prerequisite for efficient translocation across the endosomal membrane . Thus , enzymatically inactive clostridial neurotoxins may serve as effective , safe carriers for delivering proteins in functionally active form to the cytosol of neurones .", "Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK13___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .", "Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers . PURPOSE : This study evaluated mechanistic differences of pralatrexate , methotrexate , and pemetrexed . METHODS : Inhibition of dihydrofolate reductase ( P00374 ) was quantified using recombinant human P00374 . Cellular uptake and folylpolyglutamate synthetase ( Q05932 ) activity were determined using radiolabeled pralatrexate , methotrexate , and pemetrexed in NCI - H460 non - small cell lung cancer ( NSCLC ) cells . The tumor growth inhibition ( TGI ) was assessed using MV522 and NCI - H460 human NSCLC xenografts . RESULTS : Apparent K ( i ) values for P00374 inhibition were 45 , 26 , and > 200 nM for pralatrexate , methotrexate , and pemetrexed , respectively . A significantly greater percentage of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed . In vivo , pralatrexate showed superior anti - tumor activity in both NSCLC models , with more effective dose - dependent TGI in the more rapidly growing NCI - H460 xenografts . CONCLUSIONS : DB06813 demonstrated a distinct mechanistic and anti - tumor activity profile relative to methotrexate and pemetrexed . DB06813 exhibited enhanced cellular uptake and increased polyglutamylation , which correlated with increased TGI in NSCLC xenograft models .", "Order of genes on human chromosome 5q with respect to 5q interstitial deletions . Using ( a ) somatic cell hybrids retaining partial chromosome 5 and ( b ) clinical samples from patients with acquired deletions of the long arm of chromosome 5 , combined with chromosome 5 - linked DNA probes , some of which exhibited RFLPs , we have determined the order of a series of genes on chromosome 5 . The order established is 5pter ---- MLVI - 2 ---- cen ---- P07686 ---- P00374 ---- Pi227 - --- cp12 . 6 ---- ( P05113 , P05112 ) ---- P08700 ---- P04141 ---- P05230 ---- ( P07333 , P09619 ) ---- ( treC , ADRBR ) ---- ( Q5SW96 - Q13585 , P09603 ) ---- qter . The suggested order and orientation for the closely linked P08700 / P04141 gene pair is cen ---- 5 ' P08700 3 ' ---- 5 ' P04141 3 ' ---- qter , on the basis of analysis of the P04141 rearrangement in HL60 DNA . The map position of the GRL locus , which was consistent with both somatic cell hybrid and 5q - analyses , was telomeric to P04141 and centromeric to P07333 / P09619 , near P05230 . Long - range restriction - enzyme analysis of 5q - DNAs did not detect rearrangements of 5q - linked probes except in HL60 DNA , but it did reveal putative long - range RFLPs of several loci . RFLPs for GRL , Pi227 , cp12 . 6 , P08700 , and P07333 can detect deletions in bone marrow and in leukemia cells from patients with acquired 5q deletions .", "Single agent and combination studies of pralatrexate and molecular correlates of sensitivity . BACKGROUND : DB06813 is a dihydrofolate reductase ( P00374 ) inhibitor with high affinity for reduced folate carrier 1 ( P41440 - 1 ) and folylpolyglutamate synthetase ( Q05932 ) , resulting in extensive internalization and accumulation in tumour cells . DB06813 is approved in the US for the treatment of relapsed or refractory peripheral T - cell lymphoma and is being investigated in various malignancies . Here , we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents . METHODS : Antiproliferative effects of pralatrexate were evaluated in 15 human - cancer cell lines using the MTT assay . Gene expression was evaluated using qRT - PCR . RESULTS : DB06813 and methotrexate had a similar pattern of cytotoxicity , pralatrexate being more potent . DB06813 potentiated the effects of platinum drugs , antimetabolites and P00533 inhibitors . Dose - and time - dependent cytotoxicity of pralatrexate correlated with high mRNA expression of Q05932 . Acquired resistance to pralatrexate was associated with decreased P41440 - 1 expression , whereas methotrexate resistance correlated with increased P00374 expression , suggesting different mechanisms of acquired resistance . CONCLUSION : DB06813 was more potent than methotrexate in a panel of solid tumour lines . Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies , and suggest that P41440 - 1 , Q05932 and P00374 may be potential biomarkers of outcome .", "P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK8___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .", "YAP modifies cancer cell sensitivity to P00533 and survivin inhibitors and is negatively regulated by the non - receptor type protein tyrosine phosphatase 14 . The Yes - associated protein ( YAP ) is a transcriptional factor involved in tissue development and tumorigenesis . Although YAP has been recognized as a key element of the Hippo signaling pathway , the mechanisms that regulate YAP activities remain to be fully characterized . In this study , we demonstrate that the non - receptor type protein tyrosine phosphatase 14 ( Q15678 ) functions as a negative regulator of YAP . We show that YAP forms a protein complex with Q15678 through the WW domains of YAP and the PPXY motifs of Q15678 . In addition , Q15678 inhibits YAP - mediated transcriptional activities . Knockdown of YAP sensitizes cancer cells to various anti - cancer agents , such as cisplatin , the P00533 tyrosine kinase inhibitor erlotinib and the small - molecule antagonist of survivin , P28222 . YAP - targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects .", "Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK23___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .", "Combination effects of paclitaxel with signaling inhibitors in endometrial cancer cells . This study was conducted to evaluate and compare molecular and cellular effects of paclitaxel in combination with epidermoid growth factor receptor ( P00533 ) or / and mammalian target of rapamycin ( P42345 ) inhibitors with two endometrial cancer lines O14777 - 1A and Ishikawa . Treatment was with the P00533 inhibitor RG14620 , the P42345 inhibitor rapamycin , and the conventional cytotoxic drug paclitaxel , alone or in combination . The 50 % inhibitory concentration ( IC50 ) and cell viability were determined by the MTT assay . Multiple drug effect / combination indexes ( CI ) analysis was applied to assess interactions between paclitaxel and the two inhibitors . Apoptosis and cell cycling were evaluated by flow cytometry analysis . Western blotting was performed to evaluate the related protein alteration in PI3K / AKT signaling pathway . RG14620 , rapamycin and paclitaxel showed obvious dose - dependent growth inhibition with time . The IC50 of paclitaxel at 24 hours decreased significantly when pretreated with low doses of RG14620 and ___MASK13___ alone or in combination . Moreover , combination index ( CI ) of paclitaxel with each inhibitor was larger than 1 , indicating a synergistic effect between pairs of drugs in these two cell lines . FACS analysis showed the cell apoptosis rate increased with a synergistic effect . On Western blotting , activation of PI3K / AKT pathway was detected in both two cell lines in the control case . When paclitaxel was used as a single - agent or in combinations , the protein expression of PI3K / AKT pathway totally abated , especially in O14777 - 1A cells , suggesting a role in chemoresistance . The combination of three drugs induced the greatest over - expression of caspase - 3 . Combining targeted inhibitors with cytotoxic chemotherapy appears to be a promising strategy for the effective treatment of endometrial cancer which merits further clinical investigation .", "DB00644 agonists reduce the migratory and the invasive behavior of androgen - independent prostate cancer cells by interfering with the activity of P05019 . Androgen - independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior . We have previously shown that DB00644 agonists exert a direct and specific inhibitory action on the proliferation of androgen - independent prostate cancer cells ( DU 145 ) . These compounds mainly act by interfering with the mitogenic activity of growth factors , such as the insulin - like growth factor - I ( P05019 ) . The present experiments were performed to clarify whether DB00644 agonists might also affect the migratory and the invasive behavior of androgen - independent prostate cancer cells and to define their mechanism of action . First we showed that the DB00644 agonist ___MASK16___ reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane . Experiments were then performed to clarify whether the DB00644 agonist might act by interfering with the pro - metastatic activity of P05019 . We found that , in androgen - independent prostate cancer cells , ___MASK16___ : a ) interferes with the P05019 system ( receptor protein expression and tyrosine - phosphorylation ) ; b ) abrogates the P05019 - induced phosphorylation of Akt ( a kinase previously shown by us to mediate the pro - metastatic activity of P05019 in prostate cancer cells ) ; c ) counteracts the migration and the invasive activity of the cells stimulated by P05019 ; d ) abolishes the effects of P05019 on cell morphology , on actin cytoskeleton organization and on alphavbeta3 integrin expression / cellular localization . These data indicate that DB00644 agonists , in addition to their well known antiproliferative effect , can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen - independent prostate cancer cells , expressing the P30968 . DB00644 agonists act by interfering with the pro - metastatic activity of the growth factor P05019 .", "Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .", "High - level synthesis of recombinant murine endostatin in Chinese hamster ovary cells . Endostatin , a carboxy - terminal fragment of collagen XVIII , has been shown to act as an anti - angiogenic agent that specifically inhibits proliferation of endothelial cells and growth of various primary tumors . Here , we describe the expression by Chinese hamster ovary ( CHO ) cells of murine endostatin and of a tagged - fusion protein , ( his ) 6 - met - endostatin . A dicistronic mRNA expression vector was utilized in which endostatin cDNA was inserted upstream of the amplifiable marker gene , dihydrofolate reductase ( P00374 ) . After transfection of the expression vectors , stepwise increments in methotrexate levels in the culture medium were applied , promoting gene amplification and increasing expression levels of the proteins of interest . The expression level of secreted native endostatin was about 78 microg / mL while the one for secreted ( his ) 6 - met - endostatin was about 114 microg / mL , for the best expressing clones . Characterization of physico - chemical and immunological activities of the proteins was performed using SDS - PAGE and Western blotting . The biological activities of recombinant endostatins were tested with a cow pulmonary artery endothelial ( C - PAE ) cell proliferation assay . Both recombinant endostatin and ( his ) 6 - met - endostatin inhibited , in a dose - dependent fashion , growth of C - PAE cells stimulated by basic fibroblast growth factor ( P09038 ) .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "Epidermal growth factor enhances androgen receptor ‑ mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock - out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N - butyl - N -( 4 - hydroxybutyl ) nitrosamine ( BBN ) carcinogen - induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and / or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 was able to potentiate AR transactivation through P00533 by activating PI3K / AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 inhibitor of PD168393 on AR function after addition of anti - androgen , DB01128 , further suggested AR might play a key role in the effects of P01133 on BCa progression and metastasis . Collectively , our results indicate that P01133 may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 and AR signaling ." ]

[ "___MASK13___", "___MASK16___", "___MASK23___", "___MASK28___", "___MASK38___", "___MASK47___", "___MASK78___", "___MASK8___", "___MASK98___" ]

[ "Sulfonylureas inhibit cytokine - induced eosinophil survival and activation . Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases . We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits P05113 - induced survival . This inhibition can not be overcome by increasing concentrations of P05113 and is not due to the blocking of Na + channels by lidocaine . Here we report that one class of K + channel blockers , the sulfonylureas , inhibits eosinophil survival in a manner similar to lidocaine . The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of P05113 . In contrast , increasing concentrations of P08700 or granulocyte - macrophage P04141 overcome glyburide inhibition . Glyburide also blocks cytokine - induced eosinophil superoxide production . Similar results were seen with the sulfonylureas tolbutamide and glipizide . Interestingly , the effects of glyburide are not antagonized by the DB00171 - sensitive K + channel openers cromakalim , pinacidil , or diazoxide . Although Scatchard analysis of [ 3H ] glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor ( Q09428 ) is not present on eosinophils , human eosinophils do express mRNA homologous to the sulfonylurea receptor family , in keeping with the presence of a sulfonylurea receptor . Finally , coculture of eosinophils with combinations of glyburide , lidocaine , and dexamethasone resulted in synergistic inhibition of cytokine - mediated eosinophil survival and superoxide production . These results have intriguing clinical implications for the treatment of eosinophil - associated diseases .", "A case of granulocyte - colony stimulating factor - producing hepatocellular carcinoma confirmed by immunohistochemistry . Granulocyte - colony stimulating factor ( DB00099 ) is a naturally occurring glycoprotein that stimulates the proliferation and maturation of precursor cells in the bone marrow into fully differentiated neutrophils . Several reports of G - P04141 - producing malignant tumors have been published , but scarcely any in the hepatobiliary system , such as in hepatocellular carcinoma ( HCC ) . Here , we encountered a 69 - yr - old man with a hepatic tumor who had received right hepatic resection . He showed leukocytosis of 25 , 450 / microL along with elevated serum DB00099 . Histological examination of surgical samples demonstrated immunohistochemical staining for DB00099 , but not for Q99062 . The patient survived without recurrence for four years , but ultimately passed away with multiple bone metastases . In light of the above , clinicians may consider G - P04141 - producing HCC when encountering patients with leukocytosis and a hepatic tumor . More cases are needed to clarify the clinical picture of G - P04141 - producing HCC .", "Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK22___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .", "A functional granulocyte colony - stimulating factor receptor is required for normal chemoattractant - induced neutrophil activation . P09919 ( DB00099 ) is a hematopoietic growth factor that is widely used to treat neutropenia . In addition to stimulating polymorphonuclear neutrophil ( PMN ) production , G - P04141 may have significant effects on PMN function . Because Q99062 ( G - CSFR ) - deficient mice do not have the expected neutrophilia after administration of human interleukin - 8 ( P10145 ) , we examined the effect of the loss of G - CSFR on P10145 - stimulated PMN function . Compared with wild - type PMNs , PMNs isolated from G - CSFR - deficient mice demonstrated markedly decreased chemotaxis to P10145 . PMN emigration into the skin of G - CSFR - deficient mice in response to P10145 was also impaired . Significant chemotaxis defects were also seen in response to N - formyl - methionyl - leucyl - phenylalanine , zymosan - activated serum , or macrophage inflammatory protein - 2 . The defective chemotactic response to P10145 does not appear to be due to impaired chemoattractant receptor function , as the number of P10145 receptors and chemoattractant - induced calcium influx , actin polymerization , and release of gelatinase B were comparable to those of wild - type PMNs . Chemoattractant - induced adhesion of G - CSFR - deficient PMNs was significantly impaired , suggesting a defect in beta2 - integrin activation . Collectively , these data demonstrate that selective defects in PMN activation are present in G - CSFR - deficient mice and indicate that G - P04141 plays an important role in regulating PMN chemokine responsiveness .", "5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK47___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .", "Bone regeneration properties of granulocyte colony - stimulating factor via neovascularization and osteogenesis . OBJECTIVES : It has been well recognized that appropriate vascularization is emerging as a prerequisite for bone development and regeneration . The aim of this study was to test the hypothesis that locally applied granulocyte colony - stimulating factor ( DB00099 ) enhances bone regeneration via revascularization and osteogenesis . METHODS : A segmental bone defect ( 20mm ) was created at the diaphysis of the rabbit ulna . The defects were treated with cationized gelatin hydrogel , which was the drug delivery system , with DB00099 , and then bone regeneration , neovascularization , and osteogenesis properties with G - P04141 were assessed . RESULTS : Radiographic , computed tomography , and histological findings revealed that bone formation was significantly promoted in G - P04141 - treated group as early as 2 weeks . Immunohistochemistry , real - time reverse transcription - polymerase chain reaction , and flow cytometry studies indicated that angiogenesis / vasculogenesis , which are regulated by mobilization and incorporation of P28906 +/ Q99062 ( CSFR + ) cells , and osteogenesis , which is regulated by osteocalcin +/ G - CSFR + cells , were also significantly enhanced in the G - P04141 group . CONCLUSIONS : This study suggests that locally applied G - P04141 contributes to an ideal local environment for fracture healing by supplying adequate blood flow and stimulating osteogenesis . G - P04141 may have the therapeutic potential for bone regeneration .", "Modulation of Q8IVT5 activity in Caenorhabditis elegans by Zn ions , P25116 kinase and PP2A phosphatase . Vulval differentiation in Caenorhabditis elegans is controlled by a conserved signal transduction pathway mediated by Ras and a kinase cascade that includes Raf , Mek and MAPK . Activation of this cascade is positively regulated by a number of proteins such as Q8IVT5 ( kinase suppressor of Ras ) , Q09428 - 8 / Q5T124 - 2 , Q09428 - 6 / PP2A - B and P05231 - 1 . We describe the functional characterization of sur - 7 and several genes that regulate signaling downstream of ras . We identified sur - 7 by isolating a mutation that suppresses an activated ras allele , and showed that Q09428 - 7 is a divergent member of the cation diffusion facilitator family of heavy metal ion transporters that is probably localized to the endoplosmic recticulum membrane and regulates cellular Zn ( 2 +) concentrations . Genetic double mutant analyses suggest that the Q09428 - 7 - mediated effect is not a general toxic response . Instead , Zn ( 2 +) ions target a specific step of the pathway , probably regulation of the scaffolding protein Q8IVT5 . Biochemical analysis in mammalian cells indicates that high Zn ( 2 +) concentration causes a dramatic increase of Q8IVT5 phosphorylation . Genetic analysis also indicates that PP2A phosphatase and P25116 kinase act downstream of Raf to positively and negatively regulate Q8IVT5 activity , respectively .", "Reduced expression of basal and probiotic - inducible G - P04141 in intestinal mononuclear cells is associated with inflammatory bowel disease . BACKGROUND : Granulocyte - colony stimulating factor ( DB00099 ) is a pleiotropic cytokine involved in the hematopoiesis of granulocytes , neuroprotection , and immunomodulation . Previously , we have shown that probiotic Lactobacillus rhamnosus GR - 1 induces G - P04141 production from bone marrow - derived macrophages . Whether this probiotic also induces G - P04141 in intestinal mononuclear cells is unknown . METHODS : G - P04141 release in response to L . rhamnosus GR - 1 was analyzed in isolated intestinal lamina propria mononuclear cells from inflammatory bowel disease ( Q9UKU7 ) and non - Q9UKU7 patients . The effects of G - P04141 on proinflammatory cytokine production in human peripheral blood mononuclear cells and intestinal tissue from C57BL / 6 wildtype and Q99062 knockout mice was examined . RESULTS : Normal mouse or human intestinal lamina propria cells constitutively express high levels of DB00099 , of which production was further enhanced by exogenous L . rhamnosus GR - 1 . However , cells obtained from Q9UKU7 patients showed reduced G - P04141 production under basal conditions and also lower production after exogenous GR - 1 treatments . Intestinal tissue samples isolated from Q99062 - deficient mice constitutively expressed higher levels of TNFalpha , IL - 23 , and IL - 12 than those from wildtype mice , and pretreatment of G - P04141 suppressed lipopolysaccharide ( LPS ) - induced IL - 23 in human peripheral blood mononuclear cells . CONCLUSIONS : These results suggest that high G - P04141 production induced by commensals such as L . rhamnosus is important in maintaining normal immunological homeostasis in the intestine and defects in the production of G - P04141 are associated with Q9UKU7 .", "P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK92___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .", "Decreased mRNA expression of Q99062 in cord blood neutrophils of term newborns : regulation of expression by G - P04141 and P01375 . P09919 ( DB00099 ) promotes neutrophil production and enhances neutrophil function . The effects of G - P04141 are mediated by binding to its receptor . Since neutrophils are an essential part of the neonatal host defense system , we studied Q99062 expression in neonatal neutrophils . We determined protein and mRNA expression of Q99062 in freshly isolated neutrophils from cord blood of healthy term newborns ( n = 16 ) and of adults ( n = 6 ) as well as the in vitro effect of supplemented recombinant human DB00099 ( rhG - P04141 ) and tumor necrosis factor - alpha ( P01375 ) on Q99062 expression of neutrophils . Expression of Q99062 on the surface of neutrophils of cord blood was significantly lower compared to adults ( 61 +/- 6 vs . 89 +/- 2 % ) . Q99062 mRNA transcripts of neutrophils from newborns compared to adults was lower , too ( 77 +/- 14 vs . 152 +/- 33 % ) . Neutrophils isolated from cord blood showed a decrease of Q99062 expression within 24 h of culture . Moreover , we were able to show that supplemented rhG - P04141 is necessary for maintenance of Q99062 expression . P01375 , however , down - regulated Q99062 expression . We conclude that low protein and mRNA expression of Q99062 in neutrophils of neonates compared to adults may adversely affect granulopoiesis and neutrophil functions by decreased responsiveness to DB00099 . Furthermore , Q99062 expression on neutrophils was modified not only by G - P04141 itself , but also by P01375 .", "Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK50___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .", "Identification of P41597 , flotillin , and gp49B genes as new G - P04141 targets during neutrophilic differentiation . P09919 ( DB00099 ) is a cytokine that stimulates myeloid progenitor cells to proliferate and differentiate into neutrophilic granulocytes . To identify genes induced by G - P04141 during neutrophil differentiation , interleukin - 3 - dependent murine myeloid precursor P18627 - P1 cells expressing the Q99062 were stimulated with DB00099 , and the gene expression profile was characterized by DNA microarray analysis . In addition to known signal transducer and activator of transcription - 3 target genes , such as suppressor of cytokine signaling - 3 ( O14543 ) , JunB , and p19 ( INK4D ) , we newly identified several G - P04141 targets , including genes for the CC chemokine receptor - 2 ( P41597 ) , raft proteins flotillin - 1 and flotillin - 2 , and immunoglobulin - like receptor gp49B . Real - time , quantitative polymerase chain reaction analyses revealed that the expression of these genes was induced in various myeloid cell lines by DB00099 . Furthermore , when HoxA9 - immortalized bone marrow progenitors were induced by G - P04141 to differentiate into mature neutrophils , all of these genes were strongly activated . These genes could be categorized into three groups based on their time - course of expression : immediate - early ( approximately 20 min , O14543 ) , mid - early ( 2 - 4 h , flotillin - 1 / 2 and gp49B ) , and late ( > 12 h , P41597 ) . This suggests that different transcriptional mechanisms are involved in the regulation of these genes . We show that bone marrow neutrophils express functional P41597 , which suggest that CC chemokines may play previously unknown roles in neutrophil activation and chemotaxis .", "P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( DB02901 ) in castrated male and female mice subjected to DB02901 replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by DB02901 in mice CPs .", "Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK60___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .", "Intrathecal upregulation of granulocyte colony stimulating factor and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis . To investigate cytokine / chemokine changes in amyotrophic lateral sclerosis ( P35858 ) , we simultaneously measured 16 cytokine / chemokines ( interleukin [ IL ] - 1beta , P60568 , P05112 , P05113 , P05231 , P13232 , P10145 , P22301 , IL - 12 [ P08133 ] , P35225 , Q16552 , interferon - gamma , tumor necrosis factor - alpha , granulocyte colony stimulating factor [ DB00099 ] , macrophage chemoattractant protein - 1 [ P13500 ] , and macrophage inflammatory protein - 1beta ) in cerebrospinal fluid ( P04141 ) and sera from 37 patients with sporadic P35858 and 33 controls using a multiplexed fluorescent bead - based immunoassay . We also conducted immunohistochemical analyses from 8 autopsied P35858 cases and 6 nonneurologic disease controls as well as cell culture analyses of relevant cytokines and their receptors . We found that concentrations of G - P04141 and P13500 were significantly increased in P35858 P04141 compared with controls . In spinal cords , G - P04141 was expressed in reactive astrocytes in P35858 cases but not controls , whereas Q99062 expression was significantly decreased in motor neurons of spinal cords from P35858 cases . Biologically , G - P04141 had a protective effect on the NSC34 cell line under conditions of both oxidative and nutritional stress . We suggested that G - P04141 has potentially neuroprotective effects on motor neurons in P35858 and that downregulation of its receptor might contribute to P35858 pathogenesis . On the other hand , P13500 correlated with disease severity , which may aggravate motor neuron damage .", "Molecular aspects of anti - inflammatory action of DB00099 . P09919 ( DB00099 ) is a cytokine which stimulates the production of neutrophils in the bone marrow and modulates cellular functions of mature neutrophils . Besides neutrophils and their precursors , monocytes are direct target cells of G - P04141 action . G - P04141 influences monocyte functions in an anti - inflammatory way : The stimulation of monocytes with G - P04141 results in an attenuation of LPS - induced release of IL - 1beta , P01375 , IL - 12 and Q14116 . G - P04141 exerts its biological functions on neutrophils and monocytes via membrane - bound receptors . Seven different human Q99062 isoforms have been described which are generated by alternative splicing . The physiologic roles of these isoforms and the expression pattern on various cell types are still unknown . The signal transduction pathway of G - P04141 receptors involves the activation of JAK tyrosine kinases and P35610 transcription factors and the ras / mitogen - activated protein kinase pathway .", "Three different mRNAs encoding human granulocyte colony - stimulating factor receptor . Three cDNAs for the human granulocyte colony - stimulating factor ( DB00099 ) receptor were isolated from the cDNA libraries of human U937 leukemia cells and placenta by using a murine Q99062 cDNA as the probe . The human Q99062 containing 813 amino acids had a marked homology ( 62 . 5 % ) with its murine counterpart and consisted of extracellular , transmembrane , and cytoplasmic domains . The WSXWS motif found in members of the newly identified growth factor receptor family was also present in the extracellular domain of the human Q99062 . Expression of the cloned cDNA in monkey COS cells gave rise to a protein that could specifically bind G - P04141 with a high affinity ( Kd , 550 pM ) . Two other classes of the human Q99062 were also identified , one of which had a deletion of the transmembrane domain and seemed to encode a secreted , soluble receptor . The third class of the Q99062 contained a 27 - amino acid insertion in the cytoplasmic domain and was highly expressed in placenta .", "Characterization of novel germline c - kit gene mutation , P10721 - Tyr553Cys , observed in a family with multiple gastrointestinal stromal tumors . We found a novel type germline mutation at exon 11 of the c - kit gene , which results in a substitution of DB00135 to DB00151 at codon 553 of the c - kit gene product ( P10721 - Tyr553Cys ) , in a 68 - year - old female patient with multiple gastrointestinal stromal tumors ( GISTs ) . In the present study , we carried out mutational analysis in her family members to determine the carriers and characterized the mutation by introducing the corresponding mutation ( murine P10721 - Tyr552Cys ) into expression vector possessing murine c - kit cDNA . Mutational analysis of peripheral blood leukocytes of her family members revealed that a 44 - year - old son had the same mutation , but at present he had neither apparent symptoms nor images of multiple GISTs . By transfection with the expression vector possessing the murine mutant c - kit cDNA , interleukin - 3 - dependent Ba / P13726 murine lymphoid cells started growing autonomously without any growth factors , indicating that the mutation was considered to be of gain - of - function . Imatinib , a small molecule of tyrosine kinase inhibitor , effectively inhibited autophosphorylation of P10721 - Tyr552Cys . ___MASK22___ , another small molecule of the P10721 inhibitor , also effectively inhibited autophosphorylation of P10721 - Tyr552Cys . In fact , proliferation of Ba / P13726 cells expressing P10721 - Tyr552Cys was effectively inhibited by both imatinib and nilotinib . These findings indicate that the novel type human P10721 - Tyr553Cys mutation is the cause of the present familial and multiple GISTs , and that both imatinib and nilotinib might effectively inhibit the growth of GISTs developing in the patients of this family .", "Detection of the granulocyte colony - stimulating factor receptor using biotinylated granulocyte colony - stimulating factor : presence of granulocyte colony - stimulating factor receptor on P28906 - positive hematopoietic progenitor cells . P09919 ( DB00099 ) was linked to Q6T4R5 - biotin to yield biotinylated DB00099 ( b - DB00099 ) , which retained the ability to stimulate colony formation by normal bone marrow ( BM ) cells in methylcellulose . The use of streptavidin - phycoerythrin conjugate in conjunction with flow cytometry demonstrated that the binding of biotinylated G - P04141 to its receptor is saturable , competitive , and specific . A 100 - fold molar excess of unlabeled G - P04141 almost completely inhibited the binding of the biotinylated G - P04141 to the human leukemia cell line U937 , which is known to possess the Q99062 . G - P04141 receptors were clearly detected by flow cytometry on adult human peripheral granulocytes and monocytes , but not on lymphocytes . Using this method , the expression of G - P04141 receptors on hematopoietic progenitor cells in bone marrow and umbilical cord blood , detected as P28906 - positive ( P28906 + ) cells , were examined . A small but significant number of P28906 + cells were detected among the bone marrow mononuclear cells and umbilical - cord - blood mononuclear cells ( 4 . 28 % +/- 0 . 31 % , 1 . 09 % +/- 0 . 20 % , respectively ) . The percentage of P28906 + BM mononuclear cells was significantly higher than for cord blood mononuclear cells ( P less than 0 . 01 ) . These P28906 + cells were then analyzed by biotinylated G - P04141 binding . P28906 + cells from bone marrow contained 25 . 8 % +/- 7 . 9 % Q99062 positive cells and those from cord blood possessed 29 . 2 % +/- 7 . 0 % of Q99062 - positive cells . The difference was not statistically significant .", "P09919 ( DB00099 ) receptor gene expression of ovarian carcinoma does not correlate with G - P04141 caused cell proliferation . BACKGROUND : Recombinant human granulocyte colony - stimulating factor ( rhG - P04141 ) is a growth factor commonly used to avoid leukopenia after chemotherapy . Endogenous G - P04141 is produced by macrophages and granulocytes that infiltrate tumors . It has been reported that rhG - P04141 stimulates the proliferation of several cell lines as well as bladder carcinoma cells . Conversely , in some hematopoietic cell lines such as U - 937 , WEHI - 3B , and K - 562 no effect or in some cases a differentiation pattern was found . Moreover , the role of rhG - P04141 on the proliferation of solid tumors is not well understood . METHODS : In this study , 10 ovarian carcinoma biopsies were characterized for the presence of G - P04141 and Q99062 by reverse transcription - polymerase chain reaction ( RT - PCR ) and immunohistochemical analysis . Proliferation was analyzed by DB00171 viability assays . RESULTS : Performing RT - PCR , these biopsies and four ovarian carcinoma cell lines were analyzed for endogenous G - P04141 production , which was found in some biopsies and in all cell lines . Despite the presence of the Q99062 in all biopsies and cell lines , no proliferation was found after rhG - P04141 incubation of the cell lines or the tumor samples for 3 and for 6 days , respectively . CONCLUSIONS : Summarizing the authors ' in vitro studies , rhG - P04141 does not affect the proliferation of ovarian carcinoma cells in vitro .", "Granulocyte - colony stimulating factor inhibits neuronal apoptosis in a rat model of diabetic cerebral ischemia . Incidence of cerebral vascular disease ( CVD ) is higher in patients with diabetes mellitus ( DM ) than that in individuals without DM , and neuronal apoptosis determines the severity of cerebral infarction . However , there is no effective therapy for CVD . Granulocyte - colony stimulating factor ( DB00099 ) , a potent hematopoietic factor , could inhibit apoptosis of hematopoietic progenitor cells . However , its effect on neuronal cells is still unclear . In this study , we investigated the anti - apoptosis properties of G - P04141 in neurons following focal cerebral ischemia in diabetic rats . The diabetic condition was generated in rats by intravenous injection of streptozotocin . After 6 weeks , diabetic rats underwent middle cerebral artery occlusion ( MCAO ) and received subcutaneous administration of DB00099 ( 50 microg / kg ) daily for 7 , 14 or 21 days . We analyzed the changes in neurological severity scores , infarct volume , number of apoptotic neurons , and the expression of Q99062 , phosphorylated signal transducer and activator of transcription 3 ( pSTAT3 ) , cellular inhibitor of apoptosis protein 2 ( cIAP2 ) , Bcl - 2 , and Bax in the brain tissue . Bax is a pro - apoptotic member of the Bcl - 2 protein family . The DM rats treated with G - P04141 not only showed the reduced infarct volume and decreased apoptosis cell number , but also presented improved neurological scores . The G - P04141 also increased the expression of pSTAT3 , Bcl - 2 , and cIAP2 proteins as well as Bcl - 2 mRNA , but inhibited Bax protein expression in the brain . These results indicate that G - P04141 partially increases neuronal survival by affecting apoptosis pathways . G - P04141 provides a potential treatment for stroke and other neurological dysfunction accompanied by neuronal apoptosis .", "P09919 and leukemogenesis . The granulocyte colony - stimulating factor ( DB00099 ) plays an important role in normal granulopoiesis . Its functions are mediated by specific receptors on the surface of responsive cells and , upon ligand binding , several cytoplasmic tyrosine kinases are activated . The cytoplasmic region proximal to the membrane of the Q99062 ( Q99062 ) transduces proliferative and survival signals , whereas the distal carboxy - terminal region transduces maturation signals and suppresses the receptor ' s proliferative signals . Mutations in the Q99062 gene resulting in truncation of the carboxy - terminal region have been detected in a subset of patients with severe congenital neutropenia who developed acute myelogenous leukemia ( AML ) . In addition , the Q01196 - Q06455 fusion protein , expressed in leukemic cells harboring the t ( 8 ; 21 ) , disrupt the physiological function of transcription factors such as C / EBPalpha and C / EBPepsilon , which in turn deregulate Q99062 expression . The resulting high levels of Q99062 and G - P04141 - dependent cell proliferation may be associated with pathogenesis of AML with t ( 8 ; 21 ) . Moreover , in vitro and in vivo studies demonstrated that G - P04141 may act as a co - stimulus augmenting the response of P29590 - RARalpha acute promyelocytic leukemia cells to all - trans - retinoic acid treatment . Finally , in the Q05516 - RARalpha acute promyelocytic leukemia transgenic model , G - P04141 deficiency suppressed leukemia development . Altogether , these data suggest that the G - P04141 signaling pathway may play a role in leukemogenesis .", "Spectra of chromosomal aberrations in 325 leukemia patients and implications for the development of new molecular detection systems . This study investigated the spectrum of chromosomal abnormalities in 325 leukemia patients and developed optimal profiles of leukemic fusion genes for multiplex RT - PCR . We prospectively analyzed blood and bone marrow specimens of patients with acute leukemia . Twenty types of chromosomal abnormalities were detected in 42 % from all patients by commercially available multiplex RT - PCR for detecting 28 fusion genes and in 35 % by cytogenetic analysis including Q5TCZ1 analysis . The most common cytogenetic aberrations in acute myeloid leukemia patients was P29590 / PARA , followed by Q01196 / MGT8 and Q03164 , and in acute lymphoid leukemia patients was P11274 / P00519 , followed by P41212 / Q01196 and Q03164 gene rearrangement . Among the negative results for multiplex RT - PCR , clinically significant t ( 3 ; 3 )( q21 ; q26 . 2 ) , t ( 8 ; 14 )( q24 ; q32 ) and i ( 17 )( q10 ) were detected by conventional cytogenetics . The spectrum and frequency of chromosomal abnormalities in our leukemia patients are differed from previous studies , and may offer optimal profiles of leukemic fusion genes for the development of new molecular detection systems .", "Lineage - specific growth factors can compensate for stem and progenitor cell deficiencies at the postprogenitor cell level : an analysis of doubly P07202 - and Q99062 - deficient mice . Multiple lines of evidence indicate that thrombopoietin ( P07202 ) substantially impacts the number of hematopoietic stem cells and progenitors of all myeloid lineages . Nevertheless , tpo knock - out mice ( T (-) ) display thrombocytopenia only ; blood erythroid and neutrophil levels are normal despite 60 % to 85 % reductions in stem and progenitor cells . The compensatory mechanism ( s ) for these deficiencies remains uncertain ; lineage - specific cytokines such as erythropoietin or granulocyte colony - stimulating factor ( DB00099 ) have been postulated but never proven to be responsible . To directly test whether G - P04141 can compensate for the myeloid progenitor cell reduction in the T (-) model of hematopoietic deficiency , T (-) and G - P04141 - receptor knock - out ( GR (-) ) mice were crossed , and F1 animals bred to obtain doubly nullizygous mice ( T (-) GR (-) ) . This experiment also allowed us to test the hypothesis that G - P04141 contributes to the residual platelet production in T (-) mice . We found that T (-) GR (-) F2 mice displayed similar blood platelet levels as that seen in T (-) mice , indicating that G - P04141 does not account for the residual megakaryopoiesis in T (-) mice . However , we also noted excessive perinatal mortality of T (-) GR (-) animals , caused by infection due to a profound and significant decrease in marrow and peripheral blood neutrophils , far greater than that seen in either T (-) or GR (-) mice . These data indicate that in the additional absence of GR , T (-) mice can not compensate for their 62 % reduction in myeloid progenitors and become profoundly neutropenic , supporting the hypothesis that G - P04141 can compensate for the myeloid effects of P07202 deficiency by expanding the pool of cells between the granulocyte - macrophage colony - forming unit and mature neutrophil stages of granulopoiesis .", "T - cell receptor Vbeta gene usage in P04141 lymphocytes in X - linked adrenoleukodystrophy . X - linked adrenoleukodystrophy ( P33897 ) is a peroxisomal disorder with impaired very - long - chain fatty acid ( VLCFA ) metabolism that produces a neurological disease with significant variability of clinical phenotypes even within kindred . The two most common forms are the cerebral form ( CALD ) with an important inflammatory reaction at the active edge of demyelinating lesions , resembling some aspects of multiple sclerosis pathology , and adrenomyeloneuropathy ( Q9BXJ7 ) , which involves the spinal cord and in which the inflammatory reaction is mild or absent . One hypothesis is that the phenotypic variability is related to T cell - mediated immune mechanisms playing a primary role in the demyelinating pathogenic process of CALD . The present study aims to test the hypothesis that P04141 of patients with the CALD form contains highly restricted T cell populations . The variable regions of the T cell receptor beta chains ( TCR Vbeta ) were studied in P04141 from 29 P33897 patients with different phenotypes . RNA was extracted and cDNA synthesized from P04141 lymphocytes ; TCR Vbeta gene segments were amplified from the cDNA by polymerase chain reaction ( PCR ) using 20 family - specific primers . PCR products were analyzed by Southern blot . Some amplified Vbeta products were sequenced . The majority of P33897 patients ( 21 / 29 ) , whatever their phenotype , exhibited oligoclonal T cell expansion . However the overexpression of some TCR Vbeta families was heterogeneous among the different patients without any preponderance of specific Vbeta families or any clustering according to clinical phenotype . In particular a dominant TCR Vbeta utilization was not found in patients with CALD .", "Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK50___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .", "In vivo expansion of cells expressing acquired Q99062 mutations in patients with severe congenital neutropenia . Severe congenital neutropenia ( CN ) is a rare bone marrow failure syndrome with a high incidence of acute leukemia . In previous studies , we could show that point mutations in the gene for the granulocyte colony - stimulating factor ( DB00099 ) receptor Q99062 are a highly predictive marker for leukemic development in CN patients . To find out at which stage of hematopoietic development these mutations emerge and how they are propagated during hematopoietic differentiation , we analyzed single cells of different hematopoietic subpopulations from CN patients with Q99062 mutations . We found that Q99062 mutations are not restricted to the myeloid compartment but are also detectable in lymphoid cells , although at a much lower percentage . From our observations , we conclude that Q99062 mutations are acquired in multipotent hematopoietic progenitor cells in CN patients and that they are clonally expanded in myeloid cells expressing the Q99062 due to the growth advantage mediated by the Q99062 mutation .", "Assignment of the human granulocyte colony - stimulating factor receptor gene ( Q99062 ) to chromosome 1 at region p35 - p34 . 3 . The gene for the granulocyte colony - stimulating factor ( DB00099 ) receptor ( Q99062 ) was localized on the p35 - p34 . 3 region of human chromosome 1 by in situ hybridization using human Q99062 cDNA as the probe . Polymerase chain reaction using oligonucleotides specific for the human Q99062 produced a specifically amplified DNA fragment with DNA from mouse A9 cells that contained human chromosome 1 but not other human chromosomes . Localization of the Q99062 on chromosome 1 was further confirmed by the spot - blot hybridization of sorted human chromosomes .", "Acute promyelocytic leukemia with a Q05516 - RARalpha fusion protein . In most cases of acute promyelocytic leukemia ( APL ) , a fusion of the promyelocytic leukemia ( P29590 ) and the retinoic acid receptor - alpha ( RARalpha ) genes occurs , resulting in the expression of a P29590 - RARalpha chimeric protein . In approximately 1 % of the cases of APL , variant chromosomal aberrations may be found fusing RARa with other genes . Four variant mutations have been described , and the t ( 11 ; 17 )( q21 ; q23 ) translocation generating a promyelocyte leukemia zinc finger ( Q05516 ) - RARalpha fusion gene is the most common . Q05516 - RARalpha - positive APL forms a clinically distinct group because unlike P29590 - RARalpha - positive leukemia , it does not respond to retinoic acid with terminal granulocytic differentiation of the cells , and remissions can not be achieved with retinoids alone . At the molecular level , this has been explained by the retinoic acid - insensitive binding of corepressor proteins to the Q05516 part of the fusion protein , leading to sustained repression of target genes that are important for cellular differentiation . Targeting of the Q05516 - RARalpha - bound corepressor complexes using a combination of all - trans retinoic acid ( DB00755 ) and deacetylase inhibitors has shown that the repression of target genes can be relieved , allowing differentiation of the cells . In addition , when a combination of retinoic acid and the hematopoietic growth factor granulocyte colony - stimulating factor ( DB00099 ) is applied , the cells may be forced to undergo terminal differentiation , both in vitro and in vivo . This suggests that signals from the activated Q99062 may induce the release of corepressor proteins from Q05516 . Together , these findings indicate that Q05516 - RARalpha - positive leukemia is not completely resistant to differentiation induction if the proper costimuli are given .", "Identification of residues critical to the activity of human granulocyte colony - stimulating factor . DB00160 scanning mutagenesis of human granulocyte colony - stimulating factor ( DB00099 ) was used to identify residues critical for the cell - proliferative activity of the protein . Fifty - eight residues , most of them on the protein surface , were independently mutated to alanine . Most of the variants retained full biological activity ; however , 15 mutants were significantly impaired in their ability to stimulate bone marrow cell proliferation in vitro . Four of these variants contain mutations at buried residues and two have substitutions at side chains involved in intramolecular hydrogen bonds . The remaining nine down mutations identify two regions on the surface of the molecule important for biological activity . Consistent with these observations , measurements of binding to NFS - 60 cells indicate that the residues most important for receptor binding are Lys40 and Phe144 in site 1 and Glu19 in site 2 . In addition to these residues , Val48 and Leu49 in site 1 and Leu15 , Asp112 , and Leu124 in site 2 are also important for biological activity . These results suggest the presence of two binding sites on the cytokine surface required for dimerization of the Q99062 .", "P40763 - mediated differentiation and survival and of myeloid cells in response to granulocyte colony - stimulating factor : role for the cyclin - dependent kinase inhibitor p27 ( Kip1 ) . The signal transducer and activator of transcription ( P35610 ) proteins have been implicated in cytokine - regulated proliferation , differentiation and cell survival . P09919 ( DB00099 ) , a regulator of granulocytic differentiation , induces a robust and sustained activation of P40763 . Here , we show that introduction of dominant negative ( DN ) forms of P40763 interferes with G - P04141 - induced differentiation and survival in murine 32D cells . G - P04141 induces expression of the cyclin - dependent kinase ( cdk ) inhibitor p27 ( KiP1 ) ( but not P38936 ( CiP1 ) ) , which is completely blocked by DN - P40763 . The ability of tyrosine - to - phenylalanine substitution mutants of the Q99062 to activate P40763 strongly correlated with their capacity to induce p27 expression and their ability to mediate differentiation and survival , suggesting a causal relationship between P40763 activation , p27 expression and the observed cellular responses . We identified a putative P35610 binding site in the promoter region of p27 that showed both P40763 binding in electrophoretic mobility shift assays and functional activity in luciferase reporter assays . Finally , we studied G - P04141 - induced responses in primary bone marrow and spleen cells of p27 - deficient mice . Compared with wild - type , myeloid progenitors from p27 - deficient mice showed significantly increased proliferation and reduced differentiation in response to DB00099 . These findings indicate that P40763 controls myeloid differentiation , at least partly , via upregulation of p27 ( Kip1 ) .", "Chemical modification and site - directed mutagenesis of methionine residues in recombinant human granulocyte colony - stimulating factor : effect on stability and biological activity . Chemical modification and mutagenesis of methionines in recombinant human granulocyte colony - stimulating factor ( DB00099 ) were investigated . Selective oxidation of G - P04141 by H2O2 and t - butyl hydroperoxide leads to generation of different oxidized forms . Four modified forms were isolated and shown to contain 1 to 4 oxidized methionyl residues . All methionines in G - P04141 are reactive , with reaction kinetics following the order of Met1 > Met138 > Met127 >>> Met122 . H2O2 oxidation of Met122 is relatively slow and is biphasic with a faster second reaction phase being affected by the oxidation of Met127 . All oxidized forms retain gross G - P04141 conformation similar to that of the native molecule and are able to bind the soluble Q99062 . However , G - P04141 form oxidized at both Met127 and Met122 is unstable and exhibits decreased ability to dimerize the receptor after exposure to acid or elevated temperature . All modified forms , except Met1 - oxidized DB00099 , also show significantly lower biological activity . Our data suggest that Met138 is solvent accessible and its surrounding microenvironment may be critical for G - P04141 function , whereas Met127 is less accessible to solvent and Met122 is near the hydrophobic core . Oxidation at both Met127 and Met122 results in alterations of G - P04141 structure that affect the apparent molecular size , polarity , and stability and lead to the loss of G - P04141 biological function . G - P04141 variants with DB00149 replacement at Met127 or at Met138 are not completely resistant to oxidation - induced inactivation , while the variant with DB00149 replacement at both sites is more stable and can retain in vitro biological activity following oxidation .", "Q99062 : stimulating granulopoiesis and much more . The granulocyte colony - stimulating factor receptor ( G - CSFR ) plays an important role in the production , survival and activation of neutrophilic granulocytes during both normal and emergency hematopoiesis . The G - CSFR also participates in the development of other myeloid lineages , the mobilization of hematopoietic stem cells and myeloid cell migration . This has lead to several important clinical applications for its ligand , DB00099 . More recently , additional important roles for G - CSFR have emerged outside the hematopoietic system , such as in the protection and repair of a diverse range of tissues , including muscle , liver and neural tissue , providing further scope for developing G - P04141 as a therapeutic agent . The G - CSFR has also been implicated in the etiology of disease , with mutations / variants of G - CSFR implicated in neutropenia , myelodysplasia and leukemia . Additionally , autocrine / paracrine stimulation of G - CSFR may be important in the biology of solid tumors , including metastasis .", "Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK56___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK56___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK73___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .", "House dust mite allergen exerts no direct proinflammatory effects on human keratinocytes . BACKGROUND : Dermatophagoides pteronyssinus is a trigger of atopic dermatitis . Many D pteronyssinus allergens are proteases that can elicit airway inflammation by stimulating the release of cytokines and chemokines by bronchial epithelial cells . OBJECTIVE : We sought to investigate whether D pteronyssinus allergens can exert a similar activity on skin keratinocytes . METHODS : Primary cultures of keratinocytes from healthy subjects or patients with atopic dermatitis and normal human bronchial epithelial cells were compared for cytokine production in response to D pteronyssinus extract . RESULTS : Keratinocytes , but not bronchial epithelial cells , displayed a modest dose - dependent release of IL - 1alpha and IL - 1 receptor antagonist but no induction of their mRNA after exposure to D pteronyssinus . However , D pteronyssinus also degraded these cytokines . On the other hand , D pteronyssinus extract induced bronchial epithelial cells , but not keratinocytes , to increased expression of P10145 / P10145 and GM - P04141 mRNA and protein . These effects were efficiently abrogated by a mixture of cysteine and serine protease inhibitors . Both P10145 and GM - P04141 were fully resistant to D pteronyssinus proteolytic attack . No induction of monocyte chemoattractant protein 1 / P13500 , RANTES / P13501 , or P01579 - induced protein of 10 kd / P02778 was detected in either cell type . Only bronchial epithelial cells expressed protease - activated receptor ( PAR ) 4 mRNA , whereas P25116 , P55085 , and PAR - 3 mRNA was found in both cell types . D pteronyssinus did not affect PAR mRNA signals . CONCLUSIONS : Although D pteronyssinus can cause proteolysis - dependent release of cytokines from keratinocytes , it appears incapable of activating de novo expression of cytokines and chemokines , arguing against a direct proinflammatory activity of house dust mite on the skin .", "Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK56___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK56___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK56___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .", "G - P04141 increases secretion of urokinase - type plasminogen activator by human lung cancer cells . We reported previously that granulocyte colony - stimulating factor ( DB00099 ) can promote the invasion of human lung cancer cell lines in vitro . However , the exact mechanism of its stimulatory effect on invasion remains to be elucidated . In the present study we mainly focused our attention on the components of the plasminogen activation system in human lung cancer cell lines , because of the central role that plasminogen activators play in regulating extracellular proteolysis . We showed that G - P04141 induced a dose - dependent increase in the urokinase - type plasminogen activator ( uPA ) activity in the conditioned medium of a PC - 9 lung cancer cell line . When the amounts of uPA activity were quantitated by densitometry , we found that even at a concentration of 0 . 01 microg / ml , G - P04141 had a stimulatory effect on the uPA release , while high concentrations caused a 3 . 6 - fold increase at a maximum concentration of 1 microg / ml . A Western blot analysis of the conditioned medium confirmed the findings observed in a zymographic analysis . The observed increase in uPA protein was paralleled by a significant increase in the uPA mRNA levels after treatment with DB00099 . However , our experiments failed to identify any alteration in the plasminogen activator inhibitor ( P05121 ) secretion caused by DB00099 . In addition , we also found the expression of Q99062 by PC - 9 cells , suggesting the possible pathway activated by DB00099 .", "Differential toxicity biomarkers for irinotecan - and oxaliplatin - containing chemotherapy in colorectal cancer . PURPOSE : DB00526 or irinotecan is usually administered jointly with fluoropyrimidines in colorectal cancer patients treated with chemotherapy . Both drugs have different toxicity patterns . Biomarkers for predicting high - risk severe adverse reactions can help select the best treatment . METHODS : A retrospective analysis of 106 colorectal cancer patients receiving an oxaliplatin - based treatment and 56 receiving an irinotecan - based treatment was performed . One copy number variant ( P30711 ) and nine polymorphisms in irinotecan and oxaliplatin metabolism , transport or DNA repair genes ( P08183 , P22309 , P18887 , P07992 , P18074 , P09211 ) were genotyped by SNaPshot , polymerase chain reactions ' length fragments , or copy number assays . RESULTS : In irinotecan - treated patients , T allele of ABCB1C1236T SNP was associated with a lower risk of asthenia ( OR = 0 . 047 ; 95 % CI = 0 . 004 – 0 . 493 ; P = 0 . 011 ) and Tallele of P08183 C3435T SNP was associated with a lower risk of diarrhea ( OR = 0 . 177 ; 95 % CI = 0 . 034 – 0 . 919 ; P = 0 . 039 ) , and individuals with two copies of P30711 gene had a lower risk for asthenia ( OR = 0 . 093 ; 95 % CI = 0 . 011 – 0 . 794 ; P = 0 . 030 ) . In oxaliplatin - treated patients , carriers of one or two T variants of Asn118Asn P07992 SNP had a lower risk for neutropenia ( OR = 0 . 205 ; 95 % CI = 0 . 061 – 0 . 690 ; P = 0 . 01 ) [ corrected ] . CONCLUSIONS : These biomarkers could help oncologists select the best treatment by reducing toxicity associated with irinotecan or oxaliplatin in colorectal cancer patients , thus increasing their quality of life .", "P09919 protects retinal photoreceptor cells against light - induced damage . PURPOSE : Granulocyte colony stimulating factor ( DB00099 ) has been shown to have neuroprotective and anti - inflammatory effects in cerebral damage models . In addition , bone - marrow - derived hematopoietic cells , which can be mobilized with DB00099 , have a neuroprotective effect in hereditary retinal cell death . The present study was conducted to investigate whether G - P04141 protects photoreceptors from light - induced cell death . METHODS : G - P04141 or vehicle was systemically injected before the light exposure and for four consecutive days after the exposure . Morphologic and electrophysiologic examinations were performed 1 week after the exposure to light . Gamma ray irradiation ( 6 . 5 Gy ) was used to examine the involvement of bone marrow - derived cells increased by G - P04141 injection . The expression of Q99062 in the retina was analyzed by immunohistochemistry and quantitative RT - PCR . RESULTS : The outer nuclear layer thickness was partially preserved in G - P04141 - treated mice ( measured at 300 microm superior from the optic disc , DB00099 : 14 . 9 +/- 6 . 3 microm versus control : 6 . 7 +/- 2 . 5 microm ) , and an electroretinogram confirmed the preservation of wave amplitudes ( maximum scotopic a - wave DB00099 : 97 . 7 +/- 48 . 0 microV versus control : 14 . 4 +/- 21 . 9 microV , maximum scotopic b - wave DB00099 : 298 . 1 +/- 145 . 3 microV versus control : 33 . 2 +/- 50 . 1 microV ) . The effect was not lost , even with leukocyte depletion by irradiation . Q99062 was expressed in retinal cells and upregulated by the light exposure ( 1 . 8 - fold upregulation 2 hours after light exposure ) . CONCLUSIONS : G - P04141 protects photoreceptor cells against light - induced damage , possibly via Q99062 expressed on retinal cells . These findings may lead to a novel treatment strategy for neural degenerating diseases of the retina .", "A new epigenetic challenge : systemic lupus erythematosus . In recent years , compelling evidence has been gathered that supports a role for epigenetic alterations in the pathogenesis of systemic lupus erythematosus ( SLE ) . Different blood cell populations of SLE patients are characterized by a global loss of DNA methylation . This process is associated with defects in P29323 pathway signalling and consequent P26358 1 downregulation . Hypomethylation of gene promoters has been described , which permits transcriptional activation and therefore functional changes in the cells and also hypomethylation of the ribosomal RNA gene cluster . Among the identified targets undergoing demethylation are genes involved in autoreactivity ( P20701 ) , osmotic lysis and apoptosis ( P14222 , P50281 and P80188 ) , antigen presentation ( Q99062 ) , inflammation ( MMP 14 ) , B - T - cell interaction ( P32970 and P29965 ) and cytokine pathways ( Q99062 , P05112 , P05231 and P38484 ) . DNA methylation inhibitors are also known to induce autoreactivity in vitro and cause a lupus - like disease in vivo . Further , altered patterns of histone modifications have been described in SLE . P01730 + lymphocytes undergo global histone H3 and H4 deacetylation and consequent skewed gene expression . Although multiple lines of evidence highlight the contribution of epigenetic alterations to the pathogenesis of lupus in genetically predisposed individuals , many questions remain to be answered . Attaining a deeper understanding of these matters will create opportunities in the promising area of epigenetic treatments .", "The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .", "Human monocytes are severely impaired in base and DNA double - strand break repair that renders them vulnerable to oxidative stress . Monocytes are key players in the immune system . Crossing the blood barrier , they infiltrate tissues and differentiate into ( i ) macrophages that fight off pathogens and ( ii ) dendritic cells ( DCs ) that activate the immune response . A hallmark of monocyte / macrophage activation is the generation of reactive oxygen species ( ROS ) as a defense against invading microorganisms . How monocytes , macrophages , and DCs in particular respond to ROS is largely unknown . Here we studied the sensitivity of primary human monocytes isolated from peripheral blood and compared them with macrophages and DCs derived from them by cytokine maturation following DNA damage induced by ROS . We show that monocytes are hypersensitive to ROS , undergoing excessive apoptosis . These cells exhibited a high yield of ROS - induced DNA single - and double - strand breaks and activation of the ATR - Chk1 - Q13315 - Chk2 - p53 pathway that led to Fas and caspase - 8 , - 3 , and - 7 activation , whereas macrophages and DCs derived from them were protected . Monocytes are also hypersensitive to ionizing radiation and oxidized low - density lipoprotein . The remarkable sensitivity of monocytes to oxidative stress is caused by a lack of expression of the DNA repair proteins P18887 , ligase IIIα , poly ( ADP - ribose ) polymerase - 1 , and catalytic subunit of DNA - dependent protein kinase ( DNA - PK ( cs ) ) , causing a severe DNA repair defect that impacts base excision repair and double - strand break repair by nonhomologous end - joining . During maturation of monocytes into macrophages and DCs triggered by the cytokines GM - P04141 and P05112 , these proteins become up - regulated , making macrophages and DCs repair - competent and ROS - resistant . We propose that impaired DNA repair in monocytes plays a role in the regulation of the monocyte / macrophage / DC system following ROS exposure .", "Granulocyte macrophage - colony stimulating factor increases the expression of histamine and histamine receptors in monocytes / macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage - colony - stimulating factor ( GM - P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine - producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM - P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM - P04141 - induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC - expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM - P04141 was also detected in the lesions . In U937 cells , GM - P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM - P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM - P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis - related genes in monocytes and smooth muscle cells . The presence of histamine - producing macrophages and gene expression of histamine receptors and GM - P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM - P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM - P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression .", "Modulation of the binding affinity of myelopoietins for the interleukin - 3 receptor by the granulocyte colony - stimulating factor receptor agonist . Myelopoietins ( MPOs ) are a family of recombinant chimeric proteins that are both interleukin - 3 ( P08700 ) receptor and granulocyte colony - stimulating factor ( DB00099 ) receptor agonists . In this study , P05164 molecules containing one of three different P08700 receptor agonists linked with a common Q99062 agonist have been examined for their P08700 receptor binding characteristics . Binding to the alpha - subunit of the P08700 receptor revealed that the affinity of the P05164 molecules was 1 . 7 - 3 . 4 - fold less potent than those of their individual cognate P08700 receptor agonists . The affinity decrease was reflected in the P05164 chimeras having approximately 2 - fold slower dissociation rates and 2 . 7 - 5 . 5 - fold slower association rates than the corresponding specific P08700 receptor agonists alone . The affinity of binding of the P05164 molecules to the heteromultimeric alphabeta P08700 receptor expressed on TF - 1 cells was either 3 - , 10 - , or 42 - fold less potent than that of the individual cognate P08700 receptor agonist . Biophysical data from nuclear magnetic resonance , near - UV circular dichroism , dynamic light scattering , analytical ultracentrifugation , and size exclusion chromatography experiments determined that there were significant tertiary structural differences between the P05164 molecules . These structural differences suggested that the P08700 and Q99062 agonist domains within the P05164 chimera may perturb one another to varying degrees . Thus , the differential modulation of affinity observed in P08700 receptor binding may be a direct result of the magnitude of these interdomain interactions .", "Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK7___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK7___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .", "DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK62___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .", "Predictive value of circulating interleukin - 6 and heart - type fatty acid binding protein for three months clinical outcome in acute cerebral infarction : multiple blood markers profiling study . INTRODUCTION : There is no single blood marker for predicting the prognosis in ischemic stroke . A combination of multiple blood markers may enhance the ability to predict long - term outcome following ischemic stroke . METHODS : Blood concentrations of neuronal markers ( neuron - specific enolase , visinin - like protein 1 , heart type fatty acid binding protein ( hFABP ) and neuroglobin ) , astroglial markers ( P04271 and glial fibrillary acidic protein ) , inflammatory markers ( P05231 , P01375 - α , and P02741 ) , blood - brain barrier marker ( matrix metalloproteinase 9 ) , and haemostatic markers ( D - dimer and P05121 ) were measured within 24 hours after stroke onset . The discrimination and reclassification for favorable and poor outcome were compared after adding individual or a combination of blood markers to the clinical model of stroke outcome . RESULTS : In multivariate analysis , natural log - transformed ( log ) P05231 ( odds ratio ( OR ) : 1 . 75 , 95 % CI : 1 . 25 to 2 . 25 , P = 0 . 001 ) and loghFABP ( OR : 3 . 23 , 95 % CI : 1 . 44 to 7 . 27 , P = 0 . 005 ) were independently associated with poor outcome . The addition of a single blood marker to the clinical model did not improve the discriminating ability of the clinical model of stroke outcome . However , the addition of the combination of logIL - 6 and loghFABP to the clinical model showed improved discrimination ( area under receiver operating characteristic ( AUROC ) curve : 0 . 939 versus 0 . 910 , P = 0 . 03 ) and reclassification performance ( net reclassification improvement index : 0 . 18 , P = 0 . 005 ) . CONCLUSIONS : A combination of circulating P05231 and hFABP level has an additive clinical value for the prediction of stroke outcome .", "Receptor insertion into factor - dependent murine cell lines to develop specific bioassays for murine G - P04141 and P09603 and human GM - P04141 . cDNAs encoding the receptors for murine DB00099 , P09603 or human GM - P04141 were inserted into the murine hemopoietic continuous cell lines Ba / P13726 or P18627 - P1 and sublines selected that were then responsive to proliferative stimulation by these growth factors . When used in microwell assays the Ba / P13726 Q99062 - expressing cell line was able to detect 100 pg G - P04141 per ml , the Ba / P13726 P09603 receptor - expressing cell line 100 - 400 pg P09603 per ml and the P18627 - P1 line expressing the alpha - and beta - chains of the human GM - P04141 receptor detected 5 - 10 pg / ml of GM - P04141 in test material . These cell lines appear satisfactory for use as selective bioassays for these colony stimulating factors in material potentially containing a mixture of growth factors .", "DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .", "Evidence for the ligand - induced conversion from a dimer to a tetramer of the granulocyte colony - stimulating factor receptor . An extracellular portion of granulocyte colony - stimulating factor ( DB00099 ) receptor , which contains an immunoglobulin - like ( Ig ) domain and cytokine receptor homologous ( P06850 ) region , was secreted into the medium using Trichoplusia ni - Autographa californica nuclear polyhedrosis virus system . The gene product was purified to homogeneity mainly as a dimer ( 85 kDa ) using G - P04141 affinity column chromatography and gel filtration HPLC , although the product existed as a monomer ( 45 kDa ) in the medium . Scatchard analyses suggested that only the dimer had high affinity ligand binding ( Kd = about 100 pM ) , which is comparable with the Kd value of the cell surface receptor . The binding of G - P04141 to Ig - P06850 induced its tetramerization ( 200 - 250 kDa ) . The molecular composition of the tetrameric complex showed a stoichiometry of four ligands bound to four Ig - P06850 . These results suggested that the oligomeric mechanism of the Q99062 differs from that reported for growth hormone ( GH ) receptor , although CD spectrum spectroscopy suggested that the Ig - P06850 has a P10912 - like structure .", "High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK7___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .", "Q99062 mutations in patients with severe congenital neutropenia do not abrogate Jak2 activation and stat1 / stat3 translocation . Severe congenital neutropenia ( SCN ) is an inherited disorder of myelopoiesis , characterized by a maturation arrest at the stage of promyelocytes and myelocytes in bone marrow , and absence or low levels of mature neutrophil granulocytes in peripheral blood . Recently , studies of patients with SCN who subsequently developed acute myeloid leukemia ( AML ) revealed nonsense mutations in the cytoplasmic domain of the granulocyte colony - stimulating factor ( DB00099 ) receptor messenger RNA . We focused our interest on the G - P04141 - mediated signaling cascade to examine the consequences of the observed point mutations for the nuclear translocation of the transcription factors Stat1 and Stat3 . Expression vectors encoding for truncated G - P04141 receptors were transfected in the murine fibroblast cell line C243 expressing a fusion protein consisting of the transcription factor Stat1 and Stat3 , respectively , and the green fluorescent protein ( GFP ) . Nuclear translocation of the GFP fusion proteins was examined after G - P04141 stimulation of the transfected cells .", "Immunoreceptor tyrosine - based inhibitory motifs on activating molecules . Immunoreceptor tyrosine - based inhibitory motifs ( ITIMs ) have the restricted consensus sequence V / I / xYxxL / V , but may be more broadly defined by the sequence V / I / L / SxYxxL / V / I / S . If one includes the ITIM of P16410 , then the sequence becomes psixYxxpsi , where psi represents amino acids with nonpolar side chains . Aside from their presence in various inhibitory molecules , ITIMs are also found on many activating receptors and pathways . ITIMs with the restricted consensus sequence occur on IL - 4Ralpha , IL - 3Rbeta type II , P40189 cytokineR , P48357 ( leptinR ) , P15018 - Rbeta P19438 , Q99062 , PDGF - R , Blk , Ctk / Ntk , Lsk , Zap - 70 , P31749 / RACalpha , P17252 , P05771 , P05129 , PKC - delta , PKC - zeta , PKC - epsilon , PKC - eta , PKC - phi , PKC - mu , calmodulin - dependent kinase IIdelta , SLP - 76 - associated protein , O15117 , Shc binding protein , RasGRF2 , Q13972 homologue , Jak2 , Jak3 , PLCbeta1 , and PLCbeta3 . If ITIMs are defined by a broader consensus sequence , the list of ITIMs on activating molecules becomes even larger . In some instances , these ITIMs have been shown to associate with inhibitory phosphatases . Whether these ITIMs on activating receptors / pathways are necessary and sufficient for negative control of activating events and for immunologic tolerance is not yet known . In some instances , ITIMs on coinhibitory receptors are also required for appropriate negative regulation . By studying events leading to negative control during activation and to immunologic tolerance , it should be possible to discern the balance between antigen receptor - based negative events and coinhibition .", "Methylation markers for small cell lung cancer in peripheral blood leukocyte DNA . INTRODUCTION : Small cell lung cancer ( SCLC ) is the most aggressive form of lung malignancy . METHODS : To identify and validate potential DNA methylation markers for risk assessment and disease detection , we examined peripheral blood leukocyte DNA specimens for methylation differences between SCLC cases and controls . We tested 1505 CpG sites using the Illumina Beadchip assay and validated 9 CpG sites using pyrosequencing technology . RESULTS : In 44 matched SCLC case - control pairs , we identified significant differences at 62 CpG sites ( false discovery rate < or = 0 . 05 ) in 52 independent genes . Of those , we further determined 43 sites in 36 genes with a mean methylation level difference greater than 0 . 03 between the cases and controls . We then selected and validated 9 CpG sites for methylation differences in an independent set of 138 matched case - control pairs . The 9 validated CpG sites predicted a higher risk for cases than controls in 85 . 8 % of all pairs of cases and controls , and 2 ( in genes Q99062 and P07992 ) jointly contributed most of the discriminating ability . CONCLUSIONS : Our replicated results demonstrated feasibility of applying large - scale methylation arrays for biomarker discovery and subsequent validation in peripheral blood DNA . The CpG sites identified in this study may potentially assist in risk prediction and diagnosis of SCLC .", "Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK47___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .", "Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony - stimulating factor receptor gene associated with severe chronic neutropenia . Mutations in the granulocyte colony - stimulating factor ( DB00099 ) receptor gene are found in a number of patients with severe chronic neutropenia predisposed to acute myeloid leukemia . These mutations result in the absence of the C - terminal domain of the Q99062 , a region which has been implicated in differentiation signaling . We generated mice with an equivalent mutation ( gcsfr - triangle Delta715 ) by homologous and Cre - mediated recombination in embryonic stem cells . Both wt / triangle Delta715 and triangle Delta715 / triangle Delta715 mice have significantly reduced numbers of blood neutrophils compared with their wt / wt littermates . However , under continuous G - P04141 administration mutant mice develop peripheral neutrophil counts that significantly exceed those of wild - type littermates . These findings indicate that depending on G - P04141 levels in mice , the triangle Delta715 mutation can contribute both to neutropenia and to neutrophilia .", "Cost - effectiveness of P22309 genotyping in second - line , high - dose , once every 3 weeks irinotecan monotherapy treatment of colorectal cancer . AIM : The aim of the present study was to evaluate the cost - effectiveness of P22309 genotyping in second - line , high - dose , once every 3 weeks irinotecan monotherapy treatment of colorectal cancer . METHODS : Standard therapy was compared with alternative strategies based on P22309 genotyping from the US healthcare payer perspective . Two alternative strategies ( dose reduction and prophylactic use of G - P04141 with prior genotyping ) and standard therapy were evaluated in a decision analysis , whereas alternative regimens were considered in discussion . The effectiveness outcome was severe neutropenia occurrence and number of life - years gained . RESULTS & CONCLUSION : Genotyping in combination with a subsequent reduction of initial irinotecan dose for P22309 7 / 7 genotype patients was cost - saving for the population of African and Caucasian origin . By contrast , P22309 genotyping was not cost effective for the population of Asian ancestry . Furthermore , the prophylactic use of G - CSFs in P22309 7 / 7 genotype patients was not cost effective in any population group . Finally , the application of a 3 - weekly high - dose treatment regimen with a 20 % reduced dosage compared with the low - dose weekly irinotecan regimen in patients with P22309 7 / 7 genotype was less expensive and is more convenient for the patient .", "Expression of the Evi - 1 zinc finger gene in 32Dc13 myeloid cells blocks granulocytic differentiation in response to granulocyte colony - stimulating factor . Expression of the Evi - 1 gene is frequently activated in murine myeloid leukemias by retroviral insertions immediately 5 ' or 90 kb 5 ' of the gene . The Evi - 1 gene product is a nuclear , DNA - binding zinc finger protein of 145 kDa . On the basis of the properties of the myeloid cell lines in which the Evi - 1 gene is activated , it has been hypothesized that its expression blocks normal differentiation . To explore this proposed role , we have constructed a retrovirus vector containing the gene and examined its effects on an interleukin - 3 - dependent myeloid cell line that differentiates in response to granulocyte colony - stimulating factor ( DB00099 ) . Expression of the Evi - 1 gene in these cells did not alter the normal growth factor requirements of the cells . However , expression of the Evi - 1 gene blocked the ability of the cells to express myeloperoxidase and to terminally differentiate to granulocytes in response to DB00099 . This effect was not due to altered expression of the Q99062 or to changes in the initial responses of the cells to DB00099 . These results support the hypothesis that the inappropriate expression of the Evi - 1 gene in myeloid cells interferes with the ability of the cells to terminally differentiate ." ]

[ "___MASK22___", "___MASK47___", "___MASK50___", "___MASK56___", "___MASK60___", "___MASK62___", "___MASK73___", "___MASK7___", "___MASK92___" ]

[ "Pharmacological approach to acute pancreatitis . The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis ( AP ) based on experimental animal models and clinical trials . Somatostatin ( SS ) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis ( PEP ) . The protease inhibitor gabexate mesilate ( GM ) is used routinely as treatment to AP in some countries , but randomized clinical trials and a meta - analysis do not support this practice . Nitroglycerin ( P04626 ) is a nitrogen oxide ( NO ) donor , which relaxes the sphincter of Oddi . Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted . Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials . The non - steroidal anti - inflammatory drugs ( NSAID ) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP . Interleukin 10 ( P22301 ) is a cytokine with anti - inflammatory properties but two trials testing P22301 as prophylaxis to PEP have returned conflicting results . Antibodies against tumor necrosis factor - alpha ( P01375 ) have a potential as rescue therapy but no clinical trials are currently being conducted . The antibiotics beta - lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis . Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti - inflammatory drugs are warranted .", "Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .", "Predictive factors for response to docetaxel in human breast cancers . DB01248 has come into wide use recently for the treatment of breast cancer in neoadjuvant , adjuvant and metastatic settings . DB01248 binds to beta - tubulin and causes kinetic abnormalities in the dynamics of microtubules by increasing their polymerization and inhibiting their depolymerization , resulting in elevated levels of microtubule formation . During metaphase , defective spindle formation induced by docetaxel activates the mitotic checkpoint and leads to cell cycle arrest , culminating in apoptosis . However , docetaxel is not effective for all breast cancers . For example , in metastatic settings , the response rate to docetaxel reportedly ranges from 30 to 50 % . It is therefore very important to develop a diagnostic method with high accuracy for the prediction of sensitivity to docetaxel in order to avoid unnecessary treatment . Currently it is impossible to identify , before the initiation of therapy , the patients for whom docetaxel will be effective . Various biological parameters have been studied clinically for their ability to predict response to docetaxel , such as parameters related to : ( 1 ) efflux ( p - glycoprotein ) and metabolism ( P08684 ) ; ( 2 ) beta - tubulin ( somatic mutation of beta - tubulin and changes in beta - tubulin isotypes levels ) ; ( 3 ) cell cycle ( P04626 , P38398 and Aurora - A ) ; and ( 4 ) apoptosis ( p53 , P10415 and thioredoxin ) . More recently , gene expression profiling techniques have been used for the development of a prediction model for response to docetaxel . In the present paper , clinical studies that have been conducted recently to identify predictive factors for response to docetaxel are reviewed together with a presentation of our recent work in this field .", "___MASK29___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK29___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK29___ is a promising pharmacological tool in the treatment of renal edema .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "miR - 125b and miR - 155 contribute to P10415 repression and proliferation in response to P29965 ( CD154 ) in human leukemic B - cells . Developmental stage - specific regulation of P10415 occurs during B - cell maturation and has a role in normal immunity . P25942 signaling promotes proliferation and rescues B - cells from apoptosis , partly through induction of Q07817 and Q16548 and repression of P10415 . We previously showed that a stromal cell / P29965 ( CD154 ) culture system reproduced this switch in survival protein expression in primary human leukemic B - cells and we employed this model system to investigate P10415 repression . P10415 was post - transcriptionally regulated and the repressed P10415 mRNA was associated with non - polysomal , but dense fractions on sucrose density gradients . Microarrays identified a set of miRNA that were induced by culture conditions and potentially able to bind to the P10415 3 '- UTR . Luciferase reporter assays demonstrated that miR - 125b and miR - 155 repressed P10415 mRNA but while stromal cell contact alone was sufficient to induce strongly miR - 125b this did not cause P10415 repression . miR - 155 , which is the most abundant miRNA under basal conditions , specifically required CD154 for further induction above a threshold to exert its full repressive effects . Anti - miR - 125b and anti - miR - 155 prevented CD154 - mediated repression of P10415 and reduced CD154 - mediated proliferation in the MEC1 B - cell line . We suggest that miR - 155 and miR - 125b , which are induced by CD154 and stromal cell signals , contribute to regulating proliferation and that P10415 is one of their target mRNAs .", "Expression Enhancement in DB00072 Therapeutic Monoclonal Antibody Production using Genomic Amplification with ___MASK3___ . BACKGROUND : DB00072 ( Herceptin ) is a humanized monoclonal antibody ( mAb ) which is used for specific treatment of metastatic breast cancer in patients with overexpression of P04626 / neu receptor . In this study , we have attempted to develop a biosimilar version of trastuzumab mAb . METHODS : According to in silico studies , the heavy and light chains of trastuzumab mAb were designed and constructed . The recombinant constructs were co - transfected in CHO DG44 cell line . Stable transformants were selected on a semi solid medium . Genomic amplification with methotrexate was achieved for heavy chain gene amplification . Biological activity of produced antibody in comparison with Herceptin was tested by flow cytometry method . RESULTS : Three folds of amplification were obtained after seven rounds of methotrexate treatments . The results indicated the equal expression level of heavy and light chains . The yield of purified mAb was between 50 to 60 mg / l / day . According to the results , the produced mAb had similar affinity to P04626 (+) tumor cells to that of Herceptin . CONCLUSION : High - level recombinant protein expression can be achieved by amplification of the recombinant gene with a selectable marker , such as Dihydrofolate Reductase ( P00374 ) . It is usually accepted that P00374 gene can be amplified in P00374 (－) CHO cells , which consequently leads to amplification of the co - linked target gene , and finally amplification of recombinant protein . In this research , with the aim of producing a biosimilar version of herceptin , the effect of genomic amplification was investigated on the increasing the gene copy number using quantitative real - time PCR .", "Prevention and treatment of pancreatic cancer by curcumin in combination with omega - 3 fatty acids . Pancreatic cancer BxPC - 3 cells were exposed to curcumin , docosahexaenoic acid ( DB01708 ) , or combinations of both and analyzed for proliferation and apoptosis . Pancreatic tumor xenografts were established by injecting BxPC - 3 cells into each flank of nude mice . After the tumors reached a size of approximately 190 - 200 mm ( 3 ) , animals were fed diets with or without 2 , 000 ppm curcumin in 18 % corn oil or 15 % fish oil + 3 % corn oil for 6 more wk before assessing the tumor volume and expression of inducible nitric oxide synthase ( P35228 ) , cyclooxygeanse - 2 ( P35354 ) , 5 - lipoxinase ( 5 - P28300 ) , and P38936 . A synergistic effect was observed on induction of apoptosis ( approximately sixfold ) and inhibition of cell proliferation ( approximately 70 % ) when cells were treated with curcumin ( 5 microM ) together with the DB01708 ( 25 microM ) . Mice fed fish oil and curcumin showed a significantly reduced tumor volume , 25 % ( P < 0 . 04 ) and 43 % ( P < 0 . 005 ) , respectively , and importantly , a combination of curcumin and fish oil diet showed > 72 % ( P < 0 . 0001 ) tumor volume reduction . Expression and activity of P35228 , P35354 , and 5 - P28300 are downregulated , and P38936 is upregulated in tumor xenograft fed curcumin combined with fish oil diet when compared to individual diets . The preceding results evidence for the first time that curcumin combined with omega - 3 fatty acids provide synergistic pancreatic tumor inhibitory properties .", "The human SWI / SNF complex associates with Q01196 to control transcription of hematopoietic target genes . The acute myeloid leukemia 1 ( Q01196 , Q01196 ) transcription factor is a key regulator of hematopoietic differentiation that forms multi - protein complexes with co - regulatory proteins . These complexes are assembled at target gene promoters in nuclear microenvironments to mediate phenotypic gene expression and chromatin - related epigenetic modifications . Here , immunofluorescence microscopy and biochemical assays are used to show that Q01196 associates with the human DB00171 - dependent SWI / SNF chromatin remodeling complex . The SWI / SNF subunits P51532 and Q12824 bind in vivo to Q01196 target gene promoters ( e . g . , P04141 , P08700 , P09603 - R , MIP , and P38936 ) . These interactions correlate with histone modifications characteristic of active chromatin , including acetylated H4 and dimethylated H3 lysine 4 . Downregulation of Q01196 by RNA interference diminishes the binding of P51532 and Q12824 at selected target genes . Taken together , our findings indicate that Q01196 interacts with the human SWI / SNF complex to control hematopoietic - specific gene expression .", "Linkage of cytokine genes to rheumatoid arthritis . Evidence of genetic heterogeneity . OBJECTIVE : To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis ( RA ) in affected sibling pair families stratified for specific clinical features . METHOD : Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from : P27352 alpha , P27352 gamma , P27352 beta , IL1 alpha , IL1 beta , P14778 , P60568 , P05231 , Q01344 , IL8R , P10415 , P29965 , NOS3 , P49279 , alpha 1 anti - trypsin , and alpha 1 anti - chymotrypsin , using fluorescence based automated technology . Linkage was examined by defining allele sharing sibling pairs . This was assessed by maximum likelihood - inheritance by descent methods . RESULTS : An increase in allele sharing was seen for Q01344 in female sibling pairs ( LOD 0 . 91 , p = 0 . 03 ) , for P27352 gamma in sibling pairs with an affected male ( LOD 0 . 96 , p = 0 . 03 ) and most significantly for P60568 in sibling pairs where one or both were persistently seronegative ( LOD 1 . 05 , p = 0 . 02 ) . CONCLUSION : Weak evidence of linkage of RA to Q01344 , IFN gamma , and P60568 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease .", "Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK35___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK35___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .", "P41134 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of P38936 . To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance , we compared the gene expression profiles in high - risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy . Among the molecular signatures associated with chemotherapy , transcripts encoding inhibitor of DNA binding 1 ( P41134 ) were significantly upregulated . The patient biochemical relapse status was monitored in a long - term follow - up . Patients with P41134 upregulation were found to be associated with longer relapse - free survival than patients without P41134 increase . This in vivo clinical association was mechanistically investigated . The chemotherapy - induced P41134 upregulation was recapitulated in the prostate cancer cell line LNCaP . DB01248 dose - dependently induced P41134 transcription , which was mediated by P41134 promoter E - box chromatin modification and c - Myc binding . Stable P41134 overexpression in LNCaP increased cell proliferation , promoted G ( 1 ) cell cycle progression , and enhanced docetaxel - induced cytotoxicity . These changes were accompanied by a decrease in cellular mitochondria content , an increase in P10415 phosphorylation at serine 70 , caspase - 3 activation , and poly ( ADP - ribose ) polymerase cleavage . In contrast , P41134 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel - induced cytotoxicity by inhibiting cell death . P41134 - mediated chemosensitivity enhancement was in part due to P41134 suppression of P38936 . Overexpression of P38936 in LNCaP - P41134 - overexpressing cells restored the P38936 level and reversed P41134 - enhanced chemosensitivity . These molecular data provide a mechanistic rationale for the observed in vivo clinical association between P41134 upregulation and relapse - free survival . Taken together , it shows that P41134 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis .", "Carcinomatous meningitis : Leptomeningeal metastases in solid tumors . Leptomeningeal metastasis ( LM ) results from metastatic spread of cancer to the leptomeninges , giving rise to central nervous system dysfunction . Breast cancer , lung cancer , and melanoma are the most frequent causes of LM among solid tumors in adults . An early diagnosis of LM , before fixed neurologic deficits are manifest , permits earlier and potentially more effective treatment , thus leading to a better quality of life in patients so affected . Apart from a clinical suspicion of LM , diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid ( P04141 ) or radiographic manifestations as revealed by neuraxis imaging . Potentially of use , though not commonly employed , today are use of biomarkers and protein profiling in the P04141 . Symptomatic treatment is directed at pain including headache , nausea , and vomiting , whereas more specific LM - directed therapies include intra - P04141 chemotherapy , systemic chemotherapy , and site - specific radiotherapy . A special emphasis in the review discusses novel agents including targeted therapies , that may be promising in the future management of LM . These new therapies include anti - epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer , anti - P04626 monoclonal antibody trastuzumab in breast cancer , anti - P16410 ipilimumab and anti - P15056 tyrosine kinase inhibitors such as vermurafenib in melanoma , and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM . Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra - P04141 drug therapy .", "c - P05412 promotes P11274 - P00519 - induced lymphoid leukemia by inhibiting methylation of the 5 ' region of Cdk6 . The transcription factor c - P05412 and its upstream kinase P45983 have been implicated in P11274 - P00519 - induced leukemogenesis . P45983 has been shown to regulate P10415 expression , thereby altering leukemogenesis , but the impact of c - P05412 remained unclear . In this study , we show that P45983 and c - P05412 promote leukemogenesis via separate pathways , because lack of c - P05412 impairs proliferation of p185 ( P11274 - P00519 )- transformed cells without affecting their viability . The decreased proliferation of c - Jun ( Δ / Δ ) cells is associated with the loss of cyclin - dependent kinase 6 ( Q00534 ) expression . In c - Jun ( Δ / Δ ) cells , Q00534 expression becomes down - regulated upon P11274 - P00519 - induced transformation , which correlates with CpG island methylation within the 5 ' region of Cdk6 . We verified the impact of Cdk6 deficiency using Cdk6 (-/-) mice that developed P11274 - P00519 - induced B - lymphoid leukemia with significantly increased latency and an attenuated disease phenotype . In addition , we show that reexpression of Q00534 in P11274 - P00519 - transformed c - Jun ( Δ / Δ ) cells reconstitutes proliferation and tumor formation in Nu / Nu mice . In summary , our study reveals a novel function for the activating protein 1 ( AP - 1 ) transcription factor c - P05412 in leukemogenesis by antagonizing promoter methylation . Moreover , we identify Q00534 as relevant and critical target of AP - 1 - regulated DNA methylation on P11274 - P00519 - induced transformation , thereby accelerating leukemogenesis .", "Stress response genes are suppressed in mouse preimplantation embryos by granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) . BACKGROUND : P04141 ( GM - P04141 ) is known to promote the development and survival of human and mouse preimplantation embryos ; however , the mechanism of action of GM - P04141 in embryos is not defined . METHODS : Mouse blastocysts were cultured from zygote stage in vitro with and without recombinant mouse GM - P04141 ( rmGM - P04141 ) , and in vivo developed blastocysts were flushed from Csf2 null mutant and wild - type mice . The effect of GM - P04141 on blastocyst expression of stress response and apoptosis genes was evaluated by microarray , qPCR and immunochemistry . RESULTS : Microarray analysis of the gene transcription profile showed suppression of stress response and apoptosis gene pathways in blastocysts exposed to rmGM - P04141 in vitro . qPCR analysis confirmed that rmGM - P04141 inhibited expression of heat shock protein ( HSP ) and apoptosis pathway genes Cbl , Hspa5 , Hsp90aa1 , Hsp90ab1 and Gas5 in in vitro blastocysts . Immunocytochemical analysis of HSP 1 ( P0DMV8 / 1B ; HSP70 ) , Q07812 , P10415 and TRP53 ( p53 ) in in vitro blastocysts showed that P0DMV8 / 1B and P10415 proteins were less abundant when embryos were cultured with rmGM - P04141 . Q07812 and TRP53 were unchanged at the protein level , but Bax mRNA expression was reduced after GM - P04141 treatment . In in vivo developed blastocysts , Csf2 null mutation caused elevated expression of Hsph1 but not other stress response genes . CONCLUSIONS : We conclude that GM - P04141 inhibits the cellular stress response and apoptosis pathways to facilitate embryo growth and survival , and the protective effects of GM - P04141 are particularly evident in in vitro culture media , whereas in vivo other cytokines can partly compensate for absence of GM - P04141 .", "Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK11___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .", "Effect of valproic acid through regulation of DB01221 receptor - P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg / kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic - like animal model , focusing on the N - methyl - D : - aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal - regulated protein kinase ( P29323 ) , DB02527 response element - binding protein ( CREB ) , B cell chronic lymphocytic leukemia / lymphoma 2 ( P10415 ) , and brain - derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD - induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD - induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor - P29323 signaling in SD rats , preventing the SD - induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 .", "Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered .", "Stress - response pathways are altered in the hippocampus of chronic alcoholics . The chronic high - level alcohol consumption seen in alcoholism leads to dramatic effects on the hippocampus , including decreased white matter , loss of oligodendrocytes and other glial cells , and inhibition of neurogenesis . Examining gene expression in post mortem hippocampal tissue from 20 alcoholics and 19 controls allowed us to detect differentially expressed genes that may play a role in the risk for alcoholism or whose expression is modified by chronic consumption of alcohol . We identified 639 named genes whose expression significantly differed between alcoholics and controls at a False Discovery Rate ( FDR ) ≤ 0 . 20 ; 52 % of these genes differed by at least 1 . 2 - fold . Differentially expressed genes included the glucocorticoid receptor and the related gene FK506 binding protein 5 ( Q13451 ) , UDP glycosyltransferase 8 ( Q16880 ) , urea transporter ( Q13336 ) , zinc transporter ( Q9ULF5 ) , Interleukin 1 receptor type 1 ( P14778 ) , thioredoxin interacting protein ( Q9H3M7 ) , and many metallothioneins . Pathways related to inflammation , hypoxia , and stress showed activation , and pathways that play roles in neurogenesis and myelination showed decreases . The cortisol pathway dysregulation and increased inflammation identified here are seen in other stress - related conditions such as depression and post - traumatic stress disorder and most likely play a role in addiction . Many of the detrimental effects on the hippocampus appear to be mediated through NF - κB signaling . Twenty - four of the differentially regulated genes were previously identified by genome - wide association studies of alcohol use disorders ; this raises the potential interest of genes not normally associated with alcoholism , such as suppression of tumorigenicity 18 ( O60284 ) , P10415 - associated athanogene 3 ( O95817 ) , and P04275 ( P04275 ) .", "Gq - mediated Akt translocation to the membrane : a novel PIP3 - independent mechanism in platelets . Akt is an important signaling molecule regulating platelet aggregation . Akt is phosphorylated after translocation to the membrane through Gi signaling pathways by a phosphatidylinositol - 3 , 4 , 5 - trisphosphate ( PIP3 ) - dependent mechanism . However , Akt is more robustly phosphorylated by thrombin compared with adenosine 5 '- diphosphate in platelets . This study investigated the mechanisms of Akt translocation as a possible explanation for this difference . Stimulation of washed human platelets with protease - activated receptor agonists caused translocation of Akt to the membrane rapidly , whereas phosphorylation occurred later . The translocation of Akt was abolished in the presence of a Gq - selective inhibitor or in Gq - deficient murine platelets , indicating that Akt translocation is regulated downstream of Gq pathways . Interestingly , phosphatidylinositol 3 - kinase ( PI3K ) inhibitors or Q9H244 antagonist abolished Akt phosphorylation without affecting Akt translocation to the membrane , suggesting that Akt translocation occurs through a PI3K / PIP3 / Gi - independent mechanism . An Akt scaffolding protein , P38936 - activated kinase ( PAK ) , translocates to the membrane after stimulation with protease - activated receptor agonists in a Gq - dependent manner , with the kinetics of translocation similar to that of Akt . Coimmunoprecipitation studies showed constitutive association of PAK and Akt , suggesting a possible role of PAK in Akt translocation . These results show , for the first time , an important role of the Gq pathway in mediating Akt translocation to the membrane in a novel Gi / PI3K / PIP3 - independent mechanism .", "Anti - tumor effect of rutin on human neuroblastoma cell lines through inducing G2 / M cell cycle arrest and promoting apoptosis . AIMS : To further investigate the antineuroblastoma effect of rutin which is a type of flavonoid . METHODS : The antiproliferation of rutin in human neuroblastoma cells LAN - 5 were detected by 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide ( MTT ) assay . Chemotaxis of LAN - 5 cells was assessed using transwell migration chambers and scratch wound migration assay . The cell cycle arrest and apoptosis in a dose - dependent manner was measured by flow cytometric and fluorescent microscopy analyses . The apoptosis - related proteins Q07812 and P10415 as well as P04198 mRNA express were determined by RT - PCR analysis . Secreted P01375 - α level were determined using specific enzyme - linked immunosorbent assay kits . RESULTS : DB01698 significantly inhibited the growth of LAN - 5 cells and chemotactic ability . Flow cytometric analysis revealed that rutin induced G2 / M arrest in the cell cycle progression and induced cell apoptosis . The RT - PCR showed that rutin could decrease P10415 expression and P10415 / Q07812 ratio . In the meantime , the P04198 mRNA level and the secretion of P01375 - α were inhibited . CONCLUSION : These results suggest that rutin produces obvious antineuroblastoma effects via induced G2 / M arrest in the cell cycle progression and induced cell apoptosis as well as regulating the expression of gene related to apoptosis and so on . It supports the viability of developing rutin as a novel therapeutic prodrug for neuroblastoma treatment , as well as providing a new path on anticancer effect of Chinese traditional drug .", "Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .", "Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non - small - cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 / neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 / RARα for all - trans - retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .", "Intracellular signaling of the aging suppressor protein Q9UEF7 . The Q9UEF7 protein deficiency is known to participate in premature aging . As an aging suppressor , Q9UEF7 is an important molecule in aging processes and its overexpression results in longevity . Due to many reasons , the insulin / insulin - like growth factor - 1 ( DB01277 ) has been considered as a key pathway in aging research . The Q9UEF7 gene is closely related to this pathway . The Q9UEF7 gene encodes a transmembrane protein that after cleavage is also found as a secreted protein . Importantly , its overexpression suppresses insulin / DB01277 signaling and thus extends the lifespan . In addition , Q9UEF7 participates in the regulation of several other intracellular signaling pathways , including regulation of Q9GZV9 signaling , DB02527 , PKC , transforming growth factor - β ( TGF - β ) , p53 / P38936 , and Wnt signaling . The aim of this review is to summarize current literature that shows the involvement of Q9UEF7 in the regulation of several intracellular pathways . The results of our review clearly indicate that Q9UEF7 participates in several intracellular signaling pathways , and by regulating them , Q9UEF7 is involved in aging and longevity .", "Invasive Lobular Carcinomas Do Not Express Basal Cytokeratin Markers CK5 / 6 , CK14 and CK17 . The expression of basal cytokeratin markers CK5 / 6 in breast carcinomas has been associated with high histological grade and poor clinical outcome . A previous study has shown that CK5 / 6 can be detected in up to 17 % of invasive lobular carcinomas ( Q9Y4X3 ) . Here we study the expression of three basal cytokeratin markers ( CK5 / 6 , CK14 , and CK17 ) in 53 Q9Y4X3 cases diagnosed by histology and lack of P12830 expression . Among them , 42 were classic lobular carcinomas , 6 were tubular - lobular carcinoma , and 5 were pleomorphic lobular carcinomas . There was no significant difference among these three groups in patients ' age , tumor size , uni - and multi - focality , expression of ER and PR , lymphovascular invasion , perineural invasion and lymph node metastasis . The only statistically different factor was P04626 over - expression , which was observed only in pleomorphic Q9Y4X3 ( P = 0 . 0073 ) . None of the 53 cases expressed CK5 / 6 , CK14 or CK17 ; and 51 / 53 cases expressed luminal markers CK8 and CK18 , and the two negative cases were both classic lobular carcinoma , with positivity for ER and PR . In conclusion , all 53 cases of Q9Y4X3 failed to show expression by any of the three basal CK markers , suggesting that very few Q9Y4X3 will demonstrate a basal phenotype when assessed by immunohistochemistry ( IHC ) . More studies are needed to investigate molecular classification in lobular carcinoma of the breast .", "Patient age and biological aggressiveness of endometrial carcinoma . BACKGROUND : Advanced age is associated with a significantly worse prognosis of endometrial carcinoma patients . The aim of this study was to test whether age is a poor - risk factor in endometrial carcinoma because tumors arising in older patients are biologically different from those diagnosed in patients of an earlier age . MATERIALS AND METHODS : DB03843 - fixed , paraffin - embedded samples from 136 previously untreated patients with endometrial carcinoma were studied by means of immunohistochemistry . The expression of molecular markers associated with hormone responsiveness ( estrogen and progesterone receptors ) , proliferation ( Ki67 , C - ERB - B2 , p53 ) , invasiveness ( P12830 ) and apoptosis ( P10415 and p53 ) was analyzed . The obtained expression levels , together with all available clinical and pathological features were tested for correlations with the patients age and survival . RESULTS : Advanced patient age showed a direct correlation with tumor stage ( r = 0 . 29 , p = 0 . 0008 ) and mutant p53 expression ( r = 0 . 25 , p = 0 . 004 ) , and an inverse correlation with P12830 expression ( r =- 0 . 28 , p = 0 . 001 ) . Patient age above the 25th percentile ( 57 years ) of the age distribution was significantly associated with a worse prognosis ( p = 0 . 018 ) . CONCLUSION : It appears that with advancing age , endometrial carcinoma exhibits a more aggressive tumor phenotype , characterized by mutant p53 expression and down - regulation of P12830 expression , and that this , in its turn , results in tumors being diagnosed at a more advanced stage in older patients .", "Molecular systematics of armadillos ( Xenarthra , Dasypodidae ) : contribution of maximum likelihood and Bayesian analyses of mitochondrial and nuclear genes . The 30 living species of armadillos , anteaters , and sloths ( Mammalia : Xenarthra ) represent one of the three major clades of placentals . Armadillos ( Cingulata : Dasypodidae ) are the earliest and most speciose xenarthran lineage with 21 described species . The question of their tricky phylogeny was here studied by adding two mitochondrial genes ( P03886 [ P03886 ] and 12S ribosomal RNA [ 12S rRNA ] ) to the three protein - coding nuclear genes ( alpha2B adrenergic receptor [ P18089 ] , breast cancer susceptibility exon 11 [ P38398 ] , and P04275 exon 28 [ P04275 ] ) yielding a total of 6869 aligned nucleotide sites for thirteen xenarthran species . The two mitochondrial genes were characterized by marked excesses of transitions over transversions - with a strong bias toward CT transitions for the 12S rRNA - and exhibited two - to fivefold faster evolutionary rates than the fastest nuclear gene ( P18089 ) . Maximum likelihood and Bayesian phylogenetic analyses supported the monophyly of Dasypodinae , Tolypeutinae , and Euphractinae , with the latter two armadillo subfamilies strongly clustering together . Conflicting branching points between individual genes involved relationships within the subfamilies Tolypeutinae and Euphractinae . Owing to a greater number of informative sites , the overall concatenation favored the mitochondrial topology with the classical grouping of Cabassous and Priodontes within Tolypeutinae , and a close relationship between Euphractus and Chaetophractus within Euphractinae . However , low statistical support values associated with almost equal distributions of apomorphies among alternatives suggested that two parallel events of rapid speciation occurred within these two armadillo subfamilies .", "Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .", "Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK34___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .", "Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK32___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK32___ who were treated with a single dose of mifepristone .", "Autosomal - dominant hypophosphatemic rickets ( P30518 ) mutations stabilize Q9GZV9 . BACKGROUND : The gene for the renal phosphate wasting disorder autosomal - dominant hypophosphatemic rickets ( P30518 ) is Q9GZV9 , which encodes a secreted protein related to the fibroblast growth factors ( FGFs ) . We previously detected missense mutations R176Q , R179W , and R179Q in Q9GZV9 from P30518 kindreds . The mutations replace R residues within a subtilisin - like proprotein convertase ( Q969E3 ) cleavage site 176RHTR - 179 ( RXXR motif ) . The goal of these studies was to determine if the P30518 mutations lead to protease resistance of Q9GZV9 . METHODS : The P30518 mutations were introduced into human Q9GZV9 cDNA clones with or without an N - terminal FLAG tag by site - directed mutagenesis and were transiently transfected into HEK293 cells . Protein expression was determined by Western analyses . RESULTS : Antibodies directed toward the C - terminal portion of Q9GZV9 revealed that the native Q9GZV9 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media ; however , the three mutated proteins were detected only as the 32 kD band . An N - terminal FLAG - tagged native Q9GZV9 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody , whereas the R176Q mutant resolved primarily as the 36 kD protein species . Cleavage of Q9GZV9 was not enhanced by extracellular incubation of Q9GZV9 with HEK293 cells . Native and mutant FGF - 23s bound heparin . CONCLUSIONS : Q9GZV9 proteins containing the P30518 mutations are secreted , and produce polypeptides less sensitive to protease cleavage than wild - type Q9GZV9 . Therefore , the P30518 mutations may protect Q9GZV9 from proteolysis , thereby potentially elevating circulating concentrations of Q9GZV9 and leading to phosphate wasting in P30518 patients .", "Drug insight : Use of docetaxel in prostate and urothelial cancers . Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies , with two taxanes now in clinical use . Their mechanism of action against tumor cells is by alteration of microtubule dynamics , which causes cell - cycle arrest during mitosis . DB01248 binds to the microtubules with a higher affinity than paclitaxel , and over a broader range of cell - cycle activities . It has also been shown to promote apoptosis via P10415 phosphorylation . In hormone - refractory prostate cancer , docetaxel has been studied as both a single agent and in combination with estramustine , and in different treatment schedules , with demonstrated efficacy . Two phase III trials have confirmed a survival benefit , making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer . In urothelial cancer , docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens . A phase III trial comparing docetaxel and cisplatin to methotrexate , vinblastine , doxorubicin , and cisplatin was inferior when evaluating response rates and overall survival . More recent phase II trials combining docetaxel with two additional agents have shown promise , but confirmatory trials are needed .", "[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK71___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .", "___MASK71___ reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 receptor antagonists have been reported to exert anti - inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild - type C57BL / 6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg / kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet - neutrophil aggregates , neutrophil activation and P29965 expression on platelets . CLP - induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor - treated animals . Moreover , ticagrelor abolished CLP - provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet - neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 in septic mice . Our data indicate that ticagrelor can reduce CLP - induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis .", "___MASK3___ induces apoptosis through p53 / P38936 - dependent pathway and increases P12830 expression through downregulation of HDAC / Q15910 . ___MASK3___ ( MTX ) is a dihydrofolate reductase ( P00374 ) inhibitor widely used as an anticancer drug in different kinds of human cancers . Here we investigated the anti - tumor mechanism of MTX against non - small cell lung cancer ( NSCLC ) A549 cells . MTX not only inhibited in vitro cell growth via induction of apoptosis , but also inhibited tumor formation in animal xenograft model . RNase protection assay ( RPA ) and RT - PCR demonstrated its induction of p53 target genes including DR5 , P38936 , Puma and Noxa . Moreover , MTX promoted p53 phosphorylation at Ser15 and acetylaion at Lys373 / 382 , which increase its stability and expression . The apoptosis and inhibition of cell viability induced by MTX were dependent on p53 and , partially , on P38936 . In addition , MTX also increased P12830 expression through inhibition of histone deacetylase ( HDAC ) activity and downregulation of polycomb group protein enhancer of zeste homologue 2 ( Q15910 ) . Therefore , the anticancer mechanism of MTX acts through initiation of p53 - dependent apoptosis and restoration of P12830 expression by downregulation of HDAC / Q15910 .", "A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK70___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK70___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .", "___MASK28___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK28___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .", "___MASK3___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .", "Insights into cancer therapeutic design based on p53 and P50591 receptor signaling . Knowledge of the emerging pathways of cell death downstream of the p53 tumor suppressor and the P50591 death - inducing ligand is suggesting ways to improve therapeutic design in cancer . In contrast to its unique P55008 cell cycle arresting mechanism that is maintained by P38936 ( P38936 ) , there are signals transduced by p53 to multiple apoptotic effectors perhaps due to the importance of apoptosis in suppressing tumors . There is evidence for cytoplasmic as well as mitochondrial activation of caspases downstream of p53 , although in some cell lineages the signal ultimately involves the mitochondria . The P50591 signaling pathway appears promising for therapeutic development despite sharing some similarities with the toxic Fas and P01375 pathways , in terms of effector molecules and downstream signals . One of the key findings is the tissue specificity of cell death responses , a feature that could be exploited in strategies to widen the therapeutic window of combination cancer therapies . Efforts continue to develop p53 - targeted cancer therapy , and novel clues to enhance or block specific effectors may improve therapeutic design ." ]

[ "___MASK11___", "___MASK28___", "___MASK29___", "___MASK32___", "___MASK34___", "___MASK35___", "___MASK3___", "___MASK70___", "___MASK71___" ]

[ "Molecular targeted therapy in acute myeloid leukemia . The treatment of acute myeloid leukemia has not changed significantly over the last 40 years . Recent progress in understanding the biology of this disease and identification of driver mutations has ushered in a new era of molecular therapeutics . Although a number of molecular markers and pathways have been identified and may serve as potential therapeutic targets , the best studied amongst these include P07333 like tyrosine kinase 3 ( P36888 ) , DB01367 / RAF / MEK / P29323 and Janus kinase ( O60674 ) . In this review we discuss the molecular biology of AML , with a special focus on the above mentioned pathways . We discuss novel molecular targeted therapies that are in preclinical and clinical development . These include AC - 220 , sorafenib and midostaurin in P36888 mutated patients ; GSK1120212 and MSC1936369B in DB01367 mutated patients ; and ___MASK31___ in O60674 mutated patients . Identification of such molecular mutations and appropriate use of targeted therapies , either alone or in combinations , may eventually revolutionize the treatment of AML .", "Des - γ - carboxy prothrombin ( P12821 ) as a potential autologous growth factor for the development of hepatocellular carcinoma . Des - γ - carboxy prothrombin ( P12821 ) is a prothrombin precursor produced in hepatocellular carcinoma ( HCC ) . Because of deficiency of vitamin K or γ - glutamyl carboxylase in HCC cells , the 10 glutamic acid ( DB00142 ) residues in prothrombin precursor did not completely carboxylate to γ - carboxylated glutamic acid ( Gla ) residues , leaving some DB00142 residues remained in N - terminal domain . These prothrombin precursors with DB00142 residues are called DCPs . P12821 displays insufficient coagulation activity . Since Liebman reported an elevated plasma P12821 in patients with HCC , P12821 has been used in the diagnosis of HCC . Recently , its biological malignant potential has been specified to describe P12821 as an autologous growth factor to stimulate HCC growth and a paracrine factor to integrate HCC with vascular endothelial cells . P12821 was found to stimulate HCC growth through activation of the P12821 - DB00134 - P23458 - P40763 signaling pathway . P12821 might increase HCC invasion and metastasis through activation of matrix metalloproteinase ( MMPs ) and the P27361 / 2 MAPK signaling pathway . P12821 has also been found to play a crucial role in the formation of angiogenesis . P12821 could increase the angiogenic factors released from HCC and vascular endothelial cells . These effects of P12821 in angiogenesis might be related to activation of the P12821 - P35968 - P98160 - γ - MAPK signaling pathway . In this article , we summarized recent studies on P12821 in biological roles related to cancer progression and angiogenesis in HCC .", "Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .", "[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK14___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .", "DB08875 : a review of its use in patients with medullary thyroid cancer . DB08875 ( Cometriq (®) ) is an orally administered small molecule inhibitor of multiple tyrosine kinase receptors , including those involved in the pathogenesis of medullary thyroid cancer ( P04629 ) [ i . e . rearranged during transfection ( P07949 ) , MET and vascular endothelial growth factor receptor ( VEGFR ) - 2 ] . DB08875 is indicated for the treatment of adults with progressive , unresectable locally advanced ( in the EU ) or metastatic ( in the EU and USA ) P04629 . Compared with placebo , cabozantinib significantly prolonged progression - free survival , reflecting a 72 % reduction in the risk of disease progression or death , in patients with unresectable , locally advanced or metastatic P04629 participating in a multinational , phase III study . A significantly higher proportion of patients receiving cabozantinib than those receiving placebo achieved an objective response or disease stabilization ( i . e . a complete or partial response , or stable disease ) . The overall survival benefit with cabozantinib is as yet unclear , with no significant benefit observed in two interim analyses ( one prespecified , and one unplanned and conducted at the request of the US FDA ) . The tolerability profile of oral cabozantinib is typical for a small molecule targeting the VEGFR and other tyrosine kinase - mediated pathways , with adverse events associated with the inhibition of the P15692 pathway ( e . g . gastrointestinal perforation , haemorrhage , hypertension and venous thrombosis ) reported in the phase III study . Treatment - emergent adverse events were generally managed with supportive therapy , dose reductions and / or dose interruptions . Although final overall survival data are awaited , current evidence suggests cabozantinib to be a valuable treatment option for adults with progressive , unresectable locally advanced or metastatic P04629 .", "DB08875 inhibits growth of androgen - sensitive and castration - resistant prostate cancer and affects bone remodeling . DB08875 is an inhibitor of multiple receptor tyrosine kinases , including MET and P35968 . In a phase II clinical trial in advanced prostate cancer ( PCa ) , cabozantinib treatment improved bone scans in 68 % of evaluable patients . Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone - sensitive and castration - resistant PCa in preclinical models while delineating its effects on tumor and bone . Using immunohistochemistry and tissue microarrays containing normal prostate , primary PCa , and soft tissue and bone metastases , our data show that levels of MET , P - MET , and P35968 are increasing during PCa progression . Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases . To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen - sensitive LuCaP 23 . 1 and castration - resistant C4 - 2B PCa tumors . In vivo , cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors . Furthermore , cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume . In summary , the expression pattern of cabozantinib targets in primary and castration - resistant metastatic PCa , and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease .", "Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .", "Response to DB08875 in patients with P07949 fusion - positive lung adenocarcinomas . The discovery of P07949 fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes . In an unselected population of non - small cell lung carcinomas ( NSCLCs ) , P07949 fusions are present in 1 % to 2 % of cases . This incidence increases substantially , however , in never - smokers with lung adenocarcinomas that lack other known driver oncogenes . Although preclinical data provide experimental support for the use of P07949 inhibitors in the treatment of P07949 fusion - positive tumors , clinical data on response are lacking . We report preliminary data for the first three patients treated with the P07949 inhibitor cabozantinib on a prospective phase II trial for patients with P07949 fusion - positive NSCLCs ( NCT01639508 ) . Confirmed partial responses were observed in 2 patients , including one harboring a novel Q9UPN9 - P07949 fusion . A third patient with a P33176 - P07949 fusion has had prolonged stable disease approaching 8 months ( 31 weeks ) . All three patients remain progression - free on treatment .", "Sustained vascular endothelial growth factor delivery enhances angiogenesis and perfusion in ischemic hind limb . PURPOSE : We hypothesized that sustained delivery of vascular endothelial growth factor ( P15692 ) using a polymer [ 85 : 15 poly ( lactide - co - glycolide ) ( P00747 ) ] would enhance angiogenesis and improve perfusion of ischemic tissue . METHODS : C57BL / 6J mice ( n = 20 / group ) underwent unilateral hind limb ischemia surgery and were randomized to groups of no scaffold implantation ( 0 - Implant ) , unloaded scaffold implantation ( Empty - P00747 ) , or implantation of scaffolds incorporating 3 microg of VEGF165 ( P00747 - P15692 ) . Endpoints included laser Doppler perfusion imaging ( LDPI , ischemic / nonischemic limb , % ) , local vessel counts , immunohistochemistry for CD31 , and alpha - smooth muscle actin . In vitro release kinetics of P15692 from P00747 was also measured . RESULTS : P00747 - P15692 resulted in improved lower extremity perfusion vs . controls as measured by LDPI % at 7 , 14 , 21 , and 28 days ( p < 0 . 05 ) . P00747 - P15692 was associated with significantly greater percentage of vessels staining for CD31 and alpha - smooth muscle actin compared to the Empty - P00747 or 0 - Implant ( p < 0 . 05 for both ) . CONCLUSIONS : The P00747 - P15692 scaffolds resulted in sustained P15692 delivery , improved tissue perfusion , greater capillary density , and more mature vasculature compared to the controls . The sustained - release P00747 polymer vehicle is a promising delivery system for therapeutic neovascularization applications .", "Serotonin P08908 receptor binding potential declines with age as measured by [ 11C ] WAY - 100635 and PET . Positron emission tomography ( PET ) and [ 11C ] WAY - 100635 were used to examine the effect of age on serotonin - 1A ( P08908 ) receptor binding potential ( BP ) in 19 healthy subjects . Regions of interest ( ROI ) were drawn on the co - registered magnetic resonance imaging ( Q9BWK5 ) in orbitofrontal ( OFC ) , dorsolateral prefrontal ( DLPFC ) , anterior cingulate ( ACC ) , lateral ( LTC ) , and mediotemporal ( P04629 ) , parietal , occipital and cerebellar cortex , and the raphe nuclei . BP values were calculated using a simplified reference tissue method . In addition , a voxelwise analysis was performed using SPM99 . Voxelwise analysis revealed a significant global decrease of 5 - HT ( 1A ) BP with age ( set level < . 001 ) . ROI analysis revealed significant age - related 5 - HT ( 1A ) BP decreases in DLPFC ( r = - 0 . 56 ) , ACC ( r = - 0 . 44 ) , OFC ( r = - 0 . 42 ) , LTC ( r = - 0 . 40 ) , parietal ( r = - 0 . 65 ) , and occipital cortex ( r = - 0 . 43 ) , but not in P04629 or raphe nuclei . Overall , cortical 5 - HT ( 1A ) BP declined by approximately 10 % per decade , except for the P04629 , where we did not find a significant age effect . Hence , careful age matching may be recommended for future studies using PET and [ 11C ] WAY - 100635 to examine P08908 receptors .", "Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 signaling . Raddeanin A ( RA ) is an active triterpenoid saponin from a traditional Chinese medicinal herb , Anemone raddeana Regel . It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells . However , whether RA can inhibit angiogenesis , an essential step in cancer development , remains unknown . In this study , we found that RA could significantly inhibit human umbilical vein endothelial cell ( HUVEC ) proliferation , motility , migration , and tube formation . RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane ( P62158 ) , restrained the trunk angiogenesis in zebrafish , and suppressed angiogenesis and growth of human HCT - 15 colorectal cancer xenograft in mice . Western blot assay showed that RA suppressed P15692 - induced phosphorylation of P35968 and its downstream protein kinases including PLCγ1 , O60674 , Q05397 , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 kinase domain . Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis , demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy .", "P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration - response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed .", "The use of IRES - based bicistronic vectors allows the stable expression of recombinant G - protein coupled receptors such as NPY5 and histamine 4 . Stable expression of G protein coupled receptors in cell lines is a crucial tool for the characterization of the molecular pharmacology of receptors and the screening for new antagonists . However , in some instances , many difficulties have been encountered to obtain stable cell lines expressing functional receptors . Here , we addressed the question of vector optimization to establish cell lines expressing the human neuropeptide Y receptor 5 ( Q15761 ) or histamine receptor 4 ( Q9H3N8 ) . We have compared bicistronic vectors containing viral or cellular internal ribosome entry sites ( IRES ) , co - expressing the receptor and the neomycine resistance gene from a single mRNA , to a bigenic vector containing two distinct promoters upstream each different genes . This study is the first one to validate the use of three cellular IRESs for long - term transgene expression . Our results demonstrate for both Q15761 and Q9H3N8 that the bicistronic vectors with EMCV , P15692 , FGF1A or P09038 IRES provide clones expressing functional receptors with yields between 25 % and 100 % . In contrast , the bigenic vector provided no functional clones , related to a low expression of Q15761 mRNA . The cell lines expressing active receptor were stable after more than 50 passages . These data indicate that IRES - based bicistronic vectors are particularly appropriate to establish cell clones expressing active G - coupled protein receptors with a high yield . In the case of NPY5 , it was a new way to produce such a stable cell line . Furthermore , the characteristics - presented herein - of this receptor pharmacological property are perfectly in line with those reported in the literature .", "Estradiol increases cell growth in human astrocytoma cell lines through ERα activation and its interaction with Q15788 and Q9Y6Q9 coactivators . Estradiol ( E2 ) regulates several cellular functions through the interaction with estrogen receptor subtypes , ERα and ERβ , which present different functional and regulation properties . ER subtypes have been identified in human astrocytomas , the most common and aggressive primary brain tumors . We studied the role of ER subtypes in cell growth of two human astrocytoma cell lines derived from tumors of different evolution grades : U373 and D54 ( grades III and IV , respectively ) . E2 significantly increased the number of cells in both lines and the co - administration with an ER antagonist ( ICI 182 , 780 ) significantly blocked E2 effects . ERα was the predominant subtype in both cell lines . E2 and ICI 182 , 780 down - regulated ERα expression . The number of U373 and D54 cells significantly increased after PPT ( ERα agonist ) treatment but not after DPN ( ERβ agonist ) one . To determine the role of Q15788 and Q9Y6Q9 coactivators in ERα induced cell growth , we silenced them with RNA interference . Coactivator silencing blocked the increase in cell number induced by PPT . The content of proteins involved in proliferation and metastasis was also determined after PPT treatment . Western blot analysis showed that in U373 cells the content of PR isoforms ( PR - A and PR - B ) , P00533 , P15692 and cyclin D1 increased after PPT treatment while in D54 cells only the content of P00533 was increased . Our results demonstrate that E2 induces cell growth of human astrocytoma cell lines through ERα and its interaction with Q15788 and Q9Y6Q9 and also suggest differential roles of ERα on cell growth depending on astrocytoma grade .", "Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK93___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK93___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK93___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .", "AZD1480 blocks growth and tumorigenesis of P07949 - activated thyroid cancer cell lines . Persistent P07949 activation is a frequent event in papillary thyroid carcinoma ( PTC ) and medullary thyroid carcinoma ( P04629 ) . In these cancers , P07949 activates the P29323 / MAPK , the PI3K / AKT / P42345 and the JAK / P40763 pathways . Here , we tested the efficacy of a P23458 / 2 - inhibitor , AZD1480 , in the in vitro and in vivo growth of thyroid cancer cell lines expressing oncogenic P07949 . Thyroid cancer cell lines harboring P07949 / Q13635 ( TPC - 1 ) , P07949 M918T ( MZ - CRC1 ) and P07949 C634W ( TT ) alterations , as well as TPC - 1 xenografts , were treated with JAK inhibitor , AZD1480 . This inhibitor led to growth inhibition and / or apoptosis of the thyroid cancer cell lines in vitro , as well as to tumor regression of TPC - 1 xenografts , where it efficiently blocked P40763 activation in tumor and stromal cells . This inhibition was associated with decreased proliferation , decreased blood vessel density , coupled with increased necrosis . However , AZD1480 repressed the growth of P40763 - deficient TPC - 1 cells in vitro and in vivo , demonstrating that its effects in this cell line were independent of P40763 in the tumor cells . In all cell lines , the JAK inhibitor reduced phospho - Y1062 P07949 levels , and P42345 effector phospho - S6 , while P23458 / 2 downregulation by siRNA did not affect cell growth nor P07949 and S6 activation . In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated P07949 - thyroid cancer cell lines , likely through direct P07949 inhibition in cancer cells as well as by modulation of the microenvironment ( e . g . via JAK / phospho - P40763 inhibition in endothelial cells ) . Thus , AZD1480 should be considered as a therapeutic agent for the treatment of P07949 - activated thyroid cancers .", "Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .", "A dose - ranging study of cabozantinib in men with castration - resistant prostate cancer and bone metastases . BACKGROUND : DB08875 is an oral MET / P35968 inhibitor . A recent phase II study of cabozantinib ( 100 mg daily ) showed improved bone scans in subjects with metastatic castration - resistant prostate cancer ( mCRPC ) , but adverse events ( AE ) caused frequent dose reductions . This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses . EXPERIMENTAL DESIGN : An adaptive design was used to determine the lowest active daily dose among 60 , 40 , and 20 mg . The primary endpoint was week 6 bone scan response , defined as ≥ 30 % decrease in bone scan lesion area . The secondary endpoint was change in circulating tumor cells ( CTC ) . RESULTS : Among 11 evaluable subjects enrolled at 40 mg , there were 9 partial responses ( PR ) , 1 complete response , and 1 stable disease ( SD ) . Of 10 subjects subsequently enrolled at 20 mg , there were 1 PR , 5 SDs , and 4 with progressive disease . Among 13 subjects enrolled on the 40 mg expansion cohort , there were 6 PRs and 7 SDs . No subjects required dose reduction or treatment interruption at 6 or 12 weeks ; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks . At 40 mg , median treatment duration was 27 weeks . 58 % of subjects with ≥ 5 CTCs / 7 . 5 mL at baseline converted to < 5 . CONCLUSIONS : DB08875 40 mg daily was associated with a high rate of bone scan response . DB08875 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily . These observations informed the design of phase III studies of cabozantinib in mCRPC .", "[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK49___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .", "A phase I study of cabozantinib ( DB05153 ) in patients with differentiated thyroid cancer . BACKGROUND : DB08875 targets tyrosine kinases including MET , vascular endothelial growth factor ( P15692 ) receptor 2 , and rearranged during transfection ( P07949 ) . Differentiated thyroid cancer ( DTC ) is a tumor type that may be sensitive to cabozantinib . Therefore , we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC . METHODS : This single - arm open - label phase I trial assessed the safety , tolerability , and antitumor activity of cabozantinib in DTC patients taking part in a drug - drug interaction study . Adult patients with histologically confirmed metastatic or surgically unresectable DTC ( including papillary , follicular , or Hürthle cell ) were enrolled . Patients received daily oral dosing of 140 mg cabozantinib . Safety was assessed by evaluation of adverse events ( AEs ) , vital signs , electrocardiograms , laboratory tests , and concomitant medications . Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors ( RECIST ) v1 . 0 . RESULTS : The study enrolled 15 patients who had failed standard radioactive iodine therapy . Patients had received a median of two prior systemic agents , and 11 patients ( 73 % ) had previously received at least one P15692 pathway inhibiting therapy . Common AEs included diarrhea , nausea , fatigue , and decreased appetite . Partial response was reported in eight patients ( 53 % ) . Median progression - free survival and median overall survival were not reached . CONCLUSIONS : DB08875 demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients . The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC .", "Antipruritic activity of the kappa - opioid receptor agonist , P04629 - 820 . The effects of the kappa - opioid receptor agonist , P04629 - 820 , (-)- 17 -( cyclopropylmethyl )- 3 , 14beta - dihydroxy - 4 , 5alpha - epoxy - 6beta - [ N - methyl - trans - 3 -( 3 - furyl ) acrylamido ] morphinan hydrochloride , on the itch sensation were compared with those of histamine H1 receptor antagonists , using the mouse pruritogen - induced scratching model . Peroral administration of P04629 - 820 reduced the numbers of DB05875 - or histamine - induced scratches dose dependently . No obvious suppression of the spontaneous locomotor activity was observed at the doses used for the experiments , indicating that the inhibition of scratches was not due to the effect on general behavior . Furthermore , the scratching inhibitory activity of P04629 - 820 was dose dependently antagonized by the specific kappa - opioid receptor antagonist , nor - binaltorphimine , suggesting that the inhibitory activity was mediated via kappa - opioid receptors . P35367 antagonists , chlorpheniramine and ketotifen , did not inhibit DB05875 - induced scratches , or did so only partially . Both antihistamines inhibited the histamine - induced scratches completely . These results suggest that P04629 - 820 has antipruritic activity which is mediated by kappa - opioid receptors , and is effective in both antihistamine - sensitive and - resistant pruritus .", "Drug insight : Small - molecule inhibitors of protein kinases in the treatment of thyroid cancer . Molecular targeting of protein kinases is a new paradigm in the treatment of cancer . The clinical efficacy of low - molecular weight inhibitors of P00519 , stem - cell growth - factor receptor , and the epidermal growth factor receptor in different tumor types is witness to the power of this approach . The presence of activating mutations of a kinase , or an increased gene copy number , might anticipate tumor responsiveness to its targeting . Thyroid cancer is the most prevalent endocrine malignancy and is frequently associated with the oncogenic conversion of two specific protein kinases , P07949 and P15056 . Small - molecule inhibitors of both kinases have already reached the clinical testing stage . Protein kinases other than P07949 and P15056 are also being evaluated for their potential in thyroid - cancer treatment .", "DB08875 overcomes crizotinib resistance in P08922 fusion - positive cancer . PURPOSE : P08922 rearrangement leads to constitutive P08922 activation with potent transforming activity . In an ongoing phase I trial , the Q9UM73 tyrosine kinase inhibitor ( TKI ) crizotinib shows remarkable initial responses in patients with non - small cell lung cancer ( NSCLC ) harboring P08922 fusions ; however , cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in P08922 . Thus , understanding the crizotinib - resistance mechanisms in P08922 - rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required . EXPERIMENTAL DESIGN : The sensitivity of P04233 - P08922 - transformed Ba / P13726 cells to multiple Q9UM73 inhibitors was examined . Acquired P08922 inhibitor - resistant mutations in P04233 - P08922 fusion were screened by N - ethyl - N - nitrosourea mutagenesis with Ba / P13726 cells . To overcome the resistance mutation , we performed high - throughput drug screening with small - molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials . The effect of the identified drug was assessed in the P04233 - P08922 - mutant Ba / P13726 cells and crizotinib - resistant patient - derived cancer cells ( MGH047 ) harboring G2032R - mutated P04233 - P08922 . RESULTS : We identified multiple novel crizotinib - resistance mutations in the P08922 kinase domain , including the G2032R mutation . As the result of high - throughput drug screening , we found that the cMET / P07949 / VEGFR inhibitor cabozantinib ( DB05153 ) effectively inhibited the survival of P04233 - P08922 wild - type ( WT ) and resistant mutants harboring Ba / P13726 and MGH047 cells . Furthermore , cabozantinib could overcome all the resistance by all newly identified secondary mutations . CONCLUSIONS : We developed a comprehensive model of acquired resistance to P08922 inhibitors in NSCLC with P08922 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance .", "___MASK31___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK31___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK31___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK31___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .", "Combining resonance energy transfer methods reveals a complex between the alpha2A - adrenergic receptor , Galphai1beta1gamma2 , and P25098 . Traditionally , G - protein - coupled receptor ( GPCR ) interactions with their G proteins and regulatory proteins , GPCR kinases ( GRKs ) and arrestins , are described as sequential events involving rapid assemblies / disassemblies . To directly monitor the dynamics of these interactions in living cells , we combined two spectrally resolved bioluminescence and one fluorescence resonance energy transfer ( P07949 ) methods . The P07949 combination analysis revealed that stimulation of the α ( 2A )- adrenergic receptor ( α ( 2A ) AR ) leads to the recruitment of P25098 at a receptor still associated with the Gα ( i1 ) β ( 1 ) γ ( 2 ) complex . The interaction kinetics of GRKs with Gγ ( 2 ) ( 2 . 8 ± 0 . 4 s ) and α ( 2A ) AR ( 5 . 2 ± 0 . 5 s ) were similar to that of the receptor - promoted change in P07949 between Gα ( i1 ) and Gγ ( 2 ) ( 5 . 2 ± 1 . 2 s ) , and persisted until the translocation of βarrestin2 to the receptor , indicating that P25098 remains associated to the receptor / G - protein complex for longer periods than anticipated . Moreover , P25098 or a kinase - deficient P25098 mutant , but not P34947 , potentiated the receptor - promoted changes in P07949 between Gα ( i1 ) and Gγ ( 2 ) and abrogated the α ( 2A ) AR - stimulated calcium response , suggesting that the recruitment of P25098 to the complex contributes to the structural rearrangement and functional regulation of the signaling unit , independently of the kinase activity . P07949 combination analysis revealed unanticipated dynamics in GPCR signaling and will be applicable to many biological systems .", "Synergism between bosutinib ( ___MASK36___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .", "Imatinib inhibits P15692 - independent angiogenesis by targeting neuropilin 1 - dependent P00519 activation in endothelial cells . To enable new blood vessel growth , endothelial cells ( ECs ) express neuropilin 1 ( NRP1 ) , and NRP1 associates with the receptor tyrosine kinase P35968 after binding the vascular endothelial growth factor A ( P15692 ) to enhance arteriogenesis . We report that NRP1 contributes to angiogenesis through a novel mechanism . In human and mouse ECs , the integrin ligand fibronectin ( FN ) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin ( P49023 ) in a P15692 / P35968 - independent but NRP1 - dependent manner . NRP1 formed a complex with P00519 that was responsible for FN - dependent P49023 activation and actin remodeling . This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo . Accordingly , both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib , a small molecule inhibitor of P00519 which is widely used to prevent the proliferation of tumor cells that express P11274 - P00519 fusion proteins . The finding that NRP1 regulates angiogenesis in a P15692 - and P35968 - independent fashion via P00519 suggests that P00519 inhibition provides a novel opportunity for anti - angiogenic therapy to complement P15692 or P35968 blockade in eye disease or solid tumor growth .", "P00747 activator inhibitor type 1 expression induced by lipopolysaccharide of Porphyromonas gingivalis in human gingival fibroblast . In the gingival tissues of patients with periodontitis , inflammatory responses are mediated by a wide variety of genes . In our previous screening study , plasminogen activator inhibitor type 1 ( P05121 ) mRNA binding protein expression was increased in gingiva from periodontitis patients . In this study , we further investigated the signaling pathway involved in P05121 expression induced by Porphyromonas gingivalis LPS ( Pg LPS ) in human gingival fibroblasts ( P14210 ) . When HGFs were treated with Pg LPS , both P05121 mRNA expression and P05121 protein were induced in a dose - dependent manner . Pg LPS induced NF - κB activation and the expressions of P05121 mRNA and protein were suppressed by pretreating with a NF - κB inhibitor . Pg LPS also induced P29323 , p38 , and JNK activation , and Pg LPS - induced P05121 expression was inhibited by P29323 / p38 / JNK inhibitor pretreatment . In conclusion , Pg LPS induced P05121 expression through NF - κB and Q96HU1 kinases activation in P14210 .", "Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK23___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .", "P37231 ligands are potent inhibitors of angiogenesis in vitro and in vivo . P37231 ( PPARgamma ) is a nuclear receptor that functions as a transcription factor to mediate ligand - dependent transcriptional regulation . Activation of PPARgamma by the naturally occurring ligand , 15 - deoxy - Delta12 , 14 - prostaglandin J2 ( 15d - PGJ2 ) , or members of a new class of oral antidiabetic agents , e . g . BRL49653 and ciglitizone , has been linked to adipocyte differentiation , regulation of glucose homeostasis , inhibition of macrophage and monocyte activation , and inhibition of tumor cell proliferation . Here we report that human umbilical vein endothelial cells ( HUVEC ) express PPARgamma mRNA and protein . Activation of PPARgamma by the specific ligands 15d - PGJ2 , BRL49653 , or ciglitizone , dose dependently suppresses HUVEC differentiation into tube - like structures in three - dimensional collagen gels . In contrast , specific PPARalpha and - beta ligands do not affect tube formation although mRNA for these receptors are expressed in HUVEC . PPARgamma ligands also inhibit the proliferative response of HUVEC to exogenous growth factors . Treatment of HUVEC with 15d - PGJ2 also reduced mRNA levels of vascular endothelial cell growth factor receptors 1 ( Flt - 1 ) and 2 ( Flk / P35968 ) and urokinase plasminogen activator and increased plasminogen activator inhibitor - 1 ( P05121 ) mRNA . Finally , administration of 15d - PGJ2 inhibited vascular endothelial cell growth factor - induced angiogenesis in the rat cornea . These observations demonstrate that PPARgamma ligands are potent inhibitors of angiogenesis in vitro and in vivo , and suggest that PPARgamma may be an important molecular target for the development of small - molecule inhibitors of angiogenesis .", "Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK36___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK36___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .", "Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .", "Synaptic and photoreceptor components in retinal pigment epithelial cell transplanted retinas of Royal College of Surgeons dystrophic rats . Plexiform layer synaptic and photoreceptor cell components were investigated in retinas of Royal College of Surgeons ( RCS ) dystrophic rats transplanted with normal retinal pigment epithelial ( Q96AT9 ) cells by immunocytochemistry using previously characterized monoclonal antibodies . In retinas of normal adult rats and Q96AT9 - cell transplanted retinas of 4 month - old RCS rats , HNK - 1 , a marker for a carbohydrate of the neural cell adhesion molecule ( N - P62158 ) , was detected immunocytochemically in the inner and outer plexiform layers and ganglion cell bodies and their axons . HNK - 1 was also detected in the inner plexiform layer of nontreated retinas of 4 month - old RCS rats , but was reduced to scattered patches in the outer plexiform layer . In addition , immunoreactivity for the SVP - 38 antibody recognizing synaptophysin was found in both plexiform layers of normal adult rat retinas and Q96AT9 - transplanted retinas of 4 month - old RCS rats . Furthermore , photoreceptor cell bodies and their inner and outer segments were immunostained for the opsin monoclonal antibody P07949 - P1 in retinas of normal adult rats and Q96AT9 - cell transplanted retinas of 4 month - old RCS rats . However , in nontreated retinas of 4 - month - old RCS rats , only immunostained debris material was detected . These results strongly suggest that normal Q96AT9 transplants not only rescue photoreceptor cells in RCS rats , but also maintain an essential functional capacity , in this case , synaptic components in the plexiform layers .", "Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK55___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .", "Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .", "Downregulation of steroid receptor coactivator - 2 modulates estrogen - responsive genes and stimulates proliferation of mcf - 7 breast cancer cells . The P52701 / Steroid Receptor Coactivators Q15788 , P12931 - 2 / GRIP1 , and Q9Y6Q9 / Q9Y6Q9 are important regulators of Estrogen Receptor alpha ( ERα ) activity . However , whereas the functions of Q15788 and Q9Y6Q9 in breast tumourigenesis have been extensively studied , little is known about the role of P12931 - 2 . Previously , we reported that activation of the DB02527 - dependent protein kinase , PKA , facilitates ubiquitination and proteasomal degradation of P12931 - 2 which in turn leads to inhibition of P12931 - 2 - coactivation of ERα and changed expression of the ERα target gene , pS2 . Here we have characterized the global program of transcription in P12931 - 2 - depleted MCF - 7 breast cancer cells using short - hairpin RNA technology , and in MCF - 7 cells exposed to PKA activating agents . In order to identify genes that may be regulated through PKA - induced downregulation of P12931 - 2 , overlapping transcriptional targets in response to the respective treatments were characterized . Interestingly , we observed decreased expression of several breast cancer tumour suppressor genes ( e . g . , Q01995 , P18146 , BCL11b , Q03135 ) in response to both P12931 - 2 knockdown and PKA activation , whereas the expression of a number of other genes implicated in cancer progression ( e . g . , P07949 , O75363 , Q07654 , P61073 , P35318 ) was increased . In line with this , knockdown of P12931 - 2 also stimulated proliferation of MCF - 7 cells . Together , these results suggest that P12931 - 2 may have an antiproliferative function in breast cancer cells .", "Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK33___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK33___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK33___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK33___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK33___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK33___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK33___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK33___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK33___ in the treatment of changes in hypervigilance following severe stress .", "Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK49___ and Tissue P00747 Activator in Occluded Arteries .", "Genetic control and chromosomal location of Triticum timopheevii - derived resistance to septoria nodorum blotch in durum wheat . The genetic control of resistance , expressed as restricted lesion development in seedling plants , to septoria nodorum blotch of wheat was studied under controlled environmental conditions , using the parental , F1 , F2 , P13726 , BC1F1 , and BC1F2 generations of crosses of Triticum timopheevii - derived resistant durum lines S3 - 6 , S9 - 10 , and P28222 - 1 with the susceptible durum cv . Sceptre . The seedling resistance of these three resistant sources , derived from T . timopheevii ( PI 290518 ) , was monogenically controlled . The chromosomal location of the resistance gene identified was determined by crossing the complete set of ' Langdon ' - ' Chinese Spring ' D - genome disomic substitution lines with P28222 - 1 . Tests of the F1 and F2 generations of each cross indicated that only chromosome 3A was associated with resistance . Therefore , the resistance gene is considered to be located on chromosome 3A and has been designated temporarily as SnbTM .", "DB08875 ( DB05153 ) , a novel MET and P35968 inhibitor , simultaneously suppresses metastasis , angiogenesis , and tumor growth . The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor ( P14210 ) is important for cell growth , survival , and motility and is functionally linked to the signaling pathway of P15692 , which is widely recognized as a key effector in angiogenesis and cancer progression . Dysregulation of the MET / P15692 axis is found in a number of human malignancies and has been associated with tumorigenesis . DB08875 ( DB05153 ) is a small - molecule kinase inhibitor with potent activity toward MET and P15692 receptor 2 ( P35968 ) , as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology , including P07949 , P10721 , P30530 , and P36888 . Treatment with cabozantinib inhibited MET and P35968 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro . In mouse models , cabozantinib dramatically altered tumor pathology , resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose - dependent inhibition of tumor growth in breast , lung , and glioma tumor models . Importantly , treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis , which has been observed with inhibitors of P15692 signaling that do not target MET . Collectively , these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling .", "Central role of the threonine residue within the p + 1 loop of receptor tyrosine kinase in P40763 constitutive phosphorylation in metastatic cancer cells . The receptor tyrosine kinases ( RTKs ) P07949 , MET , and Q04912 all carry the DB00134 ( p + 1loop ) --> DB00156 point mutation ( i . e . , 2B mutation ) , leading to the formation of tumors with high metastatic potential . Utilizing a novel antibody array , we identified constitutive phosphorylation of P40763 in cells expressing the 2B mutation but not wild - type P07949 . MET or Q04912 with the 2B mutation also constitutively phosphorylated P40763 . Members of the P21709 , the only group of wild - type RTK that carry DB00156 ( p + 1loop ) residue , are often expressed unexpectedly in different types of cancers . Ectopic expression of wild - type but not DB00156 ( p + 1loop ) --> DB00134 substituted P21709 family members constitutively phosphorylated P40763 . In both RTK ( Metp + 1loop ) with 2B mutation and wild - type P21709 members the DB00156 ( p + 1loop ) residue is required for constitutive kinase autophosphorylation and P40763 recruitment . In multiple endocrine neoplasia 2B ( MEN - 2B ) patients expressing P07949 ( M918T ) , nuclear enrichment of P40763 and elevated expression of P61073 was detected in metastatic thyroid C - cell carcinoma in the liver . In breast adenocarcinoma cell lines expressing multiple P21709 members , P40763 constitutively bound to the promoters of P15941 , Q99102 , and Q9HC84 genes . Inhibiting P40763 expression resulted in reduced expression of these metastasis - related genes and inhibited mobility . These findings provide insight into DB00156 ( p + 1loop ) residue in RTK autophosphorylation and constitutive activation of P40763 in metastatic cancer cells .", "DB08875 inhibits prostate cancer growth and prevents tumor - induced bone lesions . PURPOSE : DB08875 , an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor ( MET ) and P15692 receptor 2 ( P35968 ) , induces resolution of bone scan lesions in men with castration - resistant prostate cancer bone metastases . The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect , an indirect effect through modulating bone , or both . EXPERIMENTAL DESIGN : Using human prostate cancer xenograft studies in mice , we determined the impact of cabozantinib on tumor growth in soft tissue and bone . In vitro studies with cabozantinib were performed using ( i ) prostate cancer cell lines to evaluate its impact on cell growth , invasive ability , and MET and ( ii ) osteoblast cell lines to evaluate its impact on viability and differentiation and P35968 . RESULTS : DB08875 inhibited progression of multiple prostate cancer cell lines ( Ace - 1 , C4 - 2B , and LuCaP 35 ) in bone metastatic and soft tissue murine models of prostate cancer , except for PC - 3 prostate cancer cells in which it inhibited only subcutaneous growth . DB08875 directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro . DB08875 had a dose - dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo . It blocked MET and P35968 phosphorylation in prostate cancer cells and osteoblast - like cells , respectively . CONCLUSION : These data indicate that cabozantinib has direct antitumor activity , and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy .", "Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia . The dual Src / Abl kinase inhibitor bosutinib ( ___MASK36___ ) targets the tyrosine kinase brc - abl , the key enzyme in the development of chronic myeloid leukemia ( CML ) . In clinical trials , bosutinib yielded promising results with regard to efficacy , tolerability and toxicity in first - , second - and third - line therapy of CML patients . Remarkably , bosutinib is able to overcome most imatinib - resistant P11274 - P00519 - 1 mutations except V299L and T315I . Mostly , low - to - moderate grade gastrointestinal toxicitis are the most common treatment - emergent adverse events observed under bosutinib . Unlike other tyrosine kinase inhibitors approved for CML treatment to date , bosutinib shows only minimal inhibitory activity against c - P10721 and the PDGF receptor . This may be causative for its favorable hematologic toxicity profile . In this review , the authors give an overview on the mechanism of action and currently available preclinical and clinical data for bosutinib in CML .", "Characterization of aberrant melting peaks in unlabeled probe assays . An unlabeled probe assay relies on a double - stranded DNA - binding dye to detect and verify target based on amplicon and probe melting . During the development and application of unlabeled probe assays , aberrant melting peaks are sometimes observed that may interfere with assay interpretation . In this report , we investigated the origin of aberrant melting profiles observed in an unlabeled probe assay for exon 10 of the P07949 gene . It was determined that incomplete 3 ' blocking of the unlabeled probe allowed polymerase - mediated probe extension resulting in extension products that generated the aberrant melting profiles . This report further examined the blocking ability of the 3 ' modifications P01024 spacer , amino - modified P13671 , phosphate , inverted dT , and single 3 ' nucleotide mismatches in unlabeled probe experiments . Although no 3 ' blocking modifications in these experiments were 100 % effective , the amino - modified P13671 , inverted dT , and P01024 spacer provided the best blocking efficiencies ( 1 % or less unblocked ) , phosphate was not as effective of a block ( up to 2 % unblocked ) , and single nucleotide mismatches should be avoided as a 3 ' blocking modification .", "[ ___MASK6___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK6___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .", "DB08875 suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of P35968 and MET . PURPOSE : MET signaling has been suggested a potential role in hepatocellular carcinoma ( HCC ) and associated with prometastasis during antiangiogenesis therapy . We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC . Antitumor effects of cabozantinib , a dual inhibitor of MET and P35968 , were examined in cultured HCC cells as well as in vivo models . EXPERIMENTAL DESIGN : Total MET and phosphorylated MET ( p - MET ) were measured in 29 resected HCC specimens , and correlated with response to sorafenib as postoperative adjuvant therapy . In the second set of experiments using cultured HCC cells , and mouse xenograft and metastatic models , effects of cabozantinib were examined . RESULTS : High level of p - MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy . In cultured HCC cells that expressed p - MET , cabozantinib inhibited the activity of MET and its downstream effectors , leading to P55008 - phase arrest . DB08875 inhibited tumor growth in p - MET - positive and p - MET - negative HCC by decreasing angiogenesis , inhibiting proliferation , and promoting apoptosis , but it exhibited more profound efficacy in p - MET - positive HCC xenografts . DB08875 blocked the hepatocyte growth factor ( P14210 ) - stimulated MET pathway and inhibited the migration and invasion of the HCC cells . Notably , cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model . CONCLUSIONS : Patients with HCC with high level of p - MET are associated with resistance to adjuvant sorafenib treatment . The dual blockade of P35968 and MET by cabozantinib has significant antitumor activities in HCC , and the activation of MET in HCC may be a promising efficacy - predicting biomarker . Clin Cancer Res ; 20 ( 11 ) ; 2959 - 70 . © 2014 AACR .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "Impaired angiogenesis during fracture healing in GPCR kinase 2 interacting protein - 1 ( Q9Y2X7 ) knock out mice . G protein coupled receptor kinase 2 ( P25098 ) interacting protein - 1 ( Q9Y2X7 ) , is a scaffold protein that plays an important role in angiogenesis and osteoclast activity . We have previously demonstrated that Q9Y2X7 knockout ( Q9Y2X7 KO ) mice have impaired angiogenesis and dysregulated osteoclast podosome formation leading to a reduction in the bone resorbing ability of these cells . Since both angiogenesis and osteoclast - mediated bone remodeling are involved in the fracture healing process , we hypothesized that Q9Y2X7 participates in the normal progression of repair following bone injury . In the present study , comparison of fracture healing in wild type ( WT ) and Q9Y2X7 KO mice revealed altered healing in mice with loss of Q9Y2X7 function . Alcian blue staining of fracture callus indicated a persistence of cartilagenous matrix in day 21 callus samples from Q9Y2X7 KO mice which was temporally correlated with increased type 2 collagen immunostaining . Q9Y2X7 KO mice also showed a decrease in chondrocyte proliferation and apoptosis at days 7 and 14 , as determined by P12004 and TUNEL staining . Vascular microcomputed tomography analysis of callus samples at days 7 , 14 and 21 revealed decreased blood vessel volume , number , and connection density in Q9Y2X7 KO mice compared to WT controls . Correlating with this , P15692 , phospho - P35968 and P16284 ( CD31 ) were decreased in Q9Y2X7 KO mice , indicating reduced angiogenesis with loss of Q9Y2X7 . Finally , calluses from Q9Y2X7 KO mice displayed a reduced number of tartrate resistant acid phosphatase - positive osteoclasts at days 14 and 21 . Collectively , these results indicate that Q9Y2X7 is an important signaling participant in fracture healing , with gene ablation leading to reduced callus vascularity and reduced osteoclast number in the healing callus .", "Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .", "DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .", "DB08875 ( DB05153 ) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer . DB08875 ( DB05153 ) is an oral multiple receptor tyrosine kinase inhibitor manufactured by Exelixis Inc . , CA , USA . It mainly inhibits three tyrosine kinase receptors : MET , P35968 and P07949 . In both preclinical and clinical studies it has been shown to inhibit tumor angiogenesis , invasiveness and metastases . The most frequent side effects are fatigue , diarrhea , decreased appetite , nausea , weight loss and palmar - plantar erythrodysesthesia . A Phase III clinical trial ( EXAM study ) of DB05153 versus placebo in advanced and progressive medullary thyroid cancer showed a 28 versus 0 % overall response rate and a progression - free survival of 11 . 2 versus 4 . 0 months ( hazard ratio : 0 . 28 ; 95 % CI : 0 . 19 - 0 . 40 ; p < 0 . 0001 ) in patients treated with cabozantinib and placebo , respectively . The drug has been approved by the US FDA for the treatment of advanced / progressive metastatic medullary thyroid cancer in the USA . The P15941 is now evaluating its approval in Europe .", "DB08875 for the treatment of advanced medullary thyroid cancer . INTRODUCTION : Patients with advanced medullary thyroid cancer ( P04629 ) have poor prognoses and limited treatment options . Improved knowledge about molecular aberrations associated with P04629 and the availability of novel targeted tyrosine kinase inhibitors ( TKIs ) have led to new potential treatment modalities . DB08875 is an oral multitargeted TKI with activity against multiple receptors including P07949 , vascular endothelial growth factor receptor type 2 ( P35968 ) , and MET that has been evaluated in P04629 in the preclinical and clinical arenas . METHODS : This article reviews unmet clinical needs in advanced P04629 . The authors consider novel agents that have been studied in P04629 , with a focus on the investigational agent cabozantinib . Up - to - date clinical data of cabozantinib in P04629 are discussed . RESULTS : Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression - free survival in patients with progressive P04629 . These findings indicate that cabozantinib may be an effective therapy in advanced P04629 . No improvement in overall survival has been demonstrated but data are not mature . CONCLUSION : DB08875 may be an effective treatment option for patients with advanced P04629 and is worthy of further evaluation .", "Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer . Medullary thyroid cancer is an uncommon malignancy for which until recently little effective treatment existed . It is often characterized by mutation and overexpression of the receptor tyrosine kinases P07949 ( rearranged during transfection ) , P35968 ( vascular endothelial growth factor receptor 2 ) and MET ( mesenchymal - epithelial transition factor ) , which make attractive targets for drug development . DB08875 is an orally bioavailable tyrosine kinase inhibitor which blocks MET , VEGRF2 and P07949 , and has shown considerable activity in medullary thyroid cancer in a Phase III trial , including in heavily pretreated patients . Its novel combination of vascular endothelial growth factor and MET inhibition is believed to address the MET escape pathway , which is thought to be the cause of nonsustained tumor responses resulting from inhibition of vascular endothelial growth factor alone .", "Q02548 / P41212 acts as a transcriptional repressor causing down - modulation of P15391 , enhances migration to P48061 , and confers survival advantage in pre - BI cells . Q02548 is a transcription factor essential for B - cell development . Recently , it has been found as a frequent target of aberrancies in childhood acute lymphoblastic leukemia ( ALL ; 30 % of B cell ALL cases ) , showing monoallelic loss , point mutations , or chromosomal translocations . The role of these aberrancies is still poorly understood . We previously cloned the Q02548 / P41212 fusion gene in a patient affected by B - cell precursor ALL with a t ( 9 ; 12 ) translocation . This is the first report investigating the molecular and functional roles of Q02548 / P41212 protein in vitro from murine wild - type pre - BI cells . We showed that Q02548 / P41212 protein acts as an aberrant transcription factor with repressor function , recruiting mSin3A , down - regulating B220 , P15391 , Q8WV28 , MB - 1 , P36888 , and mu heavy chain expression , thus suggesting a block on B - cell differentiation . In a Q02548 - deficient context , the presence of Q02548 / P41212 did not replace Q02548 functions . Q02548 / P41212 protein enhances cell migration towards P48061 , with the overexpression of P61073 . Moreover , the presence of the fusion gene overcomes interleukin - 7 withdrawal and interferes with transforming growth factor - beta1 pathway , inducing resistance and conferring cells an advantage in proliferation and survival . Thus , in vitro , the Q02548 / P41212 protein has a dominant effect on wild - type Q02548 , interferes with the process of B - cell differentiation and migration , and induces resistance to apoptosis . Taken together , these phenomena likely represent key events in the process of B - cell transformation .", "Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .", "Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .", "P00747 activator inhibitor - 1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor - 2 - αVβ3 integrin cross talk . OBJECTIVE : P00747 activator inhibitor - 1 ( P05121 ) regulates angiogenesis via effects on extracellular matrix proteolysis and cell adhesion . However , no previous study has implicated P05121 in controlling vascular endothelial growth factor ( P15692 ) signaling . We tested the hypothesis that P05121 downregulates P15692 receptor - 2 ( P35968 ) activation by inhibiting a vitronectin - dependent cooperative binding interaction between P35968 and αVβ3 . APPROACH AND RESULTS : We studied effects of P05121 on P15692 signaling in human umbilical vein endothelial cells . P05121 inhibited P15692 - induced phosphorylation of P35968 in human umbilical vein endothelial cells grown on vitronectin , but not on fibronectin or collagen . P05121 inhibited the binding of P35968 to β3 integrin , P35968 endocytosis , and intracellular signaling pathways downstream of P35968 . The anti - P15692 effect of P05121 was mediated by 2 distinct pathways , one requiring binding to vitronectin and another requiring binding to very low - density lipoprotein receptor . P05121 inhibited P15692 - induced angiogenesis in vitro and in vivo , and pharmacological inhibition of P05121 promoted collateral arteriole development and recovery of hindlimb perfusion after femoral artery interruption . CONCLUSIONS : P05121 inhibits activation of P35968 by P15692 by disrupting a vitronectin - dependent proangiogenic binding interaction involving αVβ3 and P35968 . These results broaden our understanding of the roles of P05121 , vitronectin , and endocytic receptors in regulating P35968 activation and suggest novel therapeutic strategies for regulating P15692 signaling .", "A recombinant single - chain P13232 / HGFbeta hybrid cytokine induces juxtacrine interactions of the P13232 and P14210 ( c - DB00134 ) receptors and stimulates the proliferation of CFU - P28222 , CLPs , and pre - pro - B cells . A novel recombinant interleukin - 7 / hepatocyte growth factor beta - chain ( P13232 / HGFbeta ) hybrid cytokine was constructed as a single chain ( sc ) composed of P13232 and HGFbeta connected by a flexible linker . Unlike recombinant ( r ) P13232 , which stimulated pro - B cells and pre - B cells only , scIL - 7 / HGFbeta stimulated the proliferation of pre - pro - B cells , common lymphoid progenitors ( CLPs ) , and colony - forming unit ( CFU ) - P28222 in cultures of P13232 -/- mouse BM cells . When injected in vivo , 3 - to 4 - fold more splenic B - lineage cells appeared in recipients of bone marrow ( BM ) cells from the scIL - 7 / HGFbeta - stimulated cultures than from rIL - 7 - stimulated cultures . Moreover , on a per - cell basis , scIL - 7 / HGFbeta culture - generated cells produced 16 - to 20 - fold more BM and splenic B - lineage cells than did normal BM cells . Antibody blocking , receptor phosphorylation , and confocal microscopy demonstrated that scIL - 7 / HGFbeta signals though both the P13232 and P14210 ( c - DB00134 ) receptors , which form IL - 7R / c - DB00134 complexes on the surface of CLPs and pre - pro - B cells . In addition , the IL - 7Ralpha chain , gammac chain , and c - DB00134 were coisolated from purified CLPs and pre - pro - B cells on scIL - 7 / HGFbeta affinity gels , indicating that they are major components of the P13232 / HGFbeta receptor . Hence , the present results demonstrate that the P13232 / HGFbeta hybrid cytokine efficiently and selectively stimulates the most primitive B - lineage precursors in BM by inducing juxtacrine interactions between the P13232 and c - DB00134 receptors .", "Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .", "Human endothelial progenitor cells isolated from P48444 patients are dysfunctional . Cardiovascular disease is the leading cause of morbidity and mortality in patients with moderate - to - severe chronic obstructive pulmonary disease ( P48444 ) . More than 44 % of these patients present with generalized atherosclerosis at autopsy . It is accepted that endothelial progenitor cells ( EPCs ) participate in the repair of dysfunctional endothelium and thus protects against atherosclerosis . However , whether P48444 affects the repairing capacity of EPCs is unknown . Therefore , the objective of this study was to determine whether and how EPCs are involved in the vascular repair process in patients with P48444 . In our study , EPCs from 25 P48444 and 16 control patients were isolated by Ficoll density - gradient centrifugation and identified using fluorescence activated cell sorting . Transwell Migratory Assay was performed to determine the number of EPC colony - forming units and the adherent capacity late - EPCs to human umbilical vein endothelial cells . Following arterial damage in NOD / SCID mice , the number of EPCs incorporated at the injured vascular site was determined using a fluorescence microscope . We found that the number of EPC clusters and cell migration , as well as the expression of P61073 , was significantly decreased in patients with P48444 . Additionally , the number of late - EPCs adherent to HUVEC tubules was significantly reduced , and fewer P35968 (+)- staining cells were incorporated into the injured site in P48444 patients . Our study demonstrates that EPC capacity of repair was affected in P48444 patients , which may contribute to altered vascular endothelium in this patient population .", "DB08875 : a MET , P07949 , and P35968 tyrosine kinase inhibitor . DB08875 is a receptor tyrosine kinase inhibitor with activity against MET , P35968 , P36888 , c - P10721 , and P07949 . Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies . Of note , cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET . Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer ( P04629 ) , NSCLC , breast , ovarian , pancreatic , and prostate cancer . In P04629 , gain of function mutations of P07949 are central for tumorigenesis . Hereditary forms of P04629 ( MEN II ) are caused by germline mutations of P07949 , in sporadic P04629 in up to 50 % of cases P07949 mutations occur . Additionally , activating molecular changes in VEGFR and MET pathways have also been implicated in P04629 progression . Clinical responses with cabozantinib in P04629 could be observed in early clinical trials , and following confirmation of clinical benefit in a randomized phase III trial , cabozantinib gained FDA approval for first - line treatment of advanced P04629 in 2012 . In prostate cancer models , MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis . A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer . Therefore , randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients .", "DB08875 and prostate cancer : inhibiting seed and disrupting soil ? Treatment with cabozantinib , an inhibitor of MET and P35968 signaling , has demonstrated clinical benefit in early trials in men with metastatic prostate cancer . Preclinical evidence suggests that cabozantinib can kill cancer cell seeds while disrupting angiogenesis and stromal cells in the metastatic soil .", "Targeting MET and vascular endothelial growth factor receptor signaling in castration - resistant prostate cancer . Effective management of bone metastases in men with castration - resistant prostate cancer ( CRPC ) remains an important unmet medical need . MET and vascular endothelial growth factor receptor ( VEGFR ) are rational targets for intervention in CRPC . Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival . DB08875 is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and P35968 . A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans , bone turnover markers , and pain response , but with significant adverse events leading to dose reduction and treatment discontinuation . Lower doses of cabozantinib retain high levels of activity with less toxicity . Ongoing phase III clinical trials will define the role of cabozantinib in CRPC . We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date .", "Expression and release of phosphatidylinositol anchored cell surface molecules by a cell line derived from sensory neurons . Early postnatal mouse dorsal root ganglion neurons were found to express several glycosylphosphatidylinositol - anchored ( P06744 ) molecules from the immunoglobulin superfamily ( neural cell adhesion molecule 120 kD isoform , P13726 , Thy1 ) whose expression is developmentally regulated . A hybrid cell line ( ND26 ) , made by fusing postmitotic rat dorsal root ganglion ( Q86YR7 ) neurons with the mouse neuroblastoma N18Tg2 , could be induced to differentiate by manipulating the composition of the culture medium and expressed similar P06744 molecules to Q86YR7 neurons . We used this model system to investigate the metabolism of P06744 - anchored molecules . We found that neural cell adhesion molecule 120 Kd isoform expression decreased upon differentiation , whereas the level of P13726 and Thy1 increased , suggesting a role in neurite outgrowth processes . The ratio of molecules cleavable by exogenous phosphatidylinositol phospholipase C ( PI - P98160 ) was similar for all the P06744 - anchored molecules , which could mean that cell - specific modifications of the basic anchoring structure determine the level of potentially releasable molecules . Measurements of spontaneous release indicated that this reflected the overall level of expression of these molecules by the ND26 cell line . Finally , we observed an effect of dibutyryl DB02527 on the level of expression of P13726 and Thy1 but not of N - P62158 . However , we could not detect any significant effect of nerve growth factor ( P01138 ) either on the level of expression or on the amount of spontaneously released molecules ." ]

[ "___MASK14___", "___MASK23___", "___MASK31___", "___MASK33___", "___MASK36___", "___MASK49___", "___MASK55___", "___MASK6___", "___MASK93___" ]

[ "[ Functional significance of P25942 and P29965 linking on human lung cells ] . OBJECTIVE : To determine the possible functional significance of P25942 and P29965 ( CD154 ) linking on human lung carcinomas and to assess the potential of P25942 as a therapeutic target . METHODS : We evaluated the effect of P29965 on the surface expression of major histocompatibility complex class I ( MHC - I ) , Fas , bcl2 , CD54 , epidermal growth factor receptor ( P00533 ) , p - glucoprotein ( A6NDG6 ) , lung related protein ( Q14764 ) , cell cycle , cell apoptosis and growth kinetics of 7 lung cancer cell lines ( including 1 P25942 - transfected cell line GLC - 82 / P25942 ) by gene cloning , Western blotting , and flow cytometry etc . RESULTS : Significant increased expression of MHC - I , CD54 and Fas was observed in 4 tumor lines expressing high levels of P25942 after P29965 ( 0 . 1 micro g / ml ) linked to P25942 . P29965 ( 0 . 1 micro g / ml or greater ) in the fifth day was found to significantly inhibit the proliferation of 4 cell lines expressing high levels of P25942 , decreased the percentage of aneuploid cell , and inhibited S - phase cells entering G2 / M phase . The effect of P25942 cross - linking was reversible . P25942 - moderate and low and negative tumor did not respond to P29965 . All of 7 cell lines show no significant changes in apoptosis in either the experimental ( P29965 pulsed ) or control ( medium only ) cell cultures . CONCLUSION : Expression of P25942 on lung tumors cells expressing high level of P25942 ( including P25942 - transfected cells ) may represent a potential therapeutic target .", "DB00073 - dependent cytotoxicity by natural killer cells : influence of P08637 polymorphism on the concentration - effect relationship . The P08637 gene dimorphism generates two allotypes : FcgammaRIIIa - 158V and FcgammaRIIIa - 158F . The genotype homozygous for FcgammaRIIIa - 158V ( VV ) is associated with higher clinical response to rituximab , a chimeric anti - P11836 IgG1 used in the treatment of B lymphoproliferative malignancies . Our objective was to determine whether this genetic association relates to rituximab - dependent cytotoxicity mediated by FcgammaRIIIa / CD16a + cells . The number of CD16 + circulating monocytes , T cells , and natural killer ( NK ) cells in 54 donors was first shown to be unrelated to P08637 polymorphism . We then demonstrated that FcgammaRIIIa - 158V displays higher affinity for rituximab than FcgammaRIIIa - 158F by comparing rituximab concentrations inhibiting the binding of 3G8 mAb ( anti - CD16 ) with VV NK cells and NK cells homozygous for FcgammaRIIIa - 158F ( FF ) . VV and FF NK cells killed Daudi cells similarly after FcgammaRIIIa engagement by saturating concentrations of rituximab or 3G8 . However , the rituximab concentration resulting in 50 % lysis ( EC ( 50 ) ) observed with NK cells from VV donors was 4 . 2 times lower than that observed with NK cells from FF donors ( on average 0 . 00096 and 0 . 00402 microg / ml , respectively , P = 0 . 0043 ) . Finally , the functional difference between VV and FF NK cells was restricted to rituximab concentrations weakly sensitizing P11836 . This study supports the conclusion that P08637 genotype is associated with response to rituximab because it affects the relationship between rituximab concentration and NK cell - mediated lysis of P11836 + cells . DB00073 administration could therefore be adjusted according to P08637 genotype .", "Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK17___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK17___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK17___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .", "Platelet - associated antibodies , cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia . DB00073 is widely used in autoimmune diseases including immune thrombocytopenia ( ITP ) , although the mechanism of effect remains unclear . This study describes the effects of rituximab on platelet - associated antibodies ( PA - APAs ) , B and T cell counts and clonality ( IGHV and TRG @ gene rearrangements ) , P08637 ( FcγRIIIa ) and P12318 ( FcγRIIa ) polymorphisms and correlation to anti - P29965 ( P29965 ) response . PA - APA levels fell more frequently in responders ( 6 / 8 ) than in non - responders ( 2 / 10 : P = 0 · 08 - 0 · 15 ) . Two responders had no PA - APAs . Two non - responders with a fall in PA - APAs had very high CD8 levels . One non - responder had a B cell clone , one responder and one non - responder had a T cell clone . 15 / 16 patients had the same responses to rituximab and antiCD40L . Patients with P08637 V / V polymorphisms were more likely to respond to rituximab ( P = 0 · 03 ) . In summary , the fall in PA - APAs in responders confirms the humoural effect of rituximab . Failure to respond in patients with very high CD8 levels , despite PA - APA fall indicates a role for T cell - mediated platelet / megakaryocyte destruction . Concordance of response to anti - P29965 suggests autoantibody - producing cells are under T cell control . Finally , the effect of FCGR polymorphisms on response confirms the importance of FCGR - mediated depletion of B cells in autoimmunity . This has implications on the pathology of ITP as well as the immunological effect of B cell depletion .", "Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .", "Differential effects of endotoxin and fibrinogen degradation products ( P14324 ) on liver synthesis of fibrinogen and albumin : evidence for the involvement of a novel monokine in the stimulation of fibrinogen synthesis induced by P14324 . 1 . Administration of endotoxin or fibrinogen degradation products ( FDPs ) in rats increase fibrinogen synthesis comparable to that found during the acute phase response . 2 . An increased fibrinogen synthesis is also found in co - cultures of hepatocytes with peripheral blood mononuclear cells upon administration of endotoxin or FDPs , but not in primary cultures of hepatocytes alone . 3 . However , the increased synthesis of fibrinogen by FDPs is not accompanied by a decreased albumin synthesis , as in the case of stimulated fibrinogen synthesis induced by endotoxin in vivo and in co - cultures of hepatocytes with peripheral blood mononuclear cells , or induced by monocytic products in vivo and in primary cultures of hepatocytes alone . 4 . Since IL - 1 and / or P05231 could not be accounted for the stimulation of fibrinogen synthesis without a decreased albumin synthesis , a novel monokine produced by mononuclear cells upon Q9NRC9 administration might be involved .", "Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK75___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .", "Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .", "___MASK77___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK77___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK77___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK77___ inhibits activated T cells . We show that in vitro , ___MASK77___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK77___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK77___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK77___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK77___ to treat chronic inflammatory disease .", "Activation of tumor - promoting type 2 macrophages by P00533 - targeting antibody cetuximab . PURPOSE : In a recent randomized phase III clinical trial in metastatic colorectal cancer patients , the addition of the anti - epidermal growth factor receptor ( P00533 ) monoclonal antibody ( mAb ) cetuximab to bevacizumab and chemotherapy resulted in decreased progression - free survival , in particular for patients with the high - affinity FcγRIIIA . EXPERIMENTAL DESIGN : The presence of natural killer ( NK ) cells and type 2 ( M2 ) macrophages in colorectal cancer was determined by immunohistochemistry , using antibodies to lineage - specific markers O76036 and P34810 with Q86VB7 , respectively . Influence of tumor - bound cetuximab on M2 macrophages was carried out in vitro with P00533 - expressing tumor cells and short - term differentiated monocytes from blood donors , who were typed for the FcγRIIIA polymorphism ( CD16 ) . RESULTS : Antibody - dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs . We found that Q86VB7 - positive M2 macrophages are much more abundant in colorectal carcinomas . In vitro analysis of M2 macrophages revealed high levels of Fc - gamma receptors ( FcγR ) and Q9NZQ7 and production of P22301 and P15692 but not IL - 12 . These anti - inflammatory and tumor - promoting mediators were released upon coculture with P00533 - positive tumor cells loaded with low concentrations of cetuximab . Macrophage activation depended on P00533 expression on the tumor cells , FcγRs , target specificity of the mAb and mobility of antibody complexes . Cetuximab - induced macrophage responses were more pronounced for P08637 158 - DB00161 ( high - affinity ) carriers . CONCLUSION : These results suggest that tumor - promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies .", "Flexible migration program regulates gamma delta T - cell involvement in humoral immunity . gamma delta T cells are inadequately defined both in terms of their migration potential and contribution to antimicrobial immunity . Here , we have examined the migration profile of human blood gamma delta T cells and related cell lines and correlated these findings with their distribution in secondary lymphoid tissues and their function in B - cell cocultures . We find that resting gamma delta T cells are characterized by an inflammatory migration program similar to cells of the innate immune system . However , T - cell receptor ( TCR ) triggering resulted in the rapid but transient induction of a lymph node ( LN ) - homing program , as evidenced by functional P32248 expression and concomitant reduction in expression and function of P51681 and , to a lesser degree , P41597 . Moreover , the LN - homing program was reflected by the presence of gamma delta T cells in gastrointestinal lymphoid tissues , notably in clusters within germinal centers of B - cell follicles . In line with these findings , V gamma V delta - TCR triggering resulted in prominent expression of essential B - cell costimulatory molecules , including P29965 , OX40 , P32970 , and Q9Y6W8 . Furthermore , gamma delta T cells were shown to provide potent B - cell help during in vitro antibody production . Collectively , our findings agree with a role for gamma delta T cells in humoral immunity during the early phase of antimicrobial responses .", "Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases . BACKGROUND : Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases ( Q9UKU7 ) . To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis , we investigated their effects on endotoxin - induced tumour necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 1 beta and P05231 release by elutriation - purified human monocytes in vitro . METHODS : Drugs tested were dexamethasone , DB00244 , sulphapyridine and zileuton ( a P09917 inhibitor ) . Monocytes were isolated and stimulated with endotoxin , and P01375 , IL - 1 and P05231 levels were determined using an enzyme - linked immunosorbent assay . RESULTS : Monocyte stimulation with endotoxin resulted in an average P01375 release of 2464 +/- 64 pg / 10 ( 6 ) cells , IL - 1 release of 616 +/- 47 pg / 10 ( 6 ) cells and P05231 release of 2259 +/- 148 pg / 10 ( 6 ) cells . Addition of dexamethasone resulted in a reduction of P01375 , IL - 1 and P05231 release to below background levels . DB00891 significantly reduced P01375 and induced IL - 1 release in a dose - dependent fashion , but had no significant effect on P05231 release . 5 - ___MASK75___ did not modulate P05231 synthesis , but significantly reduced IL - 1 and enhanced P01375 synthesis . Zileuton reduced P01375 and P05231 release , but enhanced IL - 1 release . CONCLUSION : We conclude that these anti - inflammatory drugs are able to modulate cytokine release by human monocytes . Further studies are needed to determine whether these effects are related to their therapeutic efficacy in Q9UKU7 .", "M2 macrophages phagocytose rituximab - opsonized leukemic targets more efficiently than m1 cells in vitro . Because macrophages have been implicated as major players in the mechanism of action of rituximab , we have investigated the factors that modulate their tumor cell killing potential . Human macrophages , differentiated in vitro from peripheral blood monocytes , were used in binding and phagocytosis assays using B - chronic lymphocytic leukemia or lymphoma target cells opsonized with rituximab . Phagocytosis was maximal at 0 . 1 microg / ml rituximab and was not significantly affected by P11836 expression levels or by P08637 polymorphism at position 158 ( DB00161 / DB00120 ) . The role of FcgammaRs was demonstrated by complete inhibition of phagocytosis by excess human Igs . Because macrophages can be differentiated to M1 - or M2 - type cells with either GM - P04141 or P09603 , respectively , and can be classically activated by proinflammatory stimuli ( P01579 / LPS ) or undergo alternative activation with cytokines such as P05112 or P22301 , we have analyzed the effect of these different polarization programs on the phagocytosis mediated by rituximab . Macrophages differentiated in presence of P09603 showed a 2 - to 3 - fold greater phagocytic capacity compared with GM - P04141 - induced cells . Furthermore , addition of P22301 significantly increased , whereas P05112 decreased phagocytosis by both P09603 - and GM - P04141 - differentiated macrophages . LPS / P01579 had little effect . Expression of CD16 , CD32 , and CD64 in different macrophage populations correlated with phagocytic activity . Interestingly , several B lymphoma cell lines were observed to secrete 400 - 1300 pg / ml P22301 in vitro , and coculture of human macrophages with lymphoma conditioned medium increased significantly their phagocytic capacity . Our data suggest that cytokines secreted by lymphoma cells can favor alternate activation of macrophages with a high phagocytic capacity toward rituximab - opsonized targets .", "Rescue of impaired NK cell activity in hodgkin lymphoma with bispecific antibodies in vitro and in patients . Natural killer ( NK ) cells represent a key component of the innate immune system against cancer . Nevertheless , malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance . Hodgkin lymphoma ( HL ) is characterized by P28908 (+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes . The latter obviously fail to eliminate the malignant cell population . Here , we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means . We demonstrate that peripheral NK cells ( pNK ) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays . Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors O14931 ( P46379 / P46379 ) and P26718 ( Q29983 ) , factors known to constrict NK cell function . In vitro , NK cell cytotoxicity could be restored by an P26718 / O14931 - independent bispecific antibody construct ( CD30xCD16A ) . It artificially links the tumor receptor P28908 with the cytotoxicity Q13241 P08637 . Moreover , we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells . These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically .", "[ Monoclonal antibody therapy for disorders of hemostasis and coagulation ] . Monoclonal antibody therapies have conducted to not only hematologic malignancies but also disorders of hemostasis and coagulation . This article describes the recent advances of monoclonal antibody therapy for bleeding disorders such as idiopathic thrombocytopenic purpura ( ITP ) , hemophilia A , disseminated intravascular coagulation ( DIC ) , and thrombosis . DB00073 , chimeric anti - P11836 monoclonal antibody treatment has a valuable effect in the patients with ITP , and clinical trials using anti - P29965 monoclonal antibody for ITP are underway . Anti - P29965 monoclonal antibody can be an alternative therapy for hemophilia A patients with inhibitors to factor VIII . In thrombosis , anti - tissue factor monoclonal antibody and anti - factor IX ( a ) monoclonal antibody were established as novel anticoagulant regents . P00747 activator inhibitor - 1 ( P05121 ) increases in endotoxin - induced DIC and many thrombotic diseases such as myocardial infarction , type 2 diabetes mellitus , and hyperlipidemia . Anti - P05121 monoclonal antibody reduced fibrin deposition in DIC mouse model . Treatment of these monoclonal antibodies for the molecules regulating coagulation - fibrinolysis system may be utilized for acute coronary syndrome and venous thrombosis .", "A new epigenetic challenge : systemic lupus erythematosus . In recent years , compelling evidence has been gathered that supports a role for epigenetic alterations in the pathogenesis of systemic lupus erythematosus ( SLE ) . Different blood cell populations of SLE patients are characterized by a global loss of DNA methylation . This process is associated with defects in P29323 pathway signalling and consequent P26358 1 downregulation . Hypomethylation of gene promoters has been described , which permits transcriptional activation and therefore functional changes in the cells and also hypomethylation of the ribosomal RNA gene cluster . Among the identified targets undergoing demethylation are genes involved in autoreactivity ( P20701 ) , osmotic lysis and apoptosis ( P14222 , P50281 and P80188 ) , antigen presentation ( Q99062 ) , inflammation ( MMP 14 ) , B - T - cell interaction ( P32970 and P29965 ) and cytokine pathways ( Q99062 , P05112 , P05231 and P38484 ) . DNA methylation inhibitors are also known to induce autoreactivity in vitro and cause a lupus - like disease in vivo . Further , altered patterns of histone modifications have been described in SLE . P01730 + lymphocytes undergo global histone H3 and H4 deacetylation and consequent skewed gene expression . Although multiple lines of evidence highlight the contribution of epigenetic alterations to the pathogenesis of lupus in genetically predisposed individuals , many questions remain to be answered . Attaining a deeper understanding of these matters will create opportunities in the promising area of epigenetic treatments .", "___MASK27___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK27___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .", "Platelets trigger a P25942 - dependent inflammatory response in the microvasculature of inflammatory bowel disease patients . BACKGROUND & AIMS : Platelets circulate in an activated state in patients with inflammatory bowel disease ( Q9UKU7 ) , but their role in the pathogenesis of Q9UKU7 is unclear . The recent demonstration that activated platelets express P29965 ( L ) provides a mechanism of interaction with P25942 - positive endothelial cells , inducing them to produce proinflammatory mediators . We investigated whether platelets from patients with Q9UKU7 express enhanced levels of P29965 and induce human intestinal microvascular endothelial cells ( HIMEC ) to up - regulate cell adhesion molecule ( P62158 ) expression and secrete chemokines . METHODS : P29965 expression was assessed in resting and thrombin - activated platelets by flow cytometry and in mucosal microthrombi by confocal microscopy . Platelet - HIMEC cocultures were used to study P62158 up - regulation , and interleukin ( IL ) - 8 and RANTES production by HIMEC . RESULTS : Q9UKU7 platelets expressed significantly higher P29965 levels than those of healthy subjects , and P29965 - positive platelets were detected in Q9UKU7 - involved mucosa . Activated platelets up - regulated expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 as well as production of interleukin 8 by HIMEC in a P25942 - dependent fashion . High levels of RANTES were present in platelet - HIMEC cocultures and platelets were identified as the source of this chemokine , which mediated T - cell adhesion to HIMEC . CONCLUSIONS : These results show that platelets can actively contribute to mucosal inflammation and represent a previously unrecognized component of Q9UKU7 pathogenesis .", "P08637 - 158 polymorphism influences the biological response to infliximab in Crohn ' s disease through affecting the ADCC activity . An association between P08637 - 158 V / F polymorphism and biological responses to infliximab has been reported in Crohn ' s disease ( CD ) in Western countries . However , little is known about the mechanism by which gene polymorphism affects the responses to infliximab . The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab . Japanese CD patients were examined retrospectively at weeks 8 and 30 . Clinical and biological responses were assessed by the Crohn ' s disease activity index and P02741 levels , respectively . The infliximab - binding affinity of natural killer ( NK ) cells from P08637 - 158 V / V , V / F and F / F donors was examined . DB00065 - mediated antibody - dependent cell - mediated cytotoxicity ( ADCC ) activities were also determined using transmembrane P01375 - α - expressing Jurkat T cells as target cells and peripheral blood mononuclear cells ( PBMCs ) from V / V , V / F and F / F donors as effector cells . Biological responses at week 8 were statistically higher in V / V patients , whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes . NK cells and PBMCs from V / V patients also showed higher infliximab - binding affinity and infliximab - mediated ADCC activity , respectively . Our results suggest that P08637 - 158 polymorphism is a predicting factor of biological responses to infliximab in the early phases . P08637 - 158 polymorphism was also found to affect the infliximab - binding affinity of NK cells and infliximab - mediated ADCC activity in vitro , suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients .", "Influence of FcγRIIIA genetic polymorphism on T - lymphocyte depletion induced by rabbit antithymocyte globulins in kidney transplant patients . INTRODUCTION : Polyclonal antithymocyte globulins ( ATG ) have been used in transplantation for several decades , but the sources of the interindividual variability of their effect are poorly understood . An influence of the P08637 - 158V / F genetic polymorphism on the horse ATG concentration - effect relationship was reported in kidney transplant patients . The objective of the present study was to confirm the influence of the P08637 polymorphism on the extent of lymphocyte depletion in kidney transplant patients treated with rabbit antithymocyte globulin ( r - ATG ) . MATERIALS AND METHODS : Of the 194 transplant patients treated with r - ATG between 1998 and 2002 in our institution , 69 patients were eligible and included in this retrospective study . Biomarkers of response were CD3 and P01730 counts . Dose - effect data were analyzed using a population approach , and a two - compartment turnover model with stimulation of lymphocyte ' output ' . Since r - ATG concentrations were not available , a K - PD model was used . The influence of P08637 genotype on estimated parameters was investigated . RESULTS : The r - ATG infusion rate leading to a 50 % stimulation of CD3 + output ( EDK ( 50 ) ) , which is inversely related to patient sensitivity to r - ATG treatment , decreased with the number of V alleles ( P = 0 . 0016 ) . CONCLUSION : The genetic polymorphism of P08637 influences r - ATG effect on CD3 count in kidney transplant patients , those with the V allele being more sensitive to antilymphocyte serum . These results also suggest that r - ATG act , at least in part , by antibody - dependent cellular cytotoxicity .", "Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK50___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .", "Genetic background of Japanese patients with antineutrophil cytoplasmic antibody - associated vasculitis : association of HLA - Q8IUH3 * 0901 with microscopic polyangiitis . OBJECTIVE : To examine association of 8 candidate genes with susceptibility to antineutrophil cytoplasmic antibody ( ANCA ) - associated vasculitis ( AAV ) in Japanese patients . Little is known on the genetic background of AAV in Japanese patients mainly because of the difficulty in collecting a sufficient number of samples for the genetics study . METHODS : Sixty - nine patients , including 50 with microscopic polyangiitis ( DB00603 ) , were recruited in a multicenter study . Among them , 64 patients were positive for myeloperoxidase ( P05164 ) - ANCA . Associations of HLA - Q8IUH3 , tumor necrosis factor - alpha promoter ( P01375 ) , P01375 receptor 2 ( P20333 ) , Fcgamma receptor IIa ( P12318 ) , IIb ( P31994 ) , IIIa ( P08637 ) , IIIb ( O75015 ) , and P16410 ( P16410 ) polymorphisms were examined in a case - control analysis . RESULTS : A significant association of HLA - Q8IUH3 * 0901 with DB00603 ( p = 0 . 0037 , OR 2 . 44 , 95 % CI 1 . 33 - 4 . 46 ) , as well as with P05164 - ANCA positivity ( p = 0 . 0014 , OR 2 . 44 , 95 % CI 1 . 41 - 4 . 22 ) , was detected . There was no difference in the P01375 promoter haplotype frequencies between patients with DB00603 and controls , excluding the possibility that the association of Q8IUH3 * 0901 was secondarily caused by linkage disequilibrium with P01375 . No association was observed for P20333 , FCGR , or P16410 with DB00603 , nor with the presence of P05164 - ANCA , although the combined genotype P12318 - 131H / H and 3A - 176F / F was increased in patients with DB00603 ( p = 0 . 025 ) . CONCLUSION : There was an association of HLA - Q8IUH3 * 0901 with DB00603 and P05164 - ANCA positive vasculitis in Japanese patients .", "Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura : a pilot study . Inflammatory cytokines and low - affinity Fcgamma receptor ( FcgammaR ) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura ( cITP ) and 218 controls . Genotype analysis included common variants in the regulatory regions of cytokines , P01375 , P01374 , P18510 , P01583 , P01584 , P05112 , P05231 and P22301 , and structural variants of the low affinity FcgammaRs , P12318 , P08637 and O75015 . Associations were observed for P01375 ( P = 0 . 0032 ) , P01374 ( P = 0 . 019 ) , P08637 ( P = 0 . 038 ) and O75015 ( P = 0 . 0034 ) . Two combinations of genotypes ( P01375 and P08637 ; P = 0 . 0003 , and P01374 and O75015 ; P = 0 . 011 ) were significantly associated with cITP . These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis .", "___MASK17___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .", "Selective inhibition of P01579 - induced autophagy by Mir155 - and Mir31 - responsive P41221 and SHH signaling . Autophagy is one of the major immune mechanisms engaged to clear intracellular infectious agents . However , several pathogens have evolved strategies to evade autophagy . Here , we demonstrated that Mycobacteria , Shigella , and Listeria but not Klebsiella , Staphylococcus , and Escherichia inhibit P01579 - induced autophagy in macrophages by evoking selective and robust activation of WNT and SHH pathways via P42345 . Utilization of gain - or loss - of - function analyses as well as mir155 - null macrophages emphasized the role of P42345 - responsive epigenetic modifications in the induction of Mir155 and Mir31 . Importantly , cellular levels of PP2A , a phosphatase , were regulated by Mir155 and Mir31 to fine - tune autophagy . Diminished expression of PP2A led to inhibition of P49841 , thus facilitating the prolonged activation of WNT and SHH signaling pathways . Sustained WNT and SHH signaling effectuated the expression of anti - inflammatory lipoxygenases , which in tandem inhibited P01579 - induced JAK - P35610 signaling and contributed to evasion of autophagy . Altogether , these results established a role for new host factors and inhibitory mechanisms employed by the pathogens to limit autophagy , which could be targeted for therapeutic interventions .", "Pathogenic role of NF - kappaB activation in tubulointerstitial inflammatory lesions in human lupus nephritis . In vitro and in vivo experimental studies suggest that the transcription factor NF - kappaB plays a role in tubulointerstitial injury . We investigated possible cellular and molecular mechanisms involving NF - kappaB activation in the progression of tubulointerstitial lesions in human lupus nephritis ( LN ) . Paraffin - embedded renal biopsies from 50 patients with LN and six control patients with minimal change disease ( O95822 ) were examined by Southwestern histochemistry for in situ detection of active NF - kappaB and AP - 1 . Immunohistochemistry was performed to examine the expression of NF - kappaB , AP - 1 , and NF - kappaB regulatory proteins ( IkappaB - alpha , p - IkappaB - alpha , and O15111 proteins ) , as well as NF - kappaB and AP - 1 downstream target proinflammatory molecules ( P05362 , P01375 , IL - 1beta , P05231 , and GM - P04141 ) and NF - kappaB upstream signaling molecules ( P25942 and P29965 ) . We observed extensive upregulation of activated NF - kappaB in renal tubular cells and interstitial cells , in parallel with overactivation of transcription factor AP - 1 in LN , as compared with normal controls and O95822 . Tubular expression of activated NF - kappaB correlated well with the degree of tubulointerstitial histopathological indices and / or renal function . Tubulointerstitial O15111 expression was specifically upregulated in LN . IkappaB - alpha and p - IkappaB - alpha were detected only in interstitial cells in LN . Tubulointerstitial expression levels of NF - kappaB and AP - 1 downstream inflammatory molecules and NF - kappaB upstream signaling molecules P25942 and P29965 were markedly enhanced in LN as compared with O95822 or normal controls and were associated with tubulointerstitial histopathological indices and / or renal function . The results suggest that altered O15111 expression and NF - kappaB activation along with AP - 1 overexpression may play a pathogenic role in tubulointerstitial injury in human LN mediated through a network of downstream proinflammatory molecules .", "Nonredundant roles for CD1d - restricted natural killer T cells and conventional P01730 + T cells in the induction of immunoglobulin E antibodies in response to interleukin 18 treatment of mice . Interleukin ( IL ) - 18 synergizes with IL - 12 to promote T helper cell ( Th ) 1 responses . Somewhat paradoxically , Q14116 administration alone strongly induces immunoglobulin ( Ig ) E production and allergic inflammation , indicating a role for Q14116 in the generation of Th2 responses . The ability of Q14116 to induce IgE is dependent on P01730 + T cells , P05112 , and signal transducer and activator of transcription ( stat ) 6 . Here , we show that Q14116 fails to induce IgE both in CD1d -/- mice that lack natural killer T ( NKT ) cells and in class II -/- mice that lack conventional P01730 + T cells . However , class II -/- mice reconstituted with conventional P01730 + T cells show the capacity to produce IgE in response to Q14116 . NKT cells express high levels of Q14116 receptor ( R ) alpha chain and produce significant amounts of P05112 , P15248 , and P35225 , and induce P29965 expression in response to P60568 and Q14116 stimulation in vitro . In contrast , conventional P01730 + T cells express low levels of IL - 18Ralpha and poorly respond to P60568 and Q14116 . Nevertheless , conventional P01730 + T cells are essential for B cell IgE responses after the administration of Q14116 . These findings indicate that NKT cells might be the major source of P05112 in response to Q14116 administration and that conventional P01730 + T cells demonstrate their helper function in the presence of NKT cells .", "Association of the P08637 - 158F / V gene polymorphism with the response to rituximab treatment in Spanish systemic autoimmune disease patients . DB00073 is being used as treatment for systemic autoimmune diseases . The objective of this study was to determine whether the genetic variant in the Fc gamma - receptor III a ( P08637 ) gene , 158F / V , contributes to the observed variation in response to rituximab in patients with systemic autoimmune diseases . DNA samples from 132 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for P08637 - 158F / V ( rs396991 ) gene polymorphism using the TaqMan (®) allelic discrimination technology . Six months after infusion with rituximab we evaluated the response to the drug : 61 % of the patients showed a complete response , partial 27 % and 12 % did not respond to the treatment . A statistically significant difference was observed in V allele frequency between responder ( 38 % ) and nonresponder ( 16 % ) patients ( p = 0 . 01 ; odds ratio [ OR ]= 3 . 24 , 95 % confidence interval [ CI ] 1 . 17 - 11 . 1 ) . DB00073 was also more effective in V allele carriers ( 94 % ) than in homozygous FF patients ( 81 % ) : p = 0 . 02 ; OR = 3 . 96 , 95 % CI 1 . 10 - 17 . 68 . These results suggest that P08637 - 158F / V ( rs396991 ) gene polymorphism play a role in the response to rituximab in autoimmune diseases . Validation of these findings in independent cohorts is warranted .", "Co - expression of sCD40LIg and ___MASK77___ mediated by adenovirus prolonged mouse skin allograft survival . OBJECTIVE : To investigate the role of simultaneous blockade of P25942 / P29965 and P33681 / P10747 pathways in the immune tolerance via co - expression of sCD40LIg and ___MASK77___ mediated by replication - defective adenovirus . METHODS : Ad - sCD40LIg - IRES ( 2 )- ___MASK77___ , replication - defective adenovirus co - expressing sCD40LIg and ___MASK77___ , was constructed and identified . The co - expression of sCD40LIg and ___MASK77___ was evaluated with confocal laser scanning microscope and Western blotting . Skin transplantations of C57BL / 6 to BALB / c mice were performed . PBS , Ad - Shuttle - CMV and Ad - sCD40LIg - IRES ( 2 )- ___MASK77___ were administered . Skin graft survival was monitored and the mRNA expression of both genes was evaluated in the skin allografts . RESULTS : Ad - sCD40LIg - IRES ( 2 )- ___MASK77___ was constructed successfully and identified . The co - expression of sCD40LIg and ___MASK77___ was identified with confocal laser scanning microscopy and Western blotting . Compared to the skin graft mean survival time ( MST ) of non - treated group ( ( 5 . 75 +/- 0 . 71 ) d ) or Ad - Shuttle - CMV - treated group ( ( 5 . 50 +/- 0 . 53 ) d ) , the skin graft MST was dramatically prolonged in the Ad - sCD40LIg - IRES ( 2 )- ___MASK77___ - treated group ( ( 16 . 38 +/- 1 . 19 ) d , P < 0 . 001 ) . The mRNA expression of both genes was detected . CONCLUSION : Ad - sCD40LIg - IRES ( 2 )- ___MASK77___ , a replication - defective adenovirus carrying genes encoding sCD40LIg and ___MASK77___ , was constructed . Simultaneous blockade of P25942 / P29965 and P33681 / P10747 costimulatory pathway mediated by replication - defective adenovirus significantly prolonged skin allograft survival in mice .", "___MASK79___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK79___ , in the USA in 2003 .", "DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "Differential radiosensitisation by ZD1839 ( ___MASK4___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK4___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .", "Leukocyte P29965 deficiency affects the CD25 (+) P01730 T cell population but does not affect atherosclerosis . Inhibition of P25942 - P29965 interactions results in a reduction of innate regulatory T cells ( Tregs ) in P25942 (-/-) mice and induces a stable plaque phenotype in atherosclerosis - prone mouse strains . Here we investigated the effects of leukocyte P29965 on the Treg population and on atherosclerosis . P01130 (-/-) mice were reconstituted with wild - type or P29965 (-/-) bone marrow ( BM ) . These BM chimeras were analysed by flow cytometry for the presence of innate Tregs ( CD45RB ( low ) CD25 (+) P01730 ) in lymphoid organs and peripheral blood . As in P25942 (-/-) mice , the CD45RB ( high ): CD45RB ( low ) P01730 T cell ratio significantly increased and the CD25 (+) P01730 (+) subpopulation significantly decreased in P01130 (-/-) mice receiving P29965 (-/-) BM compared to P01130 (-/-) mice receiving wild - type BM . However , atherosclerotic plaque progression and plaque phenotype did not change in P01130 (-/-) mice reconstituted with P29965 (-/-) BM . In conclusion , the present study shows that P25942 - P29965 interactions on leukocytes are essential for the size of the CD45RB ( low ) CD25 (+) P01730 Treg subpopulation . Nevertheless , P29965 deficiency on hemopoietic cells did not affect atherosclerosis , implying that P29965 expressing leukocytes alone are not responsible for the stable plaque phenotype observed after total P29965 blockade .", "Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK83___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .", "[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK73___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .", "DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .", "Program death - 1 engagement upon TCR activation has distinct effects on costimulation and cytokine - driven proliferation : attenuation of Q9Y6W8 , P05112 , and Q9HBE4 , but not P10747 , P13232 , and P40933 responses . The program death 1 ( P18621 ) receptor and its ligands , P18621 ligand ( PD - L ) 1 and Q9BQ51 , define a novel regulatory pathway with potential inhibitory effects on T , B , and monocyte responses . In the present study , we show that human P01730 (+) T cells express P18621 , Q9NZQ7 , and Q9BQ51 upon activation , and Abs to the receptor can be agonists or antagonists of the pathway . Under optimal conditions of stimulation , Q9Y6W8 but not P10747 costimulation can be prevented by P18621 engagement . P60568 levels induced by costimulation are critical in determining the outcome of the P18621 engagement . Thus , low to marginal P60568 levels produced upon Q9Y6W8 costimulation account for the greater sensitivity of this pathway to P18621 - mediated inhibition . Interestingly , exogenous P60568 , P13232 , and P40933 but not P05112 and Q9HBE4 can rescue P18621 inhibition , suggesting that among these cytokines only those that activate P42229 can rescue P18621 inhibition . As P42229 has been implicated in the maintenance of IL - 2Ralpha expression , these results suggest that P13232 and P40933 restore proliferation under conditions of P18621 engagement by enhancing high - affinity IL - 2R expression and hence , P60568 responsiveness .", "___MASK27___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies ." ]

[ "___MASK17___", "___MASK27___", "___MASK4___", "___MASK50___", "___MASK73___", "___MASK75___", "___MASK77___", "___MASK79___", "___MASK83___" ]

[ "A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .", "Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .", "Allele C - specific methylation of the 5 - Q13049 receptor gene : evidence for correlation with its expression and expression of DNA methylase P26358 . Differential DNA methylation has been suggested to contribute to differential activity of alleles C and T and thereby to genetic associations between the C / T ( 102 ) polymorphism in the 5 - Q13049 receptor gene ( 5HT2AR ) and psychiatric disorders . We surveyed methylation in two CpG sites , which are specific to allele C . The majority of allele C - specific CpG sites were methylated in human temporal cortex and peripheral leukocytes and levels of methylation varied between individuals . Levels of methylation in the promoter correlated significantly with the expression of 5HT2AR . Methylation of allele C - specific CpG sites in the first exon correlated significantly with the expression of DNA methylase 1 ( P26358 ) but not S - adenosylhomocysteine hydrolase ( P23526 ) . These findings support the hypothesis that allele - specific DNA methylation is involved in regulation of 5HT2AR expression , influencing expression differences between alleles C and T .", "Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK30___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK30___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .", "Molecular targeting of the oncoprotein P53350 in pediatric acute myeloid leukemia : RO3280 , a novel P53350 inhibitor , induces apoptosis in leukemia cells . P53350 ( P53350 ) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer - specific small molecule drugs . RO3280 was recently identified as a novel P53350 inhibitor ; however its therapeutic effects in leukemia treatment are still unknown . We found that the P53350 protein was highly expressed in leukemia cell lines as well as 73 . 3 % ( 11 / 15 ) of pediatric acute myeloid leukemia ( AML ) samples . P53350 mRNA expression was significantly higher in AML samples compared with control samples ( 82 . 95 ± 110 . 28 vs . 6 . 36 ± 6 . 35 ; p < 0 . 001 ) . Kaplan - Meier survival analysis revealed that shorter survival time correlated with high tumor P53350 expression ( p = 0 . 002 ) . The 50 % inhibitory concentration ( IC50 ) of RO3280 for acute leukemia cells was between 74 and 797 nM . The IC50 of RO3280 in primary acute lymphocytic leukemia ( ALL ) and AML cells was between 35 . 49 and 110 . 76 nM and 52 . 80 and 147 . 50 nM , respectively . RO3280 induced apoptosis and cell cycle disorder in leukemia cells . RO3280 treatment regulated several apoptosis - associated genes . The regulation of P43146 , P38936 , Q06187 , and O14508 was verified by western blot . These results provide insights into the potential use of RO3280 for AML therapy ; however , the underlying mechanisms remain to be determined .", "Reduced expression of inducible gelatinase B / matrix metalloproteinase - 9 in monocytes from patients with myelodysplastic syndrome : Correlation of inducible levels with the percentage of cytogenetically marked cells and with marrow cellularity . Regulatory molecules produced by stromal cells are often membrane bound until cleaved by matrix metalloproteinases ( MMPs ) ; cleavage can either activate or inactivate regulatory functions . We report here that marrow stromal cells induce the expression of P14780 in monocytes . Induction was contact independent and could be reproduced with recombinant P13500 / P13500 , whereas P05231 , P09603 , DB00099 , GM - P04141 , P10145 / P10145 , P48061 / P48061 , and P09341 / P09341 did not have this effect . Stroma - induced levels of P14780 in the monocyte population from healthy donors were relatively consistent , whereas induced levels varied significantly ( P < . 001 ) in the P08571 + population from 27 patients with myelodysplastic syndrome ( P43034 ) . In patients with a clonal chromosomal marker , the level of inducible P14780 expression in the monocyte population was inversely correlated with the percentage of marker - positive cells ( n = 11 , P = . 01 ) , suggesting that the ability to induce P14780 may be compromised in clonally derived monocytes . The inducible levels of P14780 were also inversely correlated with marrow cellularity observed in biopsies from P43034 patients ( P < . 001 ) . We conclude that monocytes can express P14780 in response to stromal factors and that this response may be significantly decreased in P43034 - derived monocytes .", "P13688 impedes thyroid cancer growth but promotes invasiveness : a putative mechanism for early metastases . P13688 , also known as biliary glycoprotein ( BGP ) , CD66a , Q00839 and C - P62158 , is a member of the P06731 immunoglobulin superfamily . P13688 is a putative tumor suppressor based on diminished expression in some solid neoplasms such as colorectal carcinoma . However , P13688 is overexpressed in some tumors such as non - small cell lung cancer . To clarify the mechanism of action of this cell adhesion molecule , we studied thyroid carcinoma that has a spectrum of morphologies and variable behavior allowing separation of proliferation from invasion and metastasis . P13688 is expressed in thyroid carcinoma cell lines derived from tumors that exhibit aggressive behavior . Introduction of P13688 into endogenously deficient WRO cells resulted in reduced cell cycle progression associated with P38936 upregulation and diminished Rb phosphorylation . Forced P13688 expression enhanced cell - matrix adhesion and migration and promoted tumor invasiveness . Conversely , small interfering RNA ( siRNA ) - mediated downregulation of P13688 expression in Q9BYG7 cells accelerated cell cycle progression and significantly enhanced tumor size in xenografted mice . P13688 is not appreciably expressed in normal thyroid tissue or benign thyroid tumors . In a human thyroid tissue array , P13688 reactivity was associated with metastatic spread but not with increased tumor size . These findings identify P13688 as a unique mediator that restricts tumor growth whereas increasing metastatic potential . Our data highlight a complex repertoire of actions providing a putative mechanism underlying the spectrum of biologic behaviors associated with thyroid cancer .", "Oxidative stress - induced p53 activity is enhanced by a redox - sensitive Q96A56 SUMOylation . Tumor Protein p53 - Induced Nuclear Protein 1 ( Q96A56 ) is a tumor suppressor that modulates the p53 response to stress . Q96A56 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes . Q96A56 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development . In this work , we report that redox - dependent induction of p53 transcriptional activity is enhanced by the oxidative stress - induced SUMOylation of Q96A56 at lysine 113 . This SUMOylation is mediated by Q9Y6X2 and O00257 , two SUMO ligases especially related to the p53 activation upon DNA damage . Importantly , this modification is reversed by three P63165 - specific proteases Q9P0U3 , 2 and 6 . Moreover , Q96A56 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions . Q96A56 mutation at lysine 113 prevents the pro - apoptotic , antiproliferative and antioxidant effects of Q96A56 by impairing the p53 response on its target genes P38936 , Bax and PUMA . We conclude that Q96A56 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress .", "Molecular genetic classification of central nervous system malformations . Traditional schemes of classifying nervous system malformations are based on descriptive morphogenesis of anatomic processes of ontogenesis , such as neurulation , neuroblast migration , and axonal pathfinding . This proposal is a first attempt to incorporate the recent molecular genetic data that explain programming of development etiologically . A scheme based purely on genetic mutations would not be practical , in part because only in a few dysgeneses are the specific defects known , but also because several genes might be involved sequentially and many genes inhibit or augment the expression of others . The same genes serve different functions at different stages and are involved in multiple organ systems . Some complex malformations , such as holoprosencephaly , result from several unrelated defective genes . Finally , a pure genetic classification would be too inflexible to incorporate some anatomic criteria . The basis for the proposed scheme is , therefore , disturbances in patterns of genetic expression ; polarity gradients of the axes of the neural tube ( eg , upregulation or downregulation of genetic influences ) ; segmentation ( eg , deletions of specific neuromeres , ectopic expression ) ; mutations that cause change in cell lineage ( eg , dysplastic gangliocytoma of cerebellum , myofiber differentiation within brain ) ; and specific genes or molecules that mediate neuroblast migration in its early ( eg , filamin - 1 ) , middle ( eg , P43034 , double - cortin ) , or late course ( eg , reelin , Q9NUQ9 - P62158 ) . The proposed scheme undoubtedly will undergo many future revisions , but it provides a starting point using currently available data .", "Enhanced sensitization to taxol - induced apoptosis by herceptin pretreatment in ErbB2 - overexpressing breast cancer cells . The recombinant humanized anti - ErbB2 / P04626 monoclonal antibody Herceptin ( ___MASK28___ ) has been shown to significantly enhance the tumoricidaleffects of antitumor drugs such as paclitaxel ( DB01229 ) in patients with ErbB2 - overexpressing breast cancers . Here , we investigated the molecular mechanisms by which Herceptin enhances the antitumor effects of DB01229 . Because activation of p34 ( Cdc2 ) is required for DB01229 - induced apoptosis and because overexpression of ErbB2 blocks DB01229 - induced apoptosis by inhibiting p34 ( Cdc2 ) activation , we studied the effect of Herceptin treatment on p34 ( Cdc2 ) kinase activation and apoptosis in DB01229 - treated human breast carcinoma cell lines MDA - MB - 435 , SKBr3 , MDA - MB - 453 , and 435 . eB , which is an ErbB2 transfectant of MDA - MB - 435 . Herceptin treatment down - regulated ErbB2 , reduced the inhibitory phosphorylation of Cdc2 on DB00135 - 15 , and down - regulated the expression of P38936 ( Cip1 ) , a Cdc2 inhibitor . Herceptin plus DB01229 treatment led to higher levels of p34 ( Cdc2 ) kinase activity and apoptosis in ErbB2 - overexpressing breast cancer cells , which is likely attributable to inhibition of Cdc2 - DB00135 - 15 phosphorylation and P38936 ( Cip1 ) expression . Because significant dephosphorylation of Cdc2 - DB00135 - 15 and down - regulation of P38936 ( Cip1 ) occur at least 24 h after Herceptin treatment , we investigated whether 24 h Herceptin pretreatment will render ErbB2 - overexpressing breast cancer cells more sensitive to DB01229 - induced apoptosis compared with the simultaneous treatment of Herceptin plus DB01229 . Indeed , Herceptin pretreatment increased DB01229 - induced apoptosis and cytotoxicity in vitro and more effectively inhibited the growth of tumor xenografts with enhanced in vivo apoptosis . Thus , Herceptin treatment of ErbB2 - overexpressing cells can inhibit ErbB2 - mediated Cdc2 - DB00135 - 15 phosphorylation and P38936 ( Cip1 ) up - regulation , which allows effective p34 ( Cdc2 ) activation and induction of apoptosis upon DB01229 treatment . Herceptin pretreatment renders ErbB2 - overexpressing breast cancers more susceptible to DB01229 - induced cell death , which may have important clinical therapeutic implications .", "Overexpression of transcriptional coactivator Q9Y6Q9 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness . Amplified in breast cancer 1 ( Q9Y6Q9 ) is a transcriptional coactivator for nuclear receptors and other transcription factors . Q9Y6Q9 has an important role in malignancy of several cancers such as breast and prostate cancers . However , its involvement in human hepatocellular carcinoma ( HCC ) progression remains unclear . Here , we found that Q9Y6Q9 protein was overexpressed in 23 of 34 human HCC specimens ( 68 % ) . Down - regulation of Q9Y6Q9 reduced HCC cell proliferation , migration , invasion , colony formation ability and tumorigenic potential in nude mice . These phenotypic changes caused by Q9Y6Q9 knockdown correlated with increased expression of the cell cycle inhibitor P38936 ( Cip1 / Waf1 ) and decreased Akt activation and the expression of proliferating cell nuclear antigen ( P12004 ) and matrix metallopeptidase P14780 . In agreement with these findings , clinical Q9Y6Q9 - positive HCC expressed higher levels of P12004 than Q9Y6Q9 - negative HCC . A positive correlation was established between the levels of Q9Y6Q9 protein and P12004 protein in HCC , suggesting that Q9Y6Q9 may contribute to HCC cell proliferation . In addition , P14780 expression in Q9Y6Q9 - postive HCC was significantly higher than that in Q9Y6Q9 - negative HCC , suggesting that Q9Y6Q9 - postive HCC may be more invasive . Collectively , our results show that overexpression of Q9Y6Q9 promotes human HCC progression by enhancing cell proliferation and invasiveness . Therefore , Q9Y6Q9 is a master regulator of human HCC growth and might be a useful molecular target for HCC prognosis and treatment .", "Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK69___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .", "Cell adhesion molecule uvomorulin expression in human breast cancer cell lines : relationship to morphology and invasive capacities . Loss of cell - cell adhesion in carcinoma cells may be an important step in the acquisition of an invasive , metastatic phenotype . We have examined the expression of the epithelial - specific cell adhesion molecule uvomorulin ( P12830 , cell - P12830 , L - P62158 ) in human breast cancer cell lines . We find that fibroblastoid , highly invasive , vimentin - expressing breast cancer cell lines do not express uvomorulin . Of the more epithelial - appearing , less invasive , keratin - expressing breast cancer cell lines , some express uvomorulin , and some do not . We examined the morphologies of the cell lines in the reconstituted basement membrane matrix Matrigel and measured the ability of the cells to traverse a Matrigel - coated filter as in vitro models for detachment of carcinoma cells from neighboring cells and invasion through basement membrane into surrounding tissue . Colonies of uvomorulin - positive cells have a characteristic fused appearance in Matrigel , whereas uvomorulin - negative cells appear detached . Cells which are uvomorulin negative and vimentin positive have a stellate morphology in Matrigel . We show that uvomorulin is responsible for the fused colony morphology in Matrigel since treatment of uvomorulin - positive MCF - 7 cells with an antibody to uvomorulin caused the cells to detach from one another but did not induce invasiveness in these cells , as measured by their ability to cross a Matrigel - coated polycarbonate filter in a modified Boyden chamber assay . Two uvomorulin - negative , vimentin - negative cell lines are also not highly invasive as measured by this assay . We suggest that loss of uvomorulin - mediated cell - cell adhesion may be one of many changes involved in the progression of a carcinoma cell to an invasive phenotype .", "Lysophosphatidic Acid disrupts junctional integrity and epithelial cohesion in ovarian cancer cells . Ovarian cancer metastasizes via exfoliation of free - floating cells and multicellular aggregates from the primary tumor to the peritoneal cavity . A key event in EOC metastasis is disruption of cell - cell contacts via modulation of intercellular junctional components including cadherins . Ascites is rich in lysophosphatidic acid ( P08519 ) , a bioactive lipid that may promote early events in ovarian cancer dissemination . The objective of this paper was to assess the effect of P08519 on P12830 junctional integrity . We report a loss of junctional P12830 in OVCAR3 , OVCA429 , and OVCA433 cells exposed to P08519 . P08519 - induced loss of P12830 was concentration and time dependent . P08519 increased P14780 expression and promoted P14780 - catalyzed P12830 ectodomain shedding . Blocking P08519 receptor signaling inhibited P14780 expression and restored junctional P12830 staining . P08519 - treated cells demonstrated a significant decrease in epithelial cohesion . Together these data support a model wherein P08519 induces P14780 expression and P14780 - catalyzed P12830 ectodomain shedding , resulting in loss of P12830 junctional integrity and epithelial cohesion , facilitating metastatic dissemination of ovarian cancer cells .", "IL - 2R common gamma - chain is epigenetically silenced by nucleophosphin - anaplastic lymphoma kinase ( P06748 - Q9UM73 ) and acts as a tumor suppressor by targeting P06748 - Q9UM73 . Q9UM73 ( Q9UM73 ) , physiologically expressed only by certain neural cells , becomes highly oncogenic , when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin ( P06748 ) and other partners . The reason why P06748 - Q9UM73 succeeds in transforming specifically P01730 (+) T lymphocytes remains unknown . The IL - 2R common γ - chain ( IL - 2Rγ ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal P01730 (+) T lymphocytes and other immune cells . We show that IL - 2Rγ expression is inhibited in T - cell lymphoma cells expressing P06748 - Q9UM73 kinase as a result of DNA methylation of the IL - 2Rγ gene promoter . IL - 2Rγ promoter methylation is induced in malignant T cells by P06748 - Q9UM73 . P06748 - Q9UM73 acts through P40763 , a transcription factor that binds to the IL - 2Rγ gene promoter and enhances binding of DNA methyltransferases ( DNMTs ) to the promoter . In addition , P40763 suppresses expression of miR - 21 , which selectively inhibits P26358 mRNA expression . Reconstitution of IL - 2Rγ expression leads to loss of the P06748 - Q9UM73 protein and , consequently , apoptotic cell death of the lymphoma cells . These results demonstrate that the oncogenic tyrosine kinase P06748 - Q9UM73 induces epigenetic silencing of the IL - 2Rγ gene and that IL - 2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of P06748 - Q9UM73 .", "P04279 - 110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome . The DNA methyltransferase ( P26358 ) inhibitor vidaza ( DB00928 ) in combination with the histone deacetylase inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model . However , the effectiveness of P26358 inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase ( P32320 ) in the liver . These studies were initiated to test the efficacy of P04279 - 110 , a dinucleotide containing decitabine that is resistant to deamination by P32320 , as a single agent and in combination with entinostat . Evaluation of in vivo plasma concentrations and pharmacokinetic properties of P04279 - 110 showed rapid conversion to decitabine and a plasma half - life of 4 hr . P04279 - 110 alone or in combination with entinostat reduced tumor burden of a K - ras / p53 mutant lung adenocarcinoma cell line ( Calu6 ) engrafted orthotopically in nude rats by 35 % and 56 % , respectively . P04279 - 110 caused widespread demethylation of more than 300 gene promoters and microarray analysis revealed expression changes for 212 and 592 genes with P04279 - 110 alone or in combination with entinostat . Epigenetic therapy also induced demethylation and expression of cancer testis antigen genes that could sensitize tumor cells to subsequent immunotherapy . In the orthotopically growing tumors , highly significant gene expression changes were seen in key cancer regulatory pathways including induction of P38936 and the apoptotic gene Q13323 . Moreover , P04279 - 110 in combination with entinostat caused widespread epigenetic reprogramming of Q15910 - target genes . These preclinical in vivo findings demonstrate the clinical potential of P04279 - 110 for reducing lung tumor burden through reprogramming the epigenome .", "Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries . Recent advances in stem cell biology have shed light on how normal stem and progenitor cells can evolve to acquire malignant characteristics during tumorigenesis . The cancer counterparts of normal stem and progenitor cells might be occurred through alterations of stem cell fates including an increase in self - renewal capability and a decrease in differentiation and / or apoptosis . This oncogenic evolution of cancer stem and progenitor cells , which often associates with aggressive phenotypes of the tumorigenic cells , is controlled in part by dysregulated epigenetic mechanisms including aberrant DNA methylation leading to abnormal epigenetic memory . Epigenetic therapy by targeting DNA methyltransferases ( P26358 ) 1 , Q9Y6K1 and Q9UBC3 via DB00928 ( Aza ) and 5 - Aza - 2 '- deoxycytidine ( Aza - dC ) has proved to be successful toward treatment of hematologic neoplasms especially for patients with myelodysplastic syndrome . In this review , I summarize the current knowledge of mechanisms underlying the inhibition of DNA methylation by Aza and Aza - dC , and of their apoptotic - and differentiation - inducing effects on cancer stem and progenitor cells in leukemia , medulloblastoma , glioblastoma , neuroblastoma , prostate cancer , pancreatic cancer and testicular germ cell tumors . Since cancer stem and progenitor cells are implicated in cancer aggressiveness such as tumor formation , progression , metastasis and recurrence , I propose that effective therapeutic strategies might be achieved through eradication of cancer stem and progenitor cells by targeting the DNA methylation machineries to interfere their \" malignant memory \" .", "Epigenetic regulation of protein tyrosine phosphatase Q05209 in triple - negative breast cancer . AIMS : The present study showed that the expression of Q05209 is epigenetically regulated . DB00928 ( 5 - Azac ) , a DNA hypomethylating agent , significantly increased the expression of Q05209 at low concentrations ( 1μM and 2 . 5μM ) and decreased the expression of Q05209 at 5μM in the MDA - MB - 231 and BT - 549 triple - negative breast cancer cell lines . MAIN METHODS : Human MCF - 7 , MDA - MB - 231 and BT - 549 cells were exposed to different concentrations of 5 - Azac for 24 and 48h . RT - PCR was performed to determine the mRNA expression of Q05209 , P12830 and miRNA - 124 . Western blotting was performed to assess the protein expression of various proteins , including Q05209 , P12830 , P26358 and PARP . KEY FINDINGS : 5 - Azac , a DNA hypomethylating agent , significantly increased the expression of Q05209 at low concentrations ( 1μM and 2 . 5μM ) and decreased Q05209 expression at 5μM . We provide the first evidence that Q05209 expression is epigenetically regulated and that it is up - regulated at a lower dose of a P26358 inhibitor in MDA - MB - 231 and BT - 549 cells . Interestingly , the levels of miRNA - 124 were increased only at 5μM , the concentration at which Q05209 expression was suppressed . SIGNIFICANCE : To the best of our knowledge , this is the first report that highlights the therapeutic potential of low - dose 5 - Azac for the treatment of TNBC . Therefore , 5 - Azac , an agent that has already been tested in acute myeloid leukemia , may be more effective at lower doses for the treatment of triple - negative breast cancer .", "Induction of DNA methylation and gene silencing by short interfering RNAs in human cells . Double - stranded RNAs ( dsRNAs ) induce post - transcriptional gene silencing in several species of animal and plant . In plants , dsRNAs targeted to CpG islands within a promoter can also induce RNA - directed DNA methylation ; however , it remains unclear whether gene silencing mediated by DNA methylation can be induced by dsRNAs in mammalian cells . Here , we demonstrate that short interfering RNAs ( siRNAs ; 21 - 25 - nucleotide RNA molecules ) induce DNA methylation and histone H3 methylation in human cells . Synthetic siRNAs targeted to CpG islands of an P12830 promoter induced significant DNA methylation and histone H3 lysine 9 methylation in both MCF - 7 and normal mammary epithelial cells . As a result , these siRNAs repressed expression of the P12830 gene at the transcriptional level . In addition , disrupting the expression of either one of two DNA methyltransferases ( P26358 or Q9UBC3 ) by specific siRNAs abolished the siRNA - mediated methylation of DNA . Moreover , vector - based siRNAs targeted to the erbB2 ( also known as P04626 ) promoter also induced DNA methylation in MCF - 7 cells . Thus , siRNAs targeted to CpG islands within the promoter of a specific gene can induce transcriptional gene silencing by means of DNA - methyltransferase - dependent methylation of DNA in human cells , and might have potential as a new type of gene therapeutic agent .", "Expression of peroxisome proliferator - activated receptor - gamma in colon cancer : correlation with histopathological parameters , cell cycle - related molecules , and patients ' survival . P37231 ( P37231 ) , a ligand - activated transcription factor , is a key regulator of adipogenic differentiation and glucose homeostasis . P37231 ligands have recently been demonstrated to affect proliferation and differentiation in cancer cells lines . The aim of the present work was to examine P37231 expression in colon cancer cases . P37231 expression was examined immunohistochemically in 86 colon cancer cases and was correlated with clinicopathological parameters , tumor proliferative capacity , cell cycle - related molecule expression , and patient survival . Positive P37231 immunostaining was prominent in 48 of 86 cases ( 56 % ) . P37231 positivity was not correlated with Dukes ' stage , histological grade of differentiation , lymph node and liver metastasis , venous invasion , tumor proliferative capacity , or patient survival . A statistically significant correlation was found between P37231 and the expression of cell cycle - related molecules P06400 ( P < 0 . 016 ) , cyclin D1 ( P < 0 . 009 ) , p16 ( P < 0 . 032 ) , and P38936 ( P < 0 . 033 ) , while a positive trend for cyclin E was also noted ( P < 0 . 057 ) . The pattern , intensity , and extent of P37231 expression in positive cases were not correlated with any of the examined variables . Our findings support evidence for participation of this protein in the biological mechanisms underlying carcinogenic evolution in the colon , also suggesting the importance of specific P37231 ligands as cell cycle modulators for a future therapeutic approach in colon cancer .", "Phenotypic analysis of conditionally immortalized cells isolated from the Q06187 model of ARPKD . To study the pathophysiology of autosomal recessive polycystic kidney disease ( ARPKD ) , we sought to develop conditionally immortalized control and cystic murine collecting tubule ( CT ) cell lines . CT cells were isolated from intercross breedings between Q06187 mice ( bpk (+/-) ) , a murine model of ARPKD , and the Immorto mice ( H - 2K ( b )- ts - A58 (+/+) ) . Second - generation outbred offspring ( Q06187 x Immorto ) homozygous for the Q06187 mutation ( bpk (-/-) ; Im (+/+/-) ; cystic Q06187 / H - 2K ( b )- ts - A58 ) , were phenotypically indistinguishable from inbred cystic Q06187 animals ( bpk (-/-) ) . Cystic Q06187 / H - 2K ( b )- ts - A58 mice developed biliary ductal ectasia and massively enlarged kidneys , leading to renal failure and death by postnatal day 24 . Principal cells ( PC ) were isolated from outbred cystic and noncystic Q06187 / H - 2K ( b )- ts - A58 littermates at specific developmental stages . Epithelial monolayers were under nonpermissive conditions for markers of epithelial cell polarity and PC function . Cystic and noncystic cells displayed several properties characteristic of PCs in vivo , including amiloride - sensitive sodium transport and aquaporin 2 expression . Cystic cells exhibited apical epidermal growth factor receptor ( P00533 ) mislocalization but normal expression of ZO - 1 and P12830 . Hence , these cell lines retain the requisite characteristics of PCs , and cystic Q06187 / H - 2K ( b )- ts - A58 PCs retained the abnormal P00533 membrane expression characteristic of ARPKD . These cell lines represent important new reagents for studying the pathogenesis of ARPKD .", "P12830 expression on human carcinoma cell affects trastuzumab - mediated antibody - dependent cellular cytotoxicity through killer cell lectin - like receptor P55008 on natural killer cells . ___MASK28___ is a recombinant antibody drug that is widely used for the treatment of P04626 - overexpressing breast carcinoma . Despite encouraging clinical results , many P04626 - overexpressing carcinomas are primarily resistant to trastuzumab . We attempted to explain trastuzumab resistance and search for solutions . Since the killer cell lectin - like receptor P55008 ( Q96E93 ) , an inhibitory receptor expressed on subsets of natural killer ( NK ) cells recognizes P12830 as ligands and may inhibit immune responses by regulating the effector function of NK cells , we used P04626 - overexpressing carcinoma cells which were expressing P12830 to investigate the role of antibody - dependent cellular cytotoxicity ( ADCC ) through Q96E93 on NK cells in vitro and vivo . The results indicated that P04626 - overexpressing carcinoma cells were killed by trastuzumab - mediated ADCC and the ADCC activity was reflected the degree of P12830 expression on carcinoma cells . We found that expression of P12830 was shown to be a predictor of response to trastuzumab - based treatment for P04626 - overexpressing carcinomas , furthermore , trastuzumab - mediated ADCC was markedly enhanced by Q96E93 - negative peripheral blood mononuclear cells ( PBMCs ( Q96E93 (-)) ) .", "___MASK53___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK53___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK53___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK53___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK53___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .", "DB02527 responsive element modulator ( Q03060 ) α mediates chromatin remodeling of CD8 during the generation of CD3 + P01730 - CD8 - T cells . TCR - αβ (+) CD3 (+) P01730 (-) CD8 (-) \" double negative \" T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus ( SLE ) and lupus - prone mice . Double negative T cells have been claimed to derive from CD8 (+) cells that down - regulate CD8 co - receptors and acquire a distinct effector phenotype that includes the expression of proinflammatory cytokines . This , along with the fact that double negative T cells have been documented in inflamed organs , suggests that they may contribute to disease expression and tissue damage . We recently linked the transcription factor DB02527 responsive element modulator ( Q03060 ) α , which is expressed at increased levels in T cells from SLE patients and lupus prone MRL / lpr mice , with trans - repression of a region syntenic to the murine CD8b promoter . However , the exact molecular mechanisms that result in a stable silencing of both P01732 and P10966 genes remain elusive . Here , we demonstrate that CREMα orchestrates epigenetic remodeling of the CD8 cluster through the recruitment of DNA methyltransferase ( P26358 ) 3a and histone methyltransferase G9a . Thus , we propose that CREMα is essential for the expansion of double negative T cells in SLE . CREMα blockade may have therapeutic value in autoimmune disorders with DN T cell expansion .", "Differential gene expression in well - regulated and dysregulated pancreatic beta - cell ( MIN6 ) sublines . To identify genes involved in regulated insulin secretion , we have established and characterized two sublines derived from the mouse pancreatic beta - cell line MIN6 , designated B1 and P01024 . They have a similar insulin content , but differ in their secretory properties . B1 responded to glucose in a concentration - and cell confluence - dependent manner , whereas P01024 did not . B1 cells were stimulated by phorbol 12 - myristate 13 - acetate , leucine , arginine , glibenclamide , isobutylmethylxanthine , and DB00761 , whereas P01024 did not respond ( leucine , arginine , and glibenclamide ) or responded to a lesser extent ( isobutylmethylxanthine , phorbol 12 - myristate 13 - acetate , and DB00761 ) . Although intracellular Ca ( 2 +) rose in response to glucose in B1 but not P01024 cells , DB00761 increased intracellular Ca ( 2 +) in a similar manner in both sublines . P11166 , P11168 , Kir6 . 2 , and Q09428 expression was not significantly different between B1 and P01024 cells , whereas P12830 was more abundantly expressed in B1 cells . A more complete list of differentially expressed genes was established by suppression subtractive hybridization and high density ( Affymetrix ) oligonucleotide microarrays . Genes were clustered according to known or putative function . Those involved in metabolism , intracellular signaling , cytoarchitecture , and cell adhesion are of potential interest . These two sublines should be useful for identification of the genes and mechanisms involved in regulated insulin secretion of the pancreatic beta - cell .", "Fasting of 3 - day - old chicks leads to changes in histone H3 methylation status . Unfavorable nutritional conditions during early developmental periods may cause neuronal network remodeling in the hypothalamus , which influences subsequent adaptability to those same stressful conditions . Alterations in hypothalamic plasticity as a result of neuronal remodeling are achieved by variations in the repertoire of proteins expressed via gene transcriptional activation or repression , both of which are modulated by histone methylation status . This study demonstrates that fasting had a stimulatory effect on dimethylation and trimethylation of histone 3 at lysine 27 ( H3K27 ) in preoptic / anterior hypothalamus ( PO / AH ) of 3 - day - old chicks . The expression of enhancer of zeste 2 ( Q15910 ) , a H3K27 - specific histone methyltransferase ( P50135 ) , was significantly increased by fasting in the paraventricular nucleus ( PVN ) and PO / AH , which is consistent with the upregulation of H3K27 dimethylation and trimethylation . Furthermore , in the PVN , corticotrophin - releasing hormone ( P06850 ) mRNA expression was significantly inhibited , while mRNA expressions of thyrotropin - releasing hormone ( TRH ) and type 2 deiodinase ( D2 ) were significantly stimulated by fasting . These findings highlight the potential role of H3K27 methylation status in early feed stress responses in chicks and may be indicative of an epigenetic mechanism for later adaptation to feed intake stress .", "Silencing of the metastasis suppressor O95980 by DB01367 oncogene is mediated by DNA methyltransferase 3b - induced promoter methylation . O95980 is a membrane - anchored glycoprotein that may negatively regulate matrix metalloproteinase activity to suppress tumor invasion and metastasis . Our previous study indicated that oncogenic DB01367 inhibited O95980 expression via a histone deacetylation mechanism . In this study , we address whether DNA methyltransferases ( P26358 ) participate in the inhibition of O95980 by DB01367 . Induction of Ha - DB01367 ( Val12 ) oncogene increased DNMT3b , but not P26358 and DNMT3a , expression in 2 - 12 cells . In addition , induction of DNMT3b by DB01367 was through the extracellular signal - regulated kinase signaling pathway . Oncogenic DB01367 increased the binding of DNMT3b to the promoter of O95980 gene and this binding induced promoter methylation , which could be reversed by 5 '- azacytidine and DNMT3b small interfering RNA ( siRNA ) . The MEK inhibitor U0126 also reversed DB01367 - induced DNMT3b binding and O95980 promoter methylation . Treatment of 5 '- azacytidine and DNMT3b siRNA restored O95980 expression in 2 - 12 cells and potently suppressed DB01367 - stimulated cell invasion . In addition , the inhibitory effect of 5 '- azacytidine on DB01367 - induced cell invasion was attenuated after knockdown of O95980 by siRNA . Interestingly , human lung cancer cells harboring constitutively activated DB01367 exhibited lower O95980 expression and higher promoter methylation of O95980 gene . 5 '- DB00928 and DNMT3b siRNA restored O95980 expression in these cells and effectively suppressed invasiveness . Collectively , our results suggest that DB01367 oncogene induces O95980 gene silencing through DNMT3b - mediated promoter methylation , and P26358 inhibitors may be useful for the treatment of DB01367 - induced metastasis .", "___MASK67___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .", "Heat shock prevents insulin resistance - induced vascular complications by augmenting angiotensin -( 1 - 7 ) signaling . We have investigated the role of heat shock ( HS ) in preventing insulin resistance - induced endothelial dysfunction . To the best of our knowledge , we report here for the first time that insulin resistance inhibits vascular HS protein ( HSP ) 72 expression . HS treatment ( 41 ° C for 20 min ) restored the HSP72 expression . High - fat diet ( HFD ) - fed , insulin - resistant rats show attenuated angiotensin ( P03950 ) -( 1 - 7 )- induced vasodilator effect , endothelial nitric oxide synthase ( P29474 ) phosphorylation , AMP - activated protein kinase phosphorylation , and sirtuin 1 ( Q96EB6 ) expression . Interestingly , HS prevented this attenuation . We also provide the first evidence that HFD - fed rats show increased vascular DNA methyltransferase 1 ( P26358 ) expression and that HS prevented this increase . Our data show that in HFD - fed rats HS prevented loss in the expression of P03950 -( 1 - 7 ) receptor Mas and Q9BYF1 , which were responsible for vascular complications . Further , the inhibition of P29474 ( l - N ( G )- nitro - L - arginine methyl ester ) , Mas ( A - 779 ) , and Q96EB6 ( nicotinamide ) prevented the favorable effects of HS . This suggests that HS augmented P03950 -( 1 - 7 ) signaling via the Mas / P29474 / Q96EB6 pathway . Our study , for the first time , suggests that induction of intracellular HSP72 alters P26358 expression , and may function as an epigenetic regulator of Q96EB6 and P29474 expression . We propose that induction of HSP72 is a novel approach to prevent insulin resistance - induced vascular complications .", "Altered regulation of P49917 activity by aberrant promoter DNA methylation and gene amplification in colorectal cancer . Colorectal cancer ( CRC ) presents as a very heterogeneous disease which can not sufficiently be characterized with the currently known genetic and epigenetic markers . To identify new markers for CRC we scrutinized the methylation status of 231 DNA repair - related genes by methyl - CpG immunoprecipitation followed by global methylation profiling on a CpG island microarray , as altered expression of these genes could drive genomic and chromosomal instability observed in these tumors . We show for the first time hypermethylation of P14780 , Q9Y6K1 and P49917 in CRC which was confirmed in two CRC patient groups with different ethnicity . P49917 ( P49917 ) showed strong differential promoter methylation ( up to 60 % ) which coincided with downregulation of mRNA in 51 % of cases . This functional association of P49917 methylation and gene expression was supported by P49917 re - expression in DB01262 - treated colon cancer cell lines , and reduced ligase IV amounts and end - joining activity in extracts of tumors with hypermethylation . Methylation of P49917 was not associated with other genetic and epigenetic markers of CRC in our study . As P49917 is located on chromosome 13 which is frequently amplified in CRC , two loci were tested for gene amplification in a subset of 47 cases . Comparison of amplification , methylation and expression data revealed that , in 30 % of samples , the P49917 gene was amplified and methylated , but expression was not changed . In conclusion , hypermethylation of the P49917 promoter is a new mechanism to control ligase IV expression . It may represent a new epigenetic marker for CRC independent of known markers .", "P40763 signaling is induced by intercellular adhesion in squamous cell carcinoma cells . The signal transducer and activator of transcription - 3 ( P40763 ) frequently activated during tumor progression has been linked to enhanced cell growth . In squamous cell carcinoma of the head and neck ( HNSCC ) , P40763 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways . In the present study , we have examined the potential mechanism by which cell - cell contact initiates P40763 activation . Using a panel of HNSCC cell lines , Ca (+ 2 )- dependent cell - cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of P40763 - Y705 and P42224 - Y701 . This intercellular adhesion - induced P40763 activation was mediated by JAK and Src signaling and partially by P00533 signaling . In addition , immunolocalization studies revealed initial formation of phosphorylated P40763 - Y705 at nascent P12830 cell junctions with eventual translocation to the nucleus in cell aggregates . Adhesion - mediated P35610 activation in monolayer and cell aggregate cultures required functional P12830 . These results indicate that , in HNSCC cells , cadherin - mediated intercellular adhesion induces P35610 signaling that may modulate cell survival and resistance to apoptosis during tumor progression .", "DB00928 and decitabine induce gene - specific and non - random DNA demethylation in human cancer cell lines . The DNA methyltransferase inhibitors azacytidine and decitabine represent archetypal drugs for epigenetic cancer therapy . To characterize the demethylating activity of azacytidine and decitabine we treated colon cancer and leukemic cells with both drugs and used array - based DNA methylation analysis of more than 14 , 000 gene promoters . Additionally , drug - induced demethylation was compared to methylation patterns of isogenic colon cancer cells lacking both DNA methyltransferase 1 ( P26358 ) and Q9UBC3 . We show that drug - induced demethylation patterns are highly specific , non - random and reproducible , indicating targeted remethylation of specific loci after replication . Correspondingly , we found that CG dinucleotides within CG islands became preferentially remethylated , indicating a role for DNA sequence context . We also identified a subset of genes that were never demethylated by drug treatment , either in colon cancer or in leukemic cell lines . These demethylation - resistant genes were enriched for Polycomb Repressive Complex 2 components in embryonic stem cells and for transcription factor binding motifs not present in demethylated genes . Our results provide detailed insights into the DNA methylation patterns induced by azacytidine and decitabine and suggest the involvement of complex regulatory mechanisms in drug - induced DNA demethylation .", "___MASK22___ affects nonapoptotic cell death of undifferentiated germ cells in the fetal mouse testis : in vivo study by exo utero transplantation of corticotropic tumor cells into embryos . ___MASK22___ ( ___MASK22___ ) has been suggested to have possible roles in the fetal testes , one of the organs that express its specific receptors , melanocortin type 2 and 5 receptors ( Q01718 and P33032 ) , during the fetal period . We investigated the effect of ___MASK22___ on the cells in the testis cord of the fetal mouse testis by inducing ___MASK22___ - secreting AtT20 tumor cells in mouse fetuses . We first identified that mouse testicular germ cells at embryonic day ( E ) 16 . 5 and E18 . 5 spermatogonia were entirely CDH1 ( P12830 ) - positive by immunohistochemistry . We next performed AtT20 - cell transplantation into the mouse fetus at Q96BH3 . 5 , and analyzed ___MASK22___ effects on the development of fetal male mouse germ cells that express Q01718 and P33032 at E16 . 5 and E18 . 5 . The spermatogonia in the testis of AtT20 - implanted embryos exhibited morphological changes , including pyknotic nuclei and swollen cytoplasm . In the AtT20 - implanted embryos , the number of spermatogonia per unit area of the testis cord was significantly lower , but there were more pyknotic spermatogonia than in the controls . Single - stranded DNA - positive ( apoptotic ) and histone H3 - positive ( mitotic ) spermatogonia were rarely observed and their numbers did not significantly differ in the two groups . Anti - Müllerian hormone ( P03971 ) - positive Sertoli cells , another cell type that constitutes the fetal testis cord but does not express Q01718 or P33032 , showed no apparent morphological changes compared with controls , nor were their numbers in the two groups significantly different between the two groups . These results suggest that ___MASK22___ , via Q01718 and / or P33032 , may be involved in the nonapoptotic cell death of fetal mouse spermatogonia that is observed during the normal perinatal period .", "Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .", "DB00928 prevents cisplatin induced nephrotoxicity and potentiates anticancer activity of cisplatin by involving inhibition of metallothionein , pAKT and P26358 expression in chemical induced cancer rats . 5 - Azactydine inhibits cell growth by direct cytotoxic action as well as by inhibition of DNA methyl transferase enzyme . Inhibitors of P26358 have been reported to potentiate the therapeutic activity of cisplatin in vitro . Dose dependent bone marrow toxicity , neurotoxicity and nephrotoxicity are the major side effects of cisplatin , limiting its use as an effective chemotherapeutic agent . The present study was aimed to reduce the nephrotoxic potential of cisplatin without compensating its potency . To best of our knowledge , this is the first report which shows that the combination of 5 - azacytidine with cisplatin leads to remarkable reduction in nephrotoxicity , by involving inhibition of cisplatin induced metallothionein expression . DB00928 treatment with cisplatin leads to maximum reduction in tumor size in Q03001 induced colon cancer and tumor volume in DMBA induced breast cancer bearing SD rats . This combination regimen prevents phosphorylation and acetylation of histone H3 which may be involved in inhibition of aberrant gene expression in colon tumors . Further , 5 - azacytidine potentiated cisplatin induced antitumor activity by involving decreased expression of pAKT , P26358 and an increased expression of p38 in colon tumors . Thus , combination of 5 - azactydine with cisplatin attenuates the cisplatin induced nephrotoxicity and potentiates the anti - cancer activity which can have profound clinical implications .", "Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK93___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .", "Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK19___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .", "Gestational hypoxia induces sex - differential methylation of Crhr1 linked to anxiety - like behavior . Stress during gestation increases vulnerability to disease and changes behavior in offspring . We previously reported that hypoxia and restraint during pregnancy sensitized the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis and induced anxiety - like behavior in the adult offspring . Here , we report that gestational intermittent hypoxia ( GIH ) elicited a sex - dependent anxiety - like behavior in male P90 offspring and activation of corticotropin - releasing hormone ( P06850 ) and P06850 type - 1 receptor ( P34998 ) mRNA in the hypothalamic paraventricular nucleus ( PVN ) and in male E19 hypothalamus . These linked to demethylation at several specific sites of CpG island of Crhr1 promoter in P90 PVN and E19 embryo hypothalamus in GIH groups . Crhr1 DNA demethylation is more crucial in CpG island 1 than island 2 for activation of P34998 mRNA . DNMT3b is required for the Crhr1 DNA methylation than P26358 and DNMT3a in increased P34998 mRNA . We first address a novel hypothesis that GIH - induced male - sex - dependent demethylation at CpG sites of Crhr1 DNA in promoter triggers elevation of P34998 mRNA in PVN and anxiety - like behavior in adult offspring .", "Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss - of - function mutations causing X - linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein - Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small - molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug - induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 - 32765 , recently renamed ___MASK9___ , has already entered several clinical trials for various forms of non - Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors .", "Anticancer drug discovery targeting DNA hypermethylation . DNA methyltransferases ( DNMTs ) are important regulators of gene transcription and their roles in carcinogenesis have been a topic of considerable interest in the last few years . Diverse classes of chemical compounds including nucleotide analogues , adenosine analogues , aminobenzoic derivatives , polyphenols , hydrazines , phthalides , disulfides and antisenses are being discovered and evaluated as P26358 inhibitors targeting DNA hypermethylation . Among them , DB00928 5 and Decitabine 6 were launched recently . Several other compounds are under clinical trials . Some of these compounds were discovered from structure - based drug design . These compounds exert their DNA methylation inhibitory by different mechanisms . This review will present a brief account of various DNA methyltransferases and their biological functions , with focus on actuality of design and synthesis of various inhibitors of DNA hypermethylation as anticancer drugs .", "Hyperhomocysteinemia during aortic aneurysm , a plausible role of epigenetics . Hyperhomocysteinemia is associated with aortic aneurysm , however , the mechanisms are unclear . We hypothesize that the expression level of genes involved in extracellular matrix ( Q13201 ) remodeling , oxidative stress , and enzymes involved in homocysteine metabolism pathway in aortic aneurysm and hyperhomocysteinemia are differentially regulated by DNA methylation . We studied the mRNA levels of P42898 , P23526 , P03956 , - 9 , P01033 , - 4 , peroxiredoxin , NOX - 2 , - 3 ( NAPDH oxidase subunits ) , collagen and elastin in normal and aortic aneurysm tissues from humans and aorta tissue from HHcy ( Cystathionine beta synthase heterozygote knockout , P35520 +/- ) mice treated with high methionine diet . The total RNA was extracted using Trizol method and RT - PCR was performed . Protein expression of P42898 , H3K9 ( trimethyl ) and Q99727 were studied in mice using immunohistochemistry . P42898 and Q99727 expression was seen to be increasing in both human aneurysm samples as well as HHcy P35520 +/- mice . There was increased expression of P14780 , peroxiredoxin and decreased expression of P03956 , Collagen I and IV was noted in thoracic aortic aneurysm samples . Increased Collagen IV and decreased Collagen I levels were seen in P35520 +/- HHcy mice compared to their wild type controls . Since DNA methylation regulates gene expression of enzymes in Hcy metabolism pathway , we also measured the mRNA levels of DNMTs , Q9UBB5 and H3K9 . The results suggest an increase in the levels of P26358 , 3a , Q9UBB5 and H3K9 in P35520 +/- aorta compared to their wild type controls . Our findings suggest a possible role of methylation in regulation of expression of genes involved in matrix remodeling and homocysteine metabolism .", "Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF - B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( ___MASK22___ ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF - B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti - oCRF and anti - rCRF antibodies . CRF - B cross - reacted well with anti - oCRF antibodies but poorly with anti - rCRF antibodies . Purification of CRF - B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4 . 7 ) , B - 2 ( pH 5 . 5 ) , B - 3 ( pH 6 . 3 ) , and B - 4 ( pH 7 . 0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF - B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .", "Equitoxic doses of 5 - azacytidine and 5 - aza - 2 ' deoxycytidine induce diverse immediate and overlapping heritable changes in the transcriptome . BACKGROUND : The hypomethylating agent DB00928 ( 5 - Aza - CR ) is the first drug to prolong overall survival in patients with myelodysplastic syndrome ( P43034 ) . Surprisingly , the deoxyribonucleoside analog 5 - Aza - 2 ' deoxycytidine ( 5 - Aza - CdR ) did not have a similar effect on survival in a large clinical trial . Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase ( P26358 ) . While 5 - Aza - CdR is incorporated into only DNA , 5 - Aza - CR is also incorporated into RNA . Here , we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs ( miRNA ) , which may potentially affect the activities of the drugs in patients . METHODOLOGY / PRINCIPAL FINDINGS : A hematopoietic ( HL - 60 ; acute myeloid leukemia ) and a solid ( T24 ; transitional cell carcinoma ) cancer cell line were treated with equitoxic doses of 5 - Aza - CR and 5 - Aza - CdR for 24 hrs , and the immediate ( day 2 ) and lasting ( day 8 ) effects on RNA expression examined . There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog . Both drugs strongly induced expression of cancer testis antigens . On day 2 more RNAs were downregulated by 5 - Aza - CR , particularly at higher doses . A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells . CONCLUSIONS / SIGNIFICANCE : Overall , this suggests that significant differences exist in the immediate action of the two drugs , however the dominant pattern of the lasting , and possible heritable changes , is overlapping .", "Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK28___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK28___ is also being investigated as part of triplet drug regimens . ___MASK28___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .", "Time - Qualified Patterns of Variation of PPARγ , P26358 , and Q9UBC3 Expression in Pancreatic Cancer Cell Lines . Carcinogenesis is related to the loss of homeostatic control of cellular processes regulated by transcriptional circuits and epigenetic mechanisms . Among these , the activities of peroxisome proliferator - activated receptors ( PPARs ) and DNA methyltransferases ( DNMTs ) are crucial and intertwined . PPARγ is a key regulator of cell fate , linking nutrient sensing to transcription processes , and its expression oscillates with circadian rhythmicity . Aim of our study was to assess the periodicity of PPARγ and DNMTs in pancreatic cancer ( PC ) . We investigated the time - related patterns of P37231 , P26358 , and Q9UBC3 expression monitoring their mRNA levels by qRT - PCR at different time points over a 28 - hour span in BxPC - 3 , CFPAC - 1 , PANC - 1 , and MIAPaCa - 2 PC cells after synchronization with serum shock . P37231 and P26358 expression in PANC - 1 cells and P37231 expression in MIAPaCa - 2 cells were characterized by a 24 h period oscillation , and a borderline significant rhythm was observed for the P37231 , P26358 , and Q9UBC3 expression profiles in the other cell lines . The time - qualified profiles of gene expression showed different shapes and phase relationships in the PC cell lines examined . In conclusion , P37231 and DNMTs expression is characterized by different time - qualified patterns in cell lines derived from human PC , and this heterogeneity could influence cell phenotype and human disease behaviour .", "Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .", "[ Determination of hematopoietic clonality by detection of multiple X - linked gene exonic polymorphic loci using transcription - based clonality assays ] . OBJECTIVE : To explore the frequencies of heterozygosity in X - linked P11413 , P55 , Q06187 , and Q13642 gene exonic polymorphic loci among Chinese females and the value of determination of hematopoietic clonality by detection of these X - chromosome exonic polymorphisms based on X - chromosome inactivation patterns ( XCIP ) - transcription - based clonality assays ( TCA ) . METHODS : Genomic DNA was extracted from peripheral blood of 446 Chinese healthy females . Allele - specific PCR ( ASPCR ) or PCR - restriction enzyme digestion method was applied for detecting P11413 , P55 , Q06187 and Q13642 polymorphisms . Those heterozygotic loci were used as markers to examine the hematopoietic clonality of bone marrow mononuclear cells by TCA from essential thrombocythemia ( ET ) patients with JAK2V617F mutation and myelodysplastic syndrome ( P43034 ) patients with abnormal karyotype . RESULTS : Among the total 446 genomic DNA samples , the frequencies of heterozygosity in P11413 , P55 , Q06187 and Q13642 loci were 12 . 8 % , 29 . 4 % , 52 . 0 % and 46 . 4 % , respectively . About 81 . 4 % of females were heterozygous at one or more loci . All 10 ET patients with JAK2V617F mutation and 2 P43034 patients with abnormal karyotype , which were heterozygotic in either locus , had monoclonal / oligoclonal hematopoiesis . CONCLUSION : Clonality detection based on X chromosome inactivation patterns - transcription based clonality assays is applicable to about 80 % of Chinese females .", "[ ___MASK9___ : A new drug of B - cell malignancies ] . ___MASK9___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK9___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK9___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .", "Candidate pathway polymorphisms in one - carbon metabolism and risk of rectal tumor mutations . We examined candidate polymorphisms in genes involved in the folate - mediated , one - carbon metabolism pathway , P26358 1311V , P11586 R134K and R653Q , P42898 R594Q , Q99707 D919G , Q9UBK8 H595Y and I22M , P34896 L474F , P41440 H27R , and Q13569 G199S , and associations with rectal tumor characteristics . We hypothesized that these candidate genes would influence CpG Island Methylator Phenotype and potentially P01116 or P04637 tumors . Data from a population - based study of 747 rectal cases ( 593 with tumor markers ) and 956 controls were evaluated using generalized estimating equations . We observed an increased risk of P04637 tumor mutations in homozygous carriers of the P11586 134K allele ( 0R = 2 . 0 , 95 % CI 1 . 2 - 3 . 1 , P - trend = 0 . 02 ) . In the presence of low folate intake , the R134K variant was associated with increased risk of CIMP + tumors ( OR = 2 . 8 , 95 % CI 1 . 04 - 7 . 7 ) . The Q9UBK8 I22M variant genotype was associated with a modest increased risk of P04637 mutations ( OR = 1 . 7 , 95 % CI 1 . 2 - 2 . 5 , P - trend = 0 . 001 ) . Our findings offer limited support that polymorphisms in one - carbon metabolism genes influence rectal tumor phenotype , and that folate may interact with P11586 to alter CIMP + risk ." ]

[ "___MASK19___", "___MASK22___", "___MASK28___", "___MASK30___", "___MASK53___", "___MASK67___", "___MASK69___", "___MASK93___", "___MASK9___" ]

[ "Association analysis between 12 genetic variants of ten genes and personality traits in a young chinese Han population . Some genes involved in neurotransmission synthesis and transmission have been hypothesized to affect personality traits . To investigate the possible roles of these genes in personality traits of 16 Personality Factor Questionnaire , we performed a population - based study in a young Chinese Han cohort . In the study , we selected some functional variations in ten candidate genes ( P21964 , P09172 , DRD ( 2 ) , DRD ( 3 ) , Q01959 , P21397 , GRM ( 1 ) , Q13224 , 5 - TH ( 2A ) , and 5 - TH ( 6 ) ) encoding components in dopamine , glutamate , and 5 - hydroxytryptamine pathways . The results showed the T102C in 5 - TH ( 2A ) was associated with X3 ( emotional and quiet alertness ) and B ( reasoning ) ( F = 4 . 71 and 6 . 23 ; p = 0 . 009 and 0 . 002 ) , Val158Met in P21964 with E ( dominance ) ( F = 7 . 01 ; p = 0 . 0009 ) , while the variations in P09172 , DRD ( 2 ) , DRD ( 3 ) , P21397 , GRM ( 1 ) , Q13224 , and 5 - TH ( 6 ) were not associated with any of the personality traits . This finding suggests that T102C in 5 - TH ( 2A ) and Val158Met in P21964 play roles in some human personality traits .", "___MASK14___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .", "Effects of Subchronic Treatment with Ibuprofen and DB04743 on Spatial Memory and NMDAR Subunits Expression in Aged Rats . Several studies point to an important function of cyclooxygenase ( P36551 ) and prostaglandin signaling in models of synaptic plasticity which is associated with N - methyl - D - aspartate receptors ( NMDARs ) . Cyclooxygenase gene is suggested to be an immediate early gene that is tightly regulated in neurons by DB01221 dependent synaptic activity . Nonsteroid Antiinflammatory Drugs ( NSAIDs ) exert their antiinflammatory effect by the inhibion of P36551 have controversial effects on learning and memory . We administered ibuprofen as a non - selective P35354 inhibitor and nimesulide as a selective P35354 inhibitor for 8 weeks for determining the cognitive impact of subchronic administration of NSAIDs to aged rats . Wistar albino rats ( 16 mo , n = 30 ) were separated into control ( n = 10 ) , ibuprofen ( n = 10 ) and nimesulide ( n = 10 ) treated groups . First we evaluated hippocampus - dependent spatial memory in the radial arm maze ( RAM ) and than we evaluated the expression of the NMDAR subunits , Q12879 and Q13224 by western blotting to see if their expressions are effected by subchronic administration with these drugs . Ibuprofen and nimesulide treated rats completed the task in a statistically significant shorter time when compared with control group ( p < 0 . 01 ) , but there was no statistically significant difference between groups about choice accuracy data in RAM . Furthermore , no statistically significant difference was detected for the protein expressions of Q12879 and Q13224 of the subjects . Oral administration of ibuprofen and nimesulide for 8 weeks showed no impairment but partly improved spatial memory .", "DB00996 prevents oxaliplatin - induced central sensitization in the dorsal horn neurons in rats . OBJECTIVES : The present study aims to study the alteration of glutamatergic transmission in the dorsal horn neurons and the effect of gabapentin on oxaliplatin - induced neuropathic pain in rats . MATERIALS AND METHODS : DB00526 ( 5 mg / kg ) or saline was administered to adult male Sprague - Dawley rats . DB00996 ( 60 mg / kg , IP ) or vehicle was injected daily . Mechanical allodynia was assessed using a series of von Frey filaments . The expression of glutamate receptor subunits ( Q13224 and GluR1 ) and brain - derived neurotrophic factor ( P23560 ) was measured in the dorsal horn . The glutamatergic strength was recorded in the spinal cord slices . RESULTS : Administration of oxaliplatin induced significant hyperreactivity to mechanical stimuli in rats , which was attenuated by gabapentin . Significant increase in the expression of P23560 was found in the dorsal horn in rats receiving oxaliplatin , which was prevented by gabapentin . Further studies also observed a significant increase in the expression of GluR1 and Q13224 , as well as enhanced glutamatergic transmission in the dorsal horn neurons in rats treated with oxaliplatin . The upregulation of glutamatergic transmission was significantly reversed by gabapentin . CONCLUSION : These results illustrated an increased expression of P23560 and enhanced glutamatergic transmission in rats with oxaliplatin - induced neuropathic pain , which was markedly attenuated by gabapentin .", "Genetics of bipolar disorder . Many linkage loci and candidate genes have been reported in molecular genetic studies of bipolar disorder . However , none of these findings have been consistently replicated . Meta - analyses of linkage studies have also reported conflicting results . Among recently reported candidate genes , P23560 , P59103 , P31749 , Q12879 , P17861 , P35626 , Q13639 , O14732 and P14867 may have some importance . Study of the possible roles of epigenetics or analysis of genetic diseases , in which bipolar disorder is one of phenotypes , may also be promising . In addition to monoaminergic and intracellular signaling pathways , recent studies have revealed possible roles for mitochondrial dysfunction , for glutamatergic dysfunction and for the endoplasmic reticulum stress pathway .", "Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK23___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .", "Inhibitory effect of gabapentin on N - methyl - D - aspartate receptors expressed in Xenopus oocytes . BACKGROUND : DB00996 ( O75925 ) is a prescription drug used for the treatment of neuropathic and post - operative pain . However , the mechanism by which it exerts its analgesic action is not well understood . Because intrathecal administration of O75925 has been shown to exert antinociceptive effects in animal studies , we hypothesized that the spinal cord may be a plausible action site . METHODS : We examined the effects of O75925 on neurotransmitter - gated ion channels and G protein - coupled inwardly rectifying potassium ( GIRK ) channels distributed in the spinal cord and involved in pain modulation . Recombinant human Q9UHB4 / Q12879 N - methyl - D - aspartate ( DB01221 ) , alpha ( 1 ) beta ( 2 ) gamma ( 2S ) gamma - aminobutyric acid type A ( GABA ( A ) ) or alpha ( 1 ) glycine receptors , or P48549 / P48051 channels were expressed in Xenopus laevis oocytes and the effects of O75925 ( 0 . 1 - 1000 microM ) on them were assessed using a two - electrode , voltage - clamp system . RESULTS : GABA ( A ) and glycine receptors and GIRK channels were not affected by O75925 , even at the highest concentrations . Conversely , DB01221 receptors were inhibited by O75925 in a concentration - dependent manner , with significant inhibition observed at 10 microM . At 30 microM , O75925 inhibited the glutamate - concentration response curve without changing the half - maximal effective concentration or the Hill coefficient , indicating a non - competitive inhibition . Glycine decreased the inhibitory effect in a concentration - dependent manner . CONCLUSIONS : These findings suggest that the inhibitory effect of O75925 on DB01221 receptors may play an important role in the antinociceptive property of O75925 ; however , it does not appear that GABA ( A ) and glycine receptors or GIRK channels contribute to the pharmacological properties of O75925 .", "Attenuation of neurotoxicity in cortical cultures and hippocampal slices from Q01094 knockout mice . The Q01094 transcription factor modulates neuronal apoptosis induced by staurosporine , DNA damage and beta - amyloid . We demonstrate Q01094 involvement in neuronal death induced by the more physiological oxygen - glucose deprivation ( OGD ) in mouse cortical cultures and by anoxia in mouse hippocampal slices . Q01094 (+/+) and ( -/- ) cultures were comparable , in that they contained similar neuronal densities , responded with similar increases in intracellular calcium concentration ( [ Ca ( 2 +)] i ) to glutamate receptor agonists , and showed similar DB01221 receptor subunit mRNA expression levels for Q9UHB4 , Q12879 and Q13224 . Despite these similarities , Q01094 (-/-) cultures were significantly less susceptible to neuronal death than Q01094 (+/+) cultures 24 and 48 h following 120 - 180 min of OGD . Furthermore , the absence of Q01094 significantly improved the ability of P00915 neurons in hippocampal slices to recover synaptic transmission following a transient anoxic insult in vitro . These results , along with our finding that Q01094 mRNA levels are significantly increased following OGD , support a role for Q01094 in the modulation of OGD - and anoxia - induced neuronal death . These findings are consistent with studies showing that overexpression of Q01094 in postmitotic neurons causes neuronal degeneration and the absence of Q01094 decreases infarct volume following cerebral ischemia .", "Expression of P35354 and DB01221 receptor genes at the cochlea and midbrain in salicylate - induced tinnitus . OBJECTIVE / HYPOTHESIS : The expression of the genes for cyclooxygenase ( P36551 ) and DB01221 receptor ( NR ) has seldom been reported in tinnitus . We hypothesized that expression of P35354 and NR was altered in the cochlea and midbrain in salicylate - induced tinnitus . STUDY DESIGN : Experimental study on mice . METHODS : We evaluated the tinnitus score and mRNA expression levels of P35354 and NR subtype 2B ( Q13224 ) in the cochlea and midbrain in response to intraperitoneal injections of salicylate for 4 days . RESULTS : At day 4 of tinnitus induction , the mean weights of the whole body and midbrain did not change greatly in both control and salicylate groups . The tinnitus score was not elevated from day 1 to day 4 in the control group , but increased day by day in the salicylate group . The mRNA expression level of P35354 decreased slightly in the salicylate group in the cochlea ( 1 . 1 ± 0 . 33 vs . 1 . 3 ± 0 . 49 , P = . 0752 ) and in the midbrain ( 0 . 9 ± 0 . 10 versus 1 . 0 ± 0 . 35 , P = . 0489 ) . Inversely , the expression levels of the Q13224 gene increased moderately in the salicylate group in the cochlea ( 3 . 7 ± 0 . 47 versus 2 . 3 ± 1 . 13 , P < 0 . 0001 ) and in the midbrain ( 1 . 6 ± 0 . 64 versus 1 . 0 ± 0 . 44 , P = . 0007 ) . CONCLUSIONS : Salicylate induced tinnitus and altered the expression of the P35354 and Q13224 genes in the cochlea and midbrain of mice . These findings might contribute to further understanding of pathophysiology and therapy of tinnitus .", "A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK86___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .", "Molecular genetics of attention deficit hyperactivity disorder . Although twin studies demonstrate that ADHD is a highly heritable condition , molecular genetic studies suggest that the genetic architecture of ADHD is complex . The handful of genome - wide linkage and association scans that have been conducted thus far show divergent findings and are , therefore , not conclusive . Similarly , many of the candidate genes reviewed here ( ie , P09172 , P21397 , P23975 , P17752 - 2 , P31645 , P43681 , Q12879 ) are theoretically compelling from neurobiological systems perspective but available data are sparse and inconsistent . However , candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder , with meta - analyses supportive of a role of the genes coding for P21917 , P21918 , Q01959 , P60880 , and P28222 in the etiology of ADHD .", "DB00142 reverses Pb2 +- induced reductions of DB01221 receptor subunits in vitro . The objective of this study is to determine the effects of Pb2 + on N - methyl - d - aspartate receptor ( NMDAR ) subunits -- Q07869 , Q12879 and Q13224 in primary cultured neuronal cells . We hypothesize that L - glutamic acid ( GA ) reverses Pb2 +- induced NMDAR damage . Neuronal cells were isolated from the fetus brain at 18 - 20th day of gestation of pregnant Sprague Dawley ( SD ) rats . All experiments were included three independent cell preparations ( N = 3 ) . The neuronal cells were exposed to Pb2 + ( 10 (- 10 ) , 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) M ) for 24 h . Neurons were pretreated with NMDAR agonist -- L - glutamic acid ( GA ) ( 200 microM ) and antagonists dizocipine ( MK - 801 , 50 nM ) for 1h and then exposed to 10 (- 7 ) M of Pb2 + for 24 h . Finally , GA at 2 , 0 . 2 and 0 . 02 mM was incubated with neurons prior to Pb2 + exposure . Aliquots of Q9UHB4 , Q12879 and Q13224 proteins from cell homogenate were immunoprecipitated with protein A agarose and detected by Western blotting . The addition of GA unconventionally reversed the reductions of NMDAR by Pb at protein levels , whereas MK - 801 exacerbated Pb2 +- induced damage . The protection by GA against Pb2 +- induced reduction of NMDAR was dose - dependent . These findings suggest that the administration of GA may be a potential approach to intervene the Pb2 +- induced NMDAR alterations .", "Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK5___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .", "Postsynaptic alteration of Q12879 subunit and defective autophosphorylation of alphaCaMKII at threonine - 286 contribute to abnormal plasticity and morphology of upper motor neurons in presymptomatic SOD1G93A mice , a murine model for amyotrophic lateral sclerosis . Although amyotrophic lateral sclerosis ( P35858 ) has long been considered as a lower motor neuron ( MN ) disease , degeneration of upper MNs arising from a combination of mechanisms including insufficient growth factor signaling and enhanced extracellular glutamate levels is now well documented . The observation that these mechanisms are altered in presymptomatic superoxide dismutase ( P00441 ) mice , an P35858 mouse model , suggests that defective primary motor cortex ( M1 ) synaptic activity might precede the onset of motor disturbances . To examine this point , we assessed the composition of AMPAR and NMDAR subunits and of the alphaCa² (+)/ calmodulin - dependent kinase autophosphorylation at threonine - 286 in the triton insoluble fraction from the M1 in postnatal P80 - P85 P00441 ( G93A ) and wild - type mice . We show that presymptomatic P00441 ( G93A ) exhibit a selective decrease of Q12879 subunit expression and of the alphaCa² (+)/ calmodulin - dependent kinase autophosphorylation at threonine - 286 in the triton insoluble fraction of upper MNs synapses . These molecular alterations are associated with synaptic plasticity defects , and a reduction in upper MN dendritic outgrowth revealing that abnormal neuronal connectivity in the M1 region precedes the onset of motor symptoms . We suggest that the progressive disruption of M1 corticocortical connections resulting from the P00441 ( G93A ) mutation might extend to adjacent regions and promote development of cognitive / dementia alterations frequently associated with P35858 .", "Acute heat stress induces edema and nitric oxide synthase upregulation and down - regulates mRNA levels of the Q05586 , Q12879 and Q13224 subunits in the rat hippocampus . The influence of heat stress on constitutive isoform of neuronal nitric oxide synthase ( P29474 ) and DB01221 receptor gene expression in hippocampus was examined in a rat model . Subjection of animals to 4 h heat stress at 38 degrees C resulted in a marked upregulation of P29474 in the hippocampus accompanied with a marked general expansion and edematous cell changes . On the other hand DB01221 receptor messenger RNA encoding Q05586 , Q12879 and Q13224 subunits showed a marked downregulation in the hippocampus of heat stressed rats compared to the controls . Our results show that upregulation of P29474 is instrumental in heat stress associated edema and cell injury . Furthermore , an increased production of NO as evident with upregulation of P29474 appears to be a key factor in the downregulation of DB01221 receptor gene expression in heat stress .", "Meta - analysis of six genes ( P23560 , P21728 , P35462 , P21917 , Q13224 and P21397 ) involved in neuroplasticity and the risk for alcohol dependence . BACKGROUND : DB00898 - related problems have a large impact on human health , accounting for around 4 % of deaths and 4 . 5 % of disability - adjusted life - years around the world . Genetic factors could explain a significant fraction of the risk for alcohol dependence ( AD ) . Recent meta - analyses have found significant pooled odds ratios ( ORs ) for variants in the P00325 , P00326 , P14416 and P28223 genes . METHODS : In the present study , we carried out a meta - analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity : P23560 , P21728 , P35462 , P21917 , Q13224 and P21397 . We carried out a systematic search for published association studies that analyzed the genes of interest . Relevant articles were retrieved and demographic and genetic data were extracted . Pooled ORs were calculated using a random - effects model using the Meta - Analyst program . Dominant , recessive and allelic models were tested and analyses were also stratified by ethnicity . RESULTS : Forty two published studies were included in the current meta - analysis : P23560 - rs6265 ( nine studies ) , P21728 - rs4532 ( four studies ) , P35462 - rs6280 ( eleven studies ) , P21917 - VNTR ( seven studies ) , Q13224 - rs1806201 ( three studies ) and P21397 - uVNTR ( eight studies ) . We did not find significant pooled ORs for any of the six genes , under different models and stratifying for ethnicity . CONCLUSIONS : In terms of the number of candidate genes included , this is one of the most comprehensive meta - analyses for genetics of AD . Pooled ORs did not support consistent associations with any of the six candidate genes tested . Future studies of novel genes of functional relevance and meta - analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD .", "Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK41___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK41___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK41___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .", "P04035 inhibition induces IL - 1beta release through Rac1 / PI3K / P31749 - dependent caspase - 1 activation . Q03426 deficiency ( MKD ) is an autoinflammatory disorder characterized by recurring fever episodes and results from disturbed isoprenoid biosynthesis . Lipopolysaccharide - stimulated peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin - 1beta ( IL - 1beta ) because of the presence of hyperactive caspase - 1 , and this has been proposed to be the primary cause of recurring inflammation . Here we show that inhibition of P04035 by simvastatin treatment , mimicking MKD , results in increased IL - 1beta secretion in a Rac1 / PI3K - dependent manner . Simvastatin treatment was found to activate protein kinase B ( P31749 ) / c - akt , a primary effector of PI3K , and ectopic expression of constitutively active P31749 was sufficient to induce IL - 1beta release . The small GTPase Rac1 was activated by simvastatin , and this was required for both P31749 activation and IL - 1beta secretion . IL - 1beta release is mediated by caspase - 1 , and simvastatin treatment resulted in increased caspase - 1 activity in a Rac1 / PI3K - dependent manner . These data suggest that , in MKD , dysregulated isoprenoid biosynthesis activates Rac1 / PI3K / P31749 , resulting in caspase - 1 activation with increased IL - 1beta release . Importantly , inhibition of Rac1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL - 1beta release . These data suggest that pharmacologic inhibition of Rac1 could provide a novel therapeutic strategy for treatment of MKD .", "P04035 inhibitor , atorvastatin , promotes sensorimotor recovery , suppressing acute inflammatory reaction after experimental intracerebral hemorrhage . BACKGROUND AND PURPOSE : Statins have neuroprotective effects on ischemic stroke . They modify the endothelial function , increase blood flow , and inhibit thrombus formation , which are independent of lipid - lowering effects . However , whether statins have a protective effect toward hemorrhagic stroke is yet unknown . To test this possibility , we attempted to determine the effect of atorvastatin on experimental intracerebral hemorrhage ( ICH ) . METHODS : ICH was induced using stereotaxic infusion of collagenase into the left basal ganglia in adult rats . ___MASK61___ ( 1 mg / kg or 10 mg / kg ) or phosphate - buffered saline was administered for 2 weeks . To monitor the sensorimotor deficits , limb placing and Rotorod tests were performed . Hematoma volume , brain water content , and hemispheric atrophy were analyzed . Immunohistochemical staining for myeloperoxidase ( P05164 ) , microglia ( OX42 ) , inducible nitric oxide synthase ( P35228 ) , or endothelial nitric oxide synthase ( P29474 ) was performed . Perihematomal cell death was determined by TUNEL staining . RESULTS : The atorvastatin - treated ICH group showed better performance on Rotorod and limb placing tests when compared with the vehicle - treated group ( P < 0 . 01 ) . The hematoma volumes between groups were not different , but the brain water content and hemispheric atrophy were reduced in the atorvastatin - treated ICH group . ___MASK61___ reduced TUNEL - positive cells , P35228 expression , and P05164 - positive or OX42 - positive cells in the perihematomal regions in a dose - dependent manner , whereas it increased P29474 expression . CONCLUSIONS : The present study shows that atorvastatin reduces the perihematomal cell death via antiinflammation , which is associated with sensorimotor recovery after experimental ICH .", "17 ___MASK68___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .", "Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .", "[ ___MASK46___ sodium ( Photofrin - II ) ] . ___MASK46___ sodium ( ___MASK46___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK46___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .", "[ Neuropsychiatric lupus and autoantibodies against ionotropic glutamate receptor ( NMDAR ) ] . Almost half of lupus patients will experience neuropsychiatric symptoms during the course of their disease . The etiology of the neuronal damages is still uncertain and probably multiple . Autoantibodies reactive with brain have been postulated to play a role . The observation of pathogenic autoantibodies binding the Q12879 and Q13224 subunits of the ionotropic glutamate receptor ( NMDAR ) illustrates this hypothesis . First studies showed that 40 % of lupus patients possess serum titers of anti - Q12879 / B antibody , but the presence of these autoantibodies is not always associated with the occurrence of neuronal damages or neuropsychiatric symptoms . Nevertheless , their presence is observed in the cerebrospinal fluid ( P04141 ) of one half of the patients suffering from neurolupus . The presence in the serum of these autoantibodies anti - Q12879 / B of the NMDAR is preliminary to their presence in the P04141 where their deleterious effect is observable . Their entry into the brain is dependent on a breach of the blood brain barrier ( BBB ) . In conclusion , the serum titer of autoantibodies against Q12879 / B subunits is an indication of the potential for neuropsychiatric manifestations during the course of the disease .", "Role of calpain - 1 in the early phase of experimental P35858 . Elevation in [ Ca ( 2 +)] i and activation of calpain - 1 occur in central nervous system of P00441 ( G93A ) transgenic mice model of amyotrophic lateral sclerosis ( P35858 ) , but few data are available about the early stage of P35858 . We here investigated the level of activation of the Ca ( 2 +)- dependent protease calpain - 1 in spinal cord of P00441 ( G93A ) mice to ascertain a possible role of the protease in the aetiology of P35858 . Comparing the events occurring in the 120 day old mice , we found that [ Ca ( 2 +)] i and activation of calpain - 1 were also increased in the spinal cord of 30 day old mice , as indicated by the digestion of some substrates of the protease such as P29475 , αII - spectrin , and the Q13224 subunit of DB01221 - R . However , the digestion pattern of these proteins suggests that calpain - 1 may play different roles depending on the phase of P35858 . In fact , in spinal cord of 30 day old mice , activation of calpain - 1 produces high amounts of P29475 active species , while in 120 day old mice enhanced - prolonged activation of calpain - 1 inactivates P29475 and down - regulates Q13224 . Our data reveal a critical role of calpain - 1 in the early phase and during progression of P35858 , suggesting new therapeutic approaches to counteract its onset and fatal course .", "P04035 inhibitors up - regulate anti - aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age - related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age - suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real - time RT - PCR . ___MASK61___ and pitavastatin increased the expression of klotho mRNA in a dose - dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho - kinase by Y27632 up - regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down - regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II - induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over - expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .", "Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice . Aging is the principal demographic risk factor for Alzheimer disease ( AD ) , the most common neurodegenerative disorder . Q9UEF7 is a key modulator of the aging process and , when overexpressed , extends mammalian lifespan , increases synaptic plasticity , and enhances cognition . Whether klotho can counteract deficits related to neurodegenerative diseases , such as AD , is unknown . Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein ( hAPP ) transgenic mice , which simulate key aspects of AD . Increasing klotho levels prevented depletion of DB01221 receptor ( NMDAR ) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice . Q9UEF7 elevation in hAPP mice increased the abundance of the Q13224 subunit of NMDAR in postsynaptic densities and NMDAR - dependent long - term potentiation , which is critical for learning and memory . Thus , increasing wild - type klotho levels or activities improves synaptic and cognitive functions , and may be of therapeutic benefit in AD and other cognitive disorders .", "Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK33___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .", "DNA methylation profiles in diffuse large B - cell lymphoma and their relationship to gene expression status . In an initial epigenetic characterization of diffuse large B - cell lymphoma ( DLBCL ) , we evaluated the DNA methylation levels of over 500 CpG islands . Twelve CpG islands ( AR , P49918 , DLC1 , P14416 , P43694 , P39905 , Q13224 , P42898 , P15172 , Q13562 , O95948 and P05549 ) showed significant methylation in over 85 % of tumors . Interestingly , the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B - cell - like ( ABC - DLBCL ) and germinal center B - cell - like ( GCB - DLBCL ) subtypes . In addition , we compared the methylation and expression status of 67 genes proximal ( within 500 bp ) to the methylation assays . We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors . However , many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated . Nevertheless , the proportional reductions in Q12983 , P16455 , RBP1 , P43694 , Q9BY67 , P29762 and FLJ21062 expression with increasing methylation suggest that epigenetic processes strongly influence these genes . Lastly , the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing . Overall , further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted .", "___MASK5___ . Aegerion Pharmaceuticals is developing lomitapide , a small - molecule , microsomal triglyceride transfer protein ( P55157 ) inhibitor , for the treatment of both familial and primary hypercholesterolemia . Oral , once - daily lomitapide will be targeted at patients resistant to P04035 inhibitors ( statins ) either due to abnormalities in liver function or to discontinuation because of muscle pain . An oral formulation of lomitapide is in phase III development for homozygous familial hypercholesterolemia ( hyperlipoproteinemia type IIa ) in the US , Canada , Italy , and South Africa . This review discusses the key development milestones and therapeutic trials of this drug .", "[ Anti - cholesterol agents , new therapeutic approaches ] . Statins and fibrates constitute the two major families of lipid - lowering agents . Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia . Both drugs are also used for the treatment of mixed dyslipidemia . Some fibrates efficiently lower serum LDL - cholesterol . Statins inhibit P04035 and decrease cellular cholesterol synthesis . The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the P01130 gene . This over expression of the P01130 in the liver increases the clearance of circulating LDL thus decreasing the LDL - cholesterol plasma levels . The effects of fibrates on lipid metabolism are entirely due to their capacity to activate Q07869 and to induce the over expression of genes containing a PPRE in their promoter . Fibrates decrease triglyceride concentrations by increasing the beta - oxidation of fatty acids in the liver and by decreasing triglyceride - VLDL synthesis . Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C - III transcription , respectively . Fibrates could decrease triglycerides partly by inducing apo A - V over - expression . These molecules increase HDL - cholesterol by increasing apo A - I and apo A - II transcription . Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism .", "P04818 inhibition induces p53 - dependent and p53 - independent apoptotic responses in human urinary bladder cancer cells . PURPOSE : In search for more effective clinical protocols , the antimetabolite drug 5 - fluorouracil ( ___MASK41___ ) has been successfully included in new regimens of bladder cancer combination chemotherapy . In the present study , we have investigated the effects of ___MASK41___ treatment on apoptosis induction in wild - type and mutant p53 urinary bladder cancer cells . METHODS : We have used MTT - based assays , FACS analysis , Western blotting and semi - quantitative RT - PCR in RT4 and RT112 ( grade I , wild - type p53 ) , as well as in T24 ( grade III , mutant p53 ) and TCCSUP ( grade IV , mutant p53 ) human urinary bladder cancer cell lines . RESULTS : In the urothelial bladder cancer cell lines RT4 and T24 , ___MASK41___ - induced TS inhibition proved to be associated with cell type - dependent ( a ) sensitivity to the drug , ( b ) Caspase - mediated apoptosis , ( c ) p53 stabilization and activation , as well as Rb phosphorylation and Q01094 expression and ( d ) transcriptional regulation of p53 target genes and their cognate proteins , while an E2F - dependent transcriptional network did not seem to be critically engaged in such type of responses . CONCLUSIONS : We have shown that in the wild - type p53 context of RT4 cells , ___MASK41___ - triggered apoptosis was prominently efficient and mainly regulated by p53 - dependent mechanisms , whereas the mutant p53 environment of T24 cells was able to provide notable levels of resistance to apoptosis , basically ascribed to E2F - independent , and still unidentified , pathways . Nevertheless , the differential vulnerability of RT4 and T24 cells to ___MASK41___ administration could also be associated with cell - type - specific transcriptional expression patterns of certain genes critically involved in ___MASK41___ metabolism .", "Drosophila Answers to Q13148 Proteinopathies . Initially implicated in the pathogenesis of P13569 and HIV - 1 transcription , nuclear factor Q13148 was subsequently found to be involved in the origin and development of several neurodegenerative diseases . In 2006 , in fact , it was reported for the first time the cytoplasmic accumulation of Q13148 in ubiquitin - positive inclusions of P35858 and FTLD patients , suggesting the presence of a shared underlying mechanism for these diseases . Today , different animal models of Q13148 proteinopathies are available in rodents , nematodes , fishes , and flies . Although these models recapitulate several of the pathological features found in patients , the mechanisms underpinning the progressive neuronal loss observed in Q13148 proteinopathies remain to be characterized . Compared to other models , Drosophila are appealing because they combine the presence of a sophisticated brain with the possibility to investigate quickly and massively phenotypic genetic modifiers as well as possible therapeutic strategies . At present , the development of Q13148 - related Drosophila models has further strengthened the hypothesis that both Q13148 \" loss - of - function \" and \" gain - of - function \" mechanisms can contribute to disease . The aim of this paper is to describe and compare the results obtained in a series of transgenic and knockout flies , along with the information they have generated , towards a better understanding of the mechanisms underlying Q13148 proteinopathies .", "Glioblastoma with ovarian teratoma having N - methyl - D - aspartate receptor ( NMDAR ) antibody in P04141 -- a case report . A 54 - year - old woman presented with complex partial seizure with impaired consciousness . Brain Q9BWK5 revealed a high intensity lesion on P24752 - weighted and FLAIR images in the left temporal lobe , indicating limbic encephalitis . CT and Q9BWK5 of the pelvis showed right ovarian teratoma . The cerebrospinal fluid ( P04141 ) were positive for antibodies against the GluRε2 , GluRδ2 , and antibodies against Q9UHB4 + Q13224 heteromers . On the basis of these data , anti - N - methyl - D - aspartate receptor ( NMDAR ) encephalitis associated with ovarian teratoma was suspected , and the right ovariectomy was performed . Six months after onset , brain biopsy from the right temporal lobe led to a diagnosed of glioblastoma . This is the first glioblastoma case with ovarian teratoma having autoantibodies against GluR and Q9UHB4 + Q13224 heteromers in P04141 . We suggest that patients with NMDAR antibodies should be carefully diagnosed with anti - NMDAR encephalitis ." ]

[ "___MASK14___", "___MASK23___", "___MASK33___", "___MASK41___", "___MASK46___", "___MASK5___", "___MASK61___", "___MASK68___", "___MASK86___" ]

[ "Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .", "Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK46___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK46___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK46___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK46___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK46___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK46___ increased the protein expression of hepatic P05181 and ___MASK46___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK46___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK46___ and RFP - induced hepatotoxicity .", "Recombinant human prothrombin kringles have potent anti - angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases . P00734 , a protein involved in blood coagulation , is a plasma glycoprotein composed of the Gla domain , two adjacent kringle domains , and a serine protease domain . Kringles are triple - disulfide - loop folding domains , which are found in several other blood proteins . In this study , we showed that recombinant human prothrombin kringle - 1 , - 2 . and - 1 - 2 ( rk - 1 , - 2 , - 1 - 2 ) all have potent anti - angiogenic activities , which inhibit Lewis lung carcinoma ( LLC ) tumor growth and metastases . Recombinant human prothrombin kringles were expressed by an E . coli expression system and purified to apparent homogeneity from crude E . coli extracts . Purified rk - 1 , - 2 , - 1 - 2 migrated with a molecular mass of 14 , 19 , and 31 kDa , respectively , on sodium dodecyl sulfate - polyacrylamide gel electrophoresis ( SDS - PAGE ) under reducing conditions . rk - 1 , - 2 , - 1 - 2 exhibited potent inhibitory effects on P09038 - stimulated bovine capillary endothelial cell growth with half - maximal concentrations ( ED50 ) of approximately 41 , 55 , and 156 nM , respectively . All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane ( P62158 ) of chick embryos at a dose of 20 microg . Systemic administration of rk - 1 , - 2 , - 1 - 2 at a dose of 0 . 5 mg / kg / day suppressed the growth of primary LLC and at dose of 0 . 5 and 1 . 0 mg / kg / day inhibited LLC metastases in C57BL6 / J mice lungs through their anti - angiogenic effects .", "First report of warfarin dose requirements in patients possessing the P11712 * 12 allele . BACKGROUND : ___MASK84___ is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S - warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S - warfarin . Numerous variant alleles of P11712 have been identified . The P11712 * 12 ( rs9332239 ) allele harbors a P489S substitution in P11712 which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 , Q9BQB6 and P02649 variant alleles . None of the four patients carried the common P11712 variant alleles ( * 2 , * 3 , * 5 , * 6 , * 7 , * 8 , * 9 , * 11 , * 13 ) despite a relatively low MWWD ( 23 . 4 ± 7 . 94 mg ) compared to 208 patients carrying the CYP29C9 * 1 genotype ( 32 . 2 ± 12 . 65 mg ) . Given that P11712 * 12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 * 12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 genotypes also demonstrated lower dose requirements in the patients that possessed P11712 * 12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 substrates . This is the first report of patients with the rare P11712 * 12 genotype and lower warfarin dose requirements .", "P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK79___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )", "[ Moclobemide ( ___MASK34___ ) , the first P21397 - inhibitor : really something new ? ] .", "Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK32___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK32___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .", "Battle of the kinases : integration of adrenal responses to DB02527 , DG and Ca2 + at the level of steroidogenic cytochromes P450 and 3betaHSD expression in H295R cells . While DB01285 receptors ( activating the protein kinase A pathway ) are expressed throughout the human / bovine / ovine zona glomerulosa ( zg ) and zona fasciculata ( zf ) , there are clear zonal differences in AII Type - 1 receptor levels ( activating protein kinase C / Ca2 + ) , as well as resting membrane potential . Thus zg is most responsive to AII and K + ( Ca2 + signalling ) , while zf is less responsive to AII with no K + response . Zonal function in turn requires differential expression of P05093 / 3betaHSD and P19099 / P15538 . We have used the H295R cell to study how differential activation of kinase A , kinase C and Ca2 +/ calmodulin ( P62158 ) kinases may alter the relative expression of the steroidogenic P450s and 3betaHSDII . While P05108 , P05093 , 3betaHSDII , P08686 , and P15538 are all induced by increases in DB02527 , studies with TPA alone or in combination with forskolin reveal subsets of steroidogenic enzymes regulated either positively ( P08686 , 3betaHSDII ) or negatively ( P05093 , P05108 ) by protein kinase C . Thus adrenal 3betaHSDII and P08686 expression is high in zg and zf , but P05093 is not expressed in the zg where AII activation of kinase C is highest . In turn both K + and AII - induced elevation of Ca2 + strongly induces P19099 but not P15538 , consistent with preferential expression of P19099 in the zg . We conclude that differential signaling through kinase C and P62158 kinases in addition to kinase A underlies zonal differences in both the early and late pathways involved in steroid hormone production within the adrenocortical zones .", "___MASK44___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK44___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .", "P62158 - mediated effects of loperamide on chloride transport by brush border membrane vesicles from human ileum . We investigated whether the synthetic opiate loperamide - HCl is able to regulate specific transport systems for sodium and chloride in brush border membrane vesicles ( BBMVs ) from human ileum and whether such activities are mediated by calcium / calmodulin . In BBMVs we studied Na +/ H + antiport , Cl +/ OH - antiport , Na +/ Cl - cotransport , and the Cl - conductive pathway . Brush border membrane vesicles were incubated with 10 microM loperamide over 4 h at 5 degrees C before the uptake experiments . In ileal BBMVs , loperamide stimulated intravesicular accumulation of Na + in the presence of Cl - and vice versa . After 1 min of incubation , the stimulatory effect was 35 % +/- 5 % ( p less than 0 . 005 ) of the control without loperamide . DB00836 also stimulated Cl -/ OH - antiport by 30 % +/- 5 % ( p less than 0 . 005 ) in BBMVs of ileum . In addition , we studied the role of Ca2 +/ calmodulin in the action of loperamide on chloride transport by human BBMVs . In loperamide - pretreated BBMVs , calmodulin activity was significantly decreased ( 12 +/- 2 vs . 38 +/- 4 pmol / mg protein ) . When loperamide - pretreated vesicles were incubated with 2 microM calcium ( free concentration ) plus 5 microM calmodulin for 1 h at 5 degrees C , complete inhibition of the stimulatory effect of loperamide on Cl -/ OH - antiport and Na +/ Cl - cotransport was observed . Increasing the Ca2 +/ calmodulin activity of loperamide - pretreated BBMVs with 2 microM calcium plus 5 microM calmodulin led to a significant inhibition of Cl -/ OH - antiport and Na +/ Cl - cotransport by 40 % +/- 5 % ( p less than 0 . 005 ) .", "P13569 modulates neurosecretory function in pulmonary neuroendocrine cell - related tumor cell line models . The pulmonary neuroendocrine cell ( PNEC ) system consists of solitary cells and distinctive cell clusters termed neuroepithelial bodies ( P20929 ) localized in the airway epithelium . PNEC / P20929 express a variety of bioactive substances , including amine ( serotonin , 5HT ) and neuropeptides . We have previously shown that P20929 cells are O ( 2 ) sensors expressing nicotinamide adenine diphosphate oxidase complex and O ( 2 ) sensitive K (+) channel . Recently , we demonstrated expression of functional cystic fibrosis transmembrane conductance regulator ( P13569 ) and Cl (-) conductances in P20929 cells of rabbit neonatal lung . Because PNEC / P20929 are sparsely distributed and difficult to study in native lung , we investigated small - cell lung carcinoma ( SCLC ) and carcinoid tumor cell lines ( tumor counterparts of normal PNEC / P20929 ) as models for PNEC / P20929 . SCLC ( H146 , H345 ) and carcinoid ( H727 ) cell lines express neuroendocrine cell markers , including chromogranin A , neural cell adhesion molecule ( N - P62158 ) , 5HT , and tryptophan hydroxylase . We report that H146 , H345 , and H727 express P13569 messenger RNA ( reverse transcription polymerase chain reaction ) and protein ( immunoblotting ) and possess functional P13569 Cl (-) conductance , demonstrated by an iodide efflux assay inhibitable by transfection with antisense P13569 . Using an immunoassay to quantitate 5HT secretion , we also show that downregulation of P13569 abolishes hypoxia - induced 5HT release , and reduces secretory response to high potassium . Our findings suggest that P13569 may modulate neurosecretory activity of PNEC / P20929 possessing O ( 2 ) sensor function . We propose that these tumor cell lines may be useful models for investigating the role of P13569 in PNEC / P20929 functions in health and disease .", "Signaling cascade that mediates endothelial nitric oxide synthase activation induced by atrial natriuretic peptide . Atrial natriuretic peptide ( P01160 ) induces activation of nitric oxide - synthase ( NOS ) . AIMS : to identify the isoform of NOS involved in P01160 effects , to study whether P01160 modifies NOS expression and to investigate the signaling pathways and receptors involved in NOS stimulation . NOS activation induced by P01160 would be mediated by endothelial NOS ( P29474 ) since neuronal or inducible NOS inhibition did not alter P01160 effect . The peptide induced no changes in P29474 protein expression . NOS activity stimulated by P01160 , in the kidney , aorta and left ventricle , was partially abolished by the P16066 / B antagonist , as well as PKG inhibition , but no difference in atria was observed . 8 - Br - cGMP partially mimicked the effect of P01160 on NOS in all tissues . NOS stimulation by P01160 in atria disappeared when G protein was inhibited , but this effect was partial in the other tissues . P62158 antagonist abolished NOS stimulation via P01160 . Inhibition of the P98160 , PKC or P19957 kinase / Akt pathway failed to alter NOS activation induced by P01160 . P01160 would activate P29474 in the aorta , heart and kidney without modifying the expression of the enzyme . P01160 would interact with P17342 coupled via G proteins leading to the activation of Ca ( 2 +)- calmodulin - dependent NOS in atria ; while in ventricle , aorta and kidney , P01160 could also interact with P16066 / B , increasing cGMP , which in turns activates PKG to stimulate P29474 .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK59___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK74___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .", "Association between iris constitution and apolipoprotein e gene polymorphism in hypertensives . OBJECTIVE : Iridology is a complementary and alternative medicine ( P62158 ) that involves the diagnosis of medical conditions by noting irregularities of the pigmentation in the iris . Iris constitution has a strong familial aggregation and heredity is implicated . P02649 ( apoE ) gene polymorphism is one of the most well - studied genetic markers for vascular diseases , including hypertension . In this study , we investigated the relationship between iris constitution and apoE polymorphism in hypertensives . DESIGN AND SUBJECTS : We classified 87 hypertensives and 79 controls according to iris constitution and determined the apoE genotype of each individual . RESULTS : A significantly higher percentage of individuals with neurogenic constitutions was found in the hypertensive group when compared with the control group ( chi ( 2 ) = 40 . 244 , p < 0 . 001 ) . In addition , a neurogenic constitution increased the relative risk for hypertension for subjects with an apo epsilon2 or an epsilon4 allele ( chi ( 2 ) = 4 . 086 , p = 0 . 049 , odds ratio = 2 . 633 , confidence interval = 1 . 004 - 6 . 905 ) . CONCLUSIONS : Our results imply that a neurogenic iris constitution enhances the relative risk for hypertension in subjects with the apo epsilon2 or epsilon4 allele . Furthermore , we attempted to evaluate the efficacy of iris constitutional medicine and to find an association with hypertension .", "Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .", "Targeting the integrated networks of aggresome formation , proteasome , and autophagy potentiates ER stress ‑ mediated cell death in multiple myeloma cells . The inhibitory effects of macrolide antibiotics including clarithromycin ( P62158 ) on autophagy flux have been reported . Although a macrolide antibiotic exhibits no cytotoxicity , its combination with bortezomib ( BZ ) , a proteasome inhibitor , for the simultaneous blocking of the ubiquitin ( Ub )‑ proteasome and autophagy ‑ lysosome pathways leads to enhanced multiple myeloma ( MM ) cell apoptosis induction via stress overloading of the endoplasmic reticulum ( ER ) . As misfolded protein cargo is recruited by histone deacetylase 6 ( Q9UBN7 ) to dynein motors for aggresome transport , serving to sequester misfolded proteins , we further investigated the cellular effects of targeting proteolytic pathways and aggresome formation concomitantly in MM cells . Pronounced apoptosis was induced by the combination of vorinostat [ suberoylanilide hydroxamic acid ( ___MASK66___ ) ; potently inhibits Q9UBN7 ] with P62158 and BZ compared with each reagent or a 2 ‑ reagent combination . P62158 / BZ treatment induced vimentin positive ‑ aggresome formation along with the accumulation of autolysosomes in the perinuclear region , whereas they were inhibited in the presence of ___MASK66___ . The ___MASK66___ / P62158 / BZ combination treatment maximally upregulated genes related to ER stress including C / EBP homologous protein ( P35638 ) . Similarly to MM cell lines , enhanced cytotoxicity with P35638 upregulation following ___MASK66___ / P62158 / BZ treatment was shown by a wild ‑ type murine embryonic fibroblast ( MEF ) cell line ; however , a CHOP ‑ deficient MEF cell line almost completely canceled this pronounced cytotoxicity . Knockdown of Q9UBN7 with siRNA exhibited further enhanced P62158 / BZ ‑ induced cytotoxicity and P35638 induction along with the cancellation of aggresome formation . Targeting the integrated networks of aggresome , proteasome , and autophagy is suggested to induce efficient ER stress ‑ mediated apoptosis in MM cells ." ]

[ "___MASK32___", "___MASK34___", "___MASK44___", "___MASK46___", "___MASK59___", "___MASK66___", "___MASK74___", "___MASK79___", "___MASK84___" ]

[ "Does anti - P01375 therapy reduce the requirement for surgery in ulcerative colitis ? A systematic review . DB00065 has demonstrated its efficacy in moderate to severe ulcerative colitis . The Active Ulcerative Colitis Trial ( ACT ) - 1 and 2 have demonstrated the beneficial impact of infliximab on the short - term colectomy rate . However , data evaluating this outcome beyond one year remains scarce . To provide evidence on the potential impact of infliximab on the long - term colectomy rate in patients suffering from ulcerative colitis , data was reviewed from randomized and controlled studies , referral centre studies and population - based studies , in adult and pediatric populations . In the pre - biologic era , 9 - 33 % , 50 % and 29 % of adult patients with ulcerative colitis underwent colectomy in clinical trials , referral center studies and population - based cohorts , respectively . In the pediatric population , 9 - 61 % and 8 - 20 % underwent colectomy in referral centers and population - based cohorts , respectively . Between 10 and 36 % of adult patients treated with infliximab for ulcerative colitis underwent colectomy in clinical trials , referral center studies and population - based cohorts . In the pediatric population treated with infliximab , long - term data is lacking , with colectomy rates ranging from 16 to 28 % . Whether infliximab proves to be a disease modifying treatment in ulcerative colitis in the long term remains to be elucidated and will require further long - term prospective studies .", "Non - response to infliximab may be due to innate neutralizing anti - tumour necrosis factor - alpha antibodies . DB00065 is a chimeric anti - tumour necrosis factor ( P01375 ) - alpha antibody that is therapeutic in many patients with inflammatory bowel disease . What causes certain patients not to respond is unknown . The question posed is whether innate anti - P01375 antibodies play any role in the response to infliximab . Blood was drawn prior to the initial dose of infliximab . Serum anti - P01375 antibodies were quantitated by enzyme - linked immunosorbent assay ( ELISA ) . Affinity - purified anti - P01375 antibodies were isolated from serum immunoglobulin G using P01375 - coated beads . The ability of these antibodies to induce apoptosis of macrophages was measured by annexin and propidium iodide staining . Changes in P01375 receptor type 2 ( P20333 ) expression and release were determined by immunofluorescence and ELISA respectively . P01375 - neutralization was assessed by the reversal of the lytic actions of P01375 on WEHI cells . The amounts of innate anti - P01375 antibodies in the serum from infliximab responders versus non - responders were the same . Apoptosis of monocytes increased with infliximab and by several of the purified anti - P01375 antibodies , but these findings did not vary with the patients ' responses to infliximab . Effects of the anti - P01375 antibodies on the expression of P20333 on monocytes and their release of soluble P20333 did not vary with the patients ' responses to infliximab . However , the neutralizing capacity of these antibodies differed , with responders having antibodies that reduced only 47 +/- 4 % of the P01375 activity while those from non - responders reduced 70 +/- 5 % of the P01375 activity ( P < 0 . 01 ) . Non - responders have innate anti - P01375 antibodies with greater neutralizing activity than antibodies from responders . Any P01375 - mediated disease process would be neutralized by intrinsic antibodies , so that the disease is likely to be driven by non - P01375 - mediated events .", "New indications for treatment of chronic inflammation by P01375 blockade . The impressive anti - inflammatory effects of the tumor necrosis factor ( P01375 ) alpha blockers etanercept and infliximab have led to their use in multiple inflammatory diseases besides their original indication , rheumatoid arthritis ( RA ) . The well - studied clinical effects of both agents in RA are the reduction of signs and symptoms of joint inflammation as well as the arrest of bone destruction . DB00065 has also been Food and Drug Administration - approved in the treatment of Crohn disease ; etanercept is now FDA - approved for juvenile chronic arthritis and psoriatic arthritis . Favorable initial clinical trials have been reported in other rheumatic diseases , including ankylosing spondylitis and adult Still disease . In addition , P01375 alpha blockade is being studied in the treatment of uveitis , myelodysplastic syndromes , and graft - versus - host disease . Studies in sepsis and septic shock have identified small subsets of patients that may benefit from P01375 alpha blockade , but broader use in septic patients has not improved survival . The P01375 alpha blockers have had relatively infrequent serious side effects , especially compared with the immunosuppressive and cytotoxic agents otherwise employed to treat these diseases . Further studies of optimal dosing , combination with other therapies , and long - term benefits and side effects will emerge from future trials .", "Listeria infections associated with infliximab : case reports . DB00065 is a human - murine chimeric monoclonal antibody directed against tumor necrosis factor alpha ( TNFalpha ) . DB00065 and other P01375 blockers are used to treat inflammatory diseases such as rheumatoid arthritis ( RA ) . P01375 blockers are suspected to play a key role in some infections . We report here two cases of Listeria monocytogenes sepsis associated with infliximab treatment for RA . The first patient developed a terminal ileitis and a bacteraemia after three doses of infliximab ; the second RA patient presented a bacteraemia associated with a prosthetic joint arthritis of the left hip , both related to Listeria . Those two cases occurred in a population of 518 patients treated with P01375 blockers in our hospitals since the year 2000 . Those events are of particular interest because of the severity of the infection , because the treatment differs from other infections , and because that , in the rheumatology unit , septic arthritis can mimic RA symptoms . They enhance the likelihood for this drug to increase the risk for infections with germs like Listeria .", "DB00065 treatment reduces the serum levels of interleukin - 23 in patients with rheumatoid arthritis . In this study , we investigated the effect of the antitumor necrosis factor alpha ( anti - P01375 ) antibody , infliximab , combined with methotrexate ( MTX ) and MTX alone on the serum levels of interleukin ( IL ) - 23 and Q16552 in rheumatoid arthritis ( RA ) patients . DB00065 combined with MTX was administered to 26 patients with RA ( infliximab group ) , and MTX alone was given to 20 patients with RA ( MTX group ) . We evaluated clinical and laboratory parameters , including the Disease Activity Scores of 28 joints ( DAS28 ) and serum levels of IL - 23 and Q16552 at baseline and at 14 and 30 weeks after the initial treatment with these drugs . Single regression analysis was performed between the levels of serum IL - 23 and other clinical and laboratory parameters at baseline before the initial treatment with infliximab or MTX . A significant reduction of DAS28 scores was observed in both the infliximab and the MTX group at 14 and 30 weeks after the initial treatment . A significant decrease in serum levels of IL - 23 was observed in the infliximab group but not in the MTX group at 14 and 30 weeks after the initial treatment . Serum Q16552 levels did not show a significant change during the follow - up period . At baseline , before the initial treatment with infliximab or MTX , serum IL - 23 levels showed a significant correlation with DAS28 and the number of swollen joints . This study indicated that the reduction of serum IL - 23 levels in RA patients was a novel action of infliximab .", "DB00065 therapy for patients with inflammatory bowel disease : 10 years on . The advent of infliximab a decade ago has drastically changed the treatment paradigm for patients with inflammatory bowel diseases ( Q9UKU7 ) . Controlled evidence supports the use of this anti - P01375 antibody to treat luminal and fistulizing Crohn ' s disease , ulcerative colitis , pediatric Crohn ' s disease and extraintestinal manifestations of Q9UKU7 . For all Q9UKU7 indications induction with infliximab 5 mg / kg IV at weeks 0 - 2 - 6 , followed by q8 week scheduled maintenance is advocated . Novel treatment goals such as mucosal healing and the reduction of hospitalizations and surgeries , have been achieved by infliximab and open the perspective of disease modification . The benefit to risk ratio of infliximab is comparable to that of other immunosuppressive treatments such as azathioprine , provided patients are correctly selected and followed . Despite this progress , optimal treatment strategies are still debated . Recent evidence supports the ' top down ' use of infliximab in patients naive to azathioprine or methotrexate , but the lack of clinically useful predictors of a debilitating disease course hinders the selection of patients eligible for early biological intervention . Secondary loss of response or intolerance due to immunogenicity is intrinsic to the use of therapeutic antibodies , and fuels the controversy over the combination of anti - P01375 agents with traditional immunosuppressives .", "Tumour necrosis factor - alpha blockade : a new era for effective management of rheumatoid arthritis . Tumour necrosis factor ( P01375 ) - alpha inhibitors have emerged as a new treatment option for rheumatoid arthritis ( RA ) . The scientific rationale for targeting P01375 in RA derives from extensive work in the laboratory , showing the importance of this pro - inflammatory cytokine as a mediator of joint inflammation . Proof of principle has now been firmly established in clinical trials where P01375 inhibitors have been shown to decrease the signs and symptoms of joint inflammation and slow radiological progression of joint damage . Presently , the two P01375 inhibitors available for use in RA are etanercept and infliximab . DB00005 is a soluble P01375 receptor : Fc fusion protein that competes with the endogenous P01375 receptors for P01375 binding . DB00065 is a chimeric anti - P01375 monoclonal antibody , which also binds with high affinity to soluble P01375 . DB00005 and infliximab will be rapidly incorporated into current treatment paradigms , which call for early and intensive treatment of RA using disease - modifying antirheumatic drugs ( DMARDs ) , such as methotrexate , sulfasalazine and hydroxychloroquine . A major drawback to the widespread use of these biologics is their high costs . Some patients with limited financial means may be denied access to these effective anti - inflammatory agents . Moreover , long - term experience with P01375 inhibitor therapy has been limited and concerns linger about the possibility that etanercept and infliximab may cause unforeseen side effects or increase the risk for opportunistic infection . Despite these caveats , P01375 inhibitors represent a major advance for the treatment of RA and will likely spawn new indications for anti - P01375 therapy and the development of novel therapeutic compounds with similar biological activity .", "Cordycepin suppresses P01375 - α - induced NF - κB activation by reducing p65 transcriptional activity , inhibiting IκBα phosphorylation , and blocking IKKγ ubiquitination . Cordycepin is reported to participate in multiple pharmacological activities including anti - tumor and anti - inflammation , and is involved in the regulation of NF - κB signaling pathway . However , the detailed molecular mechanism of cordycepin in suppression of NF - κB signaling pathway remains ambiguous . In this study , we first analyzed the effect of cordycepin on NF - κB activity in P29320 - 293T cells , and found that cordycepin resulted in a dose - dependent reduction in P01375 - α - induced NF - κB activation . Although cordycepin did not block P01375 - α - induced nuclear translocation of p65 , high concentration of cordycepin reduced the DNA - binding and transcriptional activities of NF - κB . Moreover , cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα . Further investigation revealed that cordycepin suppressed IKKs - mediated NF - κB activation and inhibited the ubiquitination of IKKγ . In conclusion , cordycepin effectively inhibits NF - κB signaling through suppressing the activities of NF - κB , IκB and IKK . Thus , cordycepin may provide some potential therapeutic application in inflammation - associated disorders and cancer .", "Use of a disease risk score to compare serious infections associated with anti - tumor necrosis factor therapy among high - versus lower - risk rheumatoid arthritis patients . OBJECTIVE : To evaluate whether rates of serious infection with anti - tumor necrosis factor ( anti - P01375 ) therapy in rheumatoid arthritis ( RA ) patients differ in magnitude by specific drugs and patient characteristics . METHODS : Among new nonbiologic disease - modifying antirheumatic drug users enrolled in Medicare and Medicaid or a large US commercial health plan , we created and validated a person - specific infection risk score based on age , demographics , insurance type , glucocorticoid dose , and comorbidities to identify patients at high risk for hospitalized infections . We then applied this risk score to new users of infliximab , etanercept , and adalimumab and compared the observed 1 - year rates of infection to one another and to the predicted infection risk score estimated in the absence of anti - P01375 exposure . RESULTS : Among 11 , 657 RA patients initiating anti - P01375 therapy , the observed 1 - year rate of infection was 14 . 2 infections per 100 person - years in older patients ( age ≥ 65 years ) and 4 . 8 in younger patients ( age < 65 years ) . There was a relatively constant rate difference of ~ 1 - 4 infections per 100 person - years associated with anti - P01375 therapy across the range of the infection risk score . DB00065 had a significantly greater adjusted rate of infection compared to etanercept and adalimumab in both high - and lower - risk RA patients . CONCLUSION : The rate of serious infections for anti - P01375 agents was incrementally increased by a fixed absolute difference irrespective of age , comorbidities , and other factors that contributed to infections . Older patients and those with high comorbidity burdens should be reassured that the magnitude of their incremental risk with anti - P01375 agents is not greater than for lower - risk patients .", "Effect of anti - P01375 therapy and vitamin D derivatives on the proliferation of peripheral blood mononuclear cells in Crohn ' s disease . DB00065 treatment demonstrated clinical and endoscopic benefits in active refractory and fistulizing Crohn ' s disease . The aim of this research was to investigate the proliferative response of peripheral blood mononuclear cells ( PBMC ) obtained from patients with active and fistulizing Crohn ' s disease treated with infliximab therapy . PBMC proliferation and P11473 protein levels were also studied when 1 , 25 ( OH ) 2D3 or its analogues ( EB 1089 , KH 1060 ) were added to cells cultures . At day 5 of culture , the proliferation of PBMC obtained from patients responsive to the therapy showed a remarkable decrease ( about 60 % ) at Q8NHM4 ( after two infusions ) with respect to T0 ( before the first infusion ) . On the contrary , in the unresponsive patient , the proliferative response was four times higher at Q8NHM4 in comparison with T0 . Vitamin D derivatives induced a decrease in cell proliferation higher in responsive patients than in the unresponsive one . Increased P11473 levels during therapy were registered only in the unresponsive patient . Our results indicate that PBMC proliferation and P11473 expression may be useful indicators to predict the response of patients with Crohn ' s disease to the infliximab therapy .", "Episcleritis Related to Drug - Induced Lupus Erythematosus following DB00065 Therapy : A Case Report . Drug - induced lupus erythematosus is defined as a lupus - like syndrome temporally related to continuous drug exposure which resolves after discontinuation of the offending drug . Herein , we describe a patient with distinct clinical manifestations of anti - P01375 - associated DILE related to infliximab therapy . The patient exhibited clinical and laboratory findings of lupus - like illnesses as well as ocular disorders , such as episcleritis . The main message is that the symptoms of DILE should not be overlooked , although sometimes other systematic conditions may underlie them . As a result , it is very important for the clinicians to evaluate the symptoms of DILE and manage appropriately these cases .", "___MASK30___ block of cloned human T - type voltage - gated calcium channels . ___MASK30___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .", "DB00065 : efficacy in psoriasis . Moderate to severe psoriasis often needs to be addressed with standard disease modifying therapies such as methotrexate , cyclosporine , acitretin or ultraviolet radiation , which have their potential benefits and limitations . The tumor necrosis factor - alpha ( P01375 - α ) is elevated in psoriatic plaques compared to non lesional skin as well as in the plasma of patients with moderate to severe psoriasis . DB00065 , a P01375 - α blocker , has been recommended for the treatment of moderate to severe plaque psoriasis in adults who have failed to respond to these therapies or who can not tolerate them . Its specific action on the bound and membrane forms of the pro - inflammatory cytokine P01375 - α has made it the molecule of choice for obtaining quicker and longer remission in recalcitrant cases . However , the widespread use of infliximab in the Indian subcontinent is limited by its cost . This article reviews the international guidelines for use of infliximab , its dosage patterns , and efficacy in chronic plaque psoriasis , nail psoriasis , erythrodermic psoriasis , and pustular psoriasis as well as Indian experience .", "Sexually dimorphic stress and pro - inflammatory cytokine responses to an intravenous corticotropin - releasing hormone challenge of Brahman cattle following transportation . This study was designed to characterize potential sexually dimorphic stress and immunological responses following a corticotropin - releasing hormone ( P06850 ) challenge in beef cattle . Six female ( heifers ) and six male ( bulls ) Brahman calves ( 264 ± 12 d of age ) were administered P06850 intravenously ( 0 . 5 µg of P06850 / kg body mass ) after which serum concentrations of cortisol increased from 0 . 5 h to 4 h . From 1 h to 4 h after P06850 administration , serum cortisol concentrations were greater in heifers than in bulls . In all cattle , increased serum concentrations of P01375 - α , P05231 and IFN - γ were observed from 2 . 5 h to 3 h after P06850 , with greater concentrations of IFN - γ and P05231 in heifers than bulls . Heifer total leukocyte counts decreased 1 h after P06850 administration , while bull leukocyte counts and percent neutrophils decreased 2 h after P06850 administration . Heifers had greater rectal temperatures than bulls , yet rectal temperatures did not change following administration of P06850 . There was no effect of P06850 administration on heart rate . However , bulls tended to have increased heart rate 2 h after P06850 administration than before P06850 . Heifer heart rate was greater than bulls throughout the study . These data demonstrate that acute P06850 administration can elicit a pro - inflammatory response , and cattle exhibit a sexually dimorphic pro - inflammatory cytokine and cortisol response to acute P06850 administration .", "[ Treatment of psoriatic arthritis with P01375 alpha - antagonists ] . The proinflammatory cytokine P01375 alpha is in the pathogenesis of PsA as important as in RA . P01375 is increased in the psoriatic skin lesion and in the synovium of the inflamed joint . The P01375 alpha blockage has been tested in double blind trials with etanercept and infliximab . All studies proved a significant and durable response in the reduction of synovitis in a comparable extend in both drugs . DB00005 showed after 12 weeks an ACR20 response in 59 % of the patients versus 15 % in the placebo arm . DB00065 had after 14 weeks a 69 % ACR20 response versus 8 % placebo response . The psoriatic skin lesion improved with both drugs . The PASI was reduced by 47 % with etanercept and by 81 % with infliximab . The safety - profile was similar to the RA - trials . For etanercept the one year data have shown a reduction in x - ray progression . DB00005 has been approved in the USA and in Europe .", "New cytokine therapeutics for inflammatory bowel disease . Conventional therapy for inflammatory bowel diseases rely on corticosteroids and 5 - aminosalicylates combined with immunosuppressive agents for maintenance . These drugs are not always effective and may inflict serious side effects . Other therapies are therefore awaited . DB00065 , a monoclonal antibody against the pro - inflammatory cytokine P01375 has been successfully applied as a treatment for Crohn ' s disease . The mechanism of action of this drug extends beyond the level of P01375 scavenging and includes induction of apoptosis of effector cells . Numerous anti - P01375 antibodies have been developed and are currently evaluated in clinical trials . Other targets for monoclonal antibodies include integrins and cytokines involved in T - cell differentiation and activation . Likewise recombinant proteins that moderate P01375 bioactivity and lymphocyte function have been developed . The therapeutic effect of recombinant interleukin - 10 seems to be dependent on local delivery of the protein . Antisense therapy targeting lymphocyte migration has also been tested in Q9UKU7 . Finally , the conventional drug thalidomide and possibly Q96HU1 - kinase inhibitors may become novel treatment entities for Q9UKU7 .", "[ DB00065 in the treatment of rheumatoid arthritis ] . DB00065 is a chimeric monoclonal antibody capable of neutralizing human P01375 alpha . A number of clinical trials for the treatment of rheumatoid arthritis ( RA ) with infliximab indicated that P01375 alpha blockade was effective and well tolerated with the excellent results occurring at 3 and 10 mg / kg in combination with methotrexate . Treatment of RA patients with the combination of infliximab and methotrexate also prevented radiographic evidence of progression of joint damage . If the clinical efficacy is sustained and the safety is confirmed over the long term , infliximab may become an essential agent of choice for the treatment of RA .", "[ DB00065 therapy for three adolescent patients with refractory Takayasu ' s arteritis ] . Takayasu ' s arteritis ( TA ) is a chronic idiopathic inflammatory disease affecting primarily aorta and its proximal branches . Pediatric patients with TA tend to have more severe clinical course and be refractory to conventional treatments compared with adults . Corticosteroids are major treatment of TA , however , high dose is required to get remission . Particularly , adolescent patients are usually suffering from side - effects of excessive dose of corticosteroids . Immunosuppressants are added expecting the corticosteroid sparing agents . However , some patients , such as HLA - B52 positive , tend to be registant to these conventional treatments . Recently , several reports showed the efficacy of DB00065 , anti - tumor necrosis factor ( P01375 ) alpha monoclonal antibody , for adult patients with refractory TA . We described three cases of adolescents with TA treated with DB00065 . It was initially effective in all three patients . However , serious infusion reaction occurred in one of them during 11 ( th ) times of DB00065 infusion and she discontinued the therapy . Other two patients showed good response in initial phase , but clinical manifestations and laboratory findings became worse after several months . In these patients with secondary failure to DB00065 , increased dosage and shortening the interval of infusions provided effectiveness again . DB00065 would be a good choice for adolescent patients with TA refractory to conventional treatments . However , we should carefully monitor safety and efficacy of this agent considering its peculiarity .", "New therapeutic approaches to the management of rheumatoid arthritis . Rheumatoid arthritis ( RA ) is a common disease that affects up to 1 % of the population , and causes significant morbidity and early mortality . The aetiology of RA is unknown ; however , in the last 10 to 15 years significant advances in molecular technology have provided a greater understanding of the pathogenesis of the disease . This has led to the development of new approaches to the treatment of RA . The disease modifying antirheumatic oral agent leflunomide inhibits the proliferation of activated T cells that are important in the inflammation and degradation of synovial tissues . The 2 biological agents approved for the treatment of RA , infliximab and etanercept , are inhibitors of the pro - inflammatory cytokine , tumour necrosis factor - alpha ( TNFalpha ) . DB00065 is a chimeric human / mouse monoclonal antibody which is administered by intravenous infusion and binds with high affinity to TNFalpha , thereby neutralising its effects . DB00005 is a recombinant , soluble P01375 receptor molecule which is administered subcutaneously and binds to TNFalpha in the serum rendering it biologically inactive . The protein A immunoadsorption column is a medical device that in conjunction with plasmapheresis can be used in patients with refractory RA . These agents have provided new and effective therapies for the treatment of patients with RA .", "DB00065 therapy efficacy and persistence at a Canadian academic centre despite a change in access procedure . Patients treated with infliximab at our centre through a special access programme ( initiation group ) had long - standing , treatment - resistant rheumatoid arthritis . The clinical experience for these patients may be different than that of patients initiating treatment after provincial government approval and cost coverage for all anti - tumour necrosis factor ( anti - P01375 ) therapies became effective ( contemporary group ) . We compared adverse events , drug survival and reasons for discontinuation in these two groups . A prospective cohort of patients treated with an anti - P01375 therapy was assembled following the availability of infliximab in 2000 . By protocol , patients are assessed for treatment response , discontinuation or switching of biologic agents and occurrence of adverse events . We report on 231 patients treated with infliximab therapy ( 680 patient - years ) . Both groups had similar drug survival ( median 2 . 2 years ) and rates of serious adverse events including infusion reactions ( 6 . 8 per 100 patient - years ) and serious infections ( 3 . 4 per 100 patient - years ) . More patients in the initiation group discontinued infliximab for adverse events [ 39 / 139 ( 28 % ) vs . 15 / 92 ( 16 % ) , p = 0 . 04 ] and developed drug - induced lupus [ 8 / 139 ( 6 % ) vs . 0 % , p = 0 . 02 ] . Subsequent biologics were discontinued for the same reason as infliximab in only 12 % ( 15 / 123 ) of cases . Patients treated with infliximab through a special access programme have comparable drug survival compared to a contemporary group , despite experiencing more adverse events . Only a minority of patients discontinuing infliximab due to the lack of effect or adverse events experience the same fate with subsequent anti - P01375 agents .", "Concomitant loss of p120 - catenin and β - catenin membrane expression and oral carcinoma progression with P12830 reduction . The binding of p120 - catenin and β - catenin to the cytoplasmic domain of P12830 establishes epithelial cell - cell adhesion . Reduction and loss of catenin expression degrades P12830 - mediated carcinoma cell - cell adhesion and causes carcinomas to progress into aggressive states . Since both catenins are differentially regulated and play distinct roles when they dissociate from P12830 , evaluation of their expression , subcellular localization and the correlation with P12830 expression are important subjects . However , the same analyses are not readily performed on squamous cell carcinomas in which P12830 expression determines the disease progression . In the present study , we examined expression and subcellular localization of p120 - catenin and β - catenin in oral carcinomas ( n = 67 ) and its implications in the carcinoma progression and P12830 expression using immunohitochemistry . At the invasive front , catenin - membrane - positive carcinoma cells were decreased in the dedifferentiated ( p120 - catenin , P < 0 . 05 ; β - catenin , P < 0 . 05 ) and invasive carcinomas ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 05 ) and with the P12830 staining ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 01 ) . Carcinoma cells with β - catenin cytoplasmic and / or nuclear staining were increased at the invasive front compared to the center of tumors ( P < 0 . 01 ) . Although the p120 - catenin isoform shift from three to one associates with carcinoma progression , it was not observed after TGF - β , P01133 or P01375 - α treatments . The total amount of p120 - catenin expression was decreased upon co - treatment of TGF - β with P01133 or P01375 - α . The above data indicate that catenin membrane staining is a primary determinant for P12830 - mediated cell - cell adhesion and progression of oral carcinomas . Furthermore , it suggests that loss of p120 - catenin expression and cytoplasmic localization of β - catenin fine - tune the carcinoma progression .", "Phenotype and functional changes of Vgamma9 / Vdelta2 T lymphocytes in Behçet ' s disease and the effect of infliximab on Vgamma9 / Vdelta2 T cell expansion , activation and cytotoxicity . INTRODUCTION : DB00065 is a chimeric monoclonal antibody against tumor necrosis factor alpha ( P01375 ) that has been introduced recently for Behçet ' s disease ( BD ) patients who were resistant to standard treatment . The aim of this study was to analyse the functional changes of Vgamma9 / Vdelta2 T lymphocytes in both active and inactive disease and the effect of infliximab on Vgamma9 / Vdelta2 T cell expansion , activation and cytotoxicity . METHODS : We investigated 1 ) cell expansion , 2 ) expression of TNFRII receptor , 3 ) perforin and gamma interferon ( IFN ) content , 4 ) release of granzyme A ( GrA ) and 5 ) phenotype changes , in vitro and in vivo , in Vgamma9 / Vdelta2 T lymphocytes by means of fluorescence - activated cell sorter analysis of lymphocyte cultures from patients with active and inactive BD and healthy subjects . RESULTS : Cell expansion , expression of TNFRII , perforin and gamma IFN content and release of granzyme A were significantly higher in active patients . In vitro and ex vivo treatment with infliximab resulted in a significant reduction of all parameters together with changes in the phenotype of Vgamma9 / Vdelta2 T cells . CONCLUSIONS : All together these data indicate that infliximab is capable of interfering with Vgamma9 / Vdelta2 T cell function in BD and although cell culture models can not reliably predict all potential effects of the drug in vivo , our results present the possibility that this drug may find use in a range of immunological disorders , characterized by dysregulated cell - mediated immunity .", "Transcriptional regulation by infliximab therapy in Kawasaki disease patients with immunoglobulin resistance . BACKGROUND : DB00065 ( IFX ) , a known monoclonal antibody against tumor necrosis factor - α ( P01375 - α ) , is used to treat Kawasaki disease ( KD ) patients with intravenous immunoglobulin ( IVIG ) resistance . The transcriptional modulation of inflammation following IFX therapy has not been reported in KD patients . METHODS : We investigated the transcript abundance profiles in whole blood obtained from eight IVIG - resistant KD subjects treated with IFX therapy using microarray platforms and compared them with those in initially IVIG - responsive subjects . A pathway analysis was performed using WikiPathways to search for the biological pathways of the transcript profiles . Four transcripts changed by IFX therapy were subsequently validated using quantitative real - time polymerase chain reaction . RESULTS : The pathway analysis showed the reduced abundance of transcripts in the nucleotide - binding oligomerization domain , matrix metalloproteinase ( MMP ) , and inflammatory cytokine pathways and the increased abundance of transcripts in the T - cell receptor , apoptosis , TGF - β , and interleukin - 2 pathways . Additionally , the levels of four transcripts ( peptidase inhibitor - 3 , P22894 , chemokine receptor - 2 , and pentraxin - 3 ) related to KD vasculitis and IVIG resistance decreased after IFX therapy . CONCLUSION : The administration of IFX was associated with both the signaling pathways of KD inflammation and several transcripts related to IVIG resistance factors . These findings provide strong theoretical support for the use of IFX in KD patients with IVIG resistance .", "Treatment of inflammatory bowel disease : a review of medical therapy . Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory diseases of the gastrointestinal tract . While a cure remains elusive , both can be treated with medications that induce and maintain remission . With the recent advent of therapies that inhibit tumor necrosis factor ( P01375 ) alpha the overlap in medical therapies for UC and CD has become greater . Although DB00244 agents have been a mainstay in the treatment of both CD and UC , the data for their efficacy in patients with CD , particularly as maintenance therapy , are equivocal . Antibiotics may have a limited role in the treatment of colonic CD . Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy ; non - systemic steroids such as oral and rectal budesonide for ileal and right - sided CD and distal UC respectively are also effective in mild - moderate disease . 6 - mercaptopurine ( DB01033 ) and its prodrug azathioprine are steroid - sparing immunomodulators effective in the maintenance of remission of both CD and UC , while methotrexate may be used in both induction and maintenance of CD . DB00065 and adalimumab are anti - P01375 agents approved in the US and Europe for the treatment of Crohn ' s disease , and infliximab is also approved for the treatment of UC .", "Treatment of intestinal Behçet ' s syndrome with chimeric tumour necrosis factor alpha antibody . Few patients with Behçet ' s syndrome have gastrointestinal ulceration . Such patients are difficult to treat and have a higher mortality . Faced with refractory symptoms in two patients with intestinal Behçet ' s , we used the tumour necrosis factor alpha ( P01375 ) monoclonal antibody infliximab to induce remission . Both women ( one aged 27 years , the other 30 years ) presented with orogenital ulceration , pustular rash , abdominal pain , bloody diarrhoea due to colonic ulceration , weight loss , and synovitis . One had thrombophlebitis , digital vasculitis , perianal fistula , and paracolic abscess ; the other had conjunctivitis and an ulcer in the natal cleft . Treatment with prednisolone , methyl prednisolone , and thalidomide in one and prednisolone , colchicine , and cyclosporin in the other was ineffective . After full discussion , infliximab ( 3 mg / kg , dose reduced because of recent sepsis in one , and 5 mg / kg in the other ) was administered . Within 10 days the ulcers healed , with resolution of bloody diarrhoea and all extraintestinal manifestations . A second infusion of infliximab was necessary eight weeks later in one case , followed by sustained ( > 15 months ) remission on low dose thalidomide . Remission was initially sustained for 12 months in the other but thalidomide had to be stopped due to intolerance , and a good response to retreatment lasted only 12 weeks without immunosuppression , before a third infusion . The cause of Behçet ' s syndrome is unknown but peripheral blood P08575 gammadelta T cells in Behçet ' s produce > 50 - fold more P01375 than controls when stimulated with phorbol myristate acetate and anti - CD3 . DB00065 could have a role for inducing remission in Behçet ' s syndrome .", "Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK63___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK63___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .", "How does infliximab work in rheumatoid arthritis ? Since the initial characterization of tumor necrosis factor alpha ( TNFalpha ) , it has become clear that TNFalpha has diverse biologic activity . The realization that TNFalpha plays a role in rheumatoid arthritis ( RA ) has led to the development of anti - P01375 agents for the treatment of RA . DB00065 , a chimeric monoclonal antibody that specifically , and with high affinity , binds to TNFalpha and neutralizes the cytokine , is currently approved for the treatment of RA and Crohn ' s disease , another immune - inflammatory disorder . In addition to establishing the safety and efficacy of infliximab , clinical research has also provided insights into the complex cellular and cytokine - dependent pathways involved in the pathophysiology of RA , including evidence that supports TNFalpha involvement in cytokine regulation , cell recruitment , angiogenesis , and tissue destruction .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "Meta - analysis technique confirms the effectiveness of anti - P01375 in the management of active ulcerative colitis when administered in combination with corticosteroids . BACKGROUND : P01375 has an important role in the pathogenesis of ulcerative colitis ( UC ) . It therefore seems that infliximab , the antibody against P01375 , is beneficial in the treatment of UC . The aim was to determine whether infliximab induces clinical response and remission in patients with UC using the meta - analysis technique . MATERIAL / METHODS : The Pubmed and Embase databases were searched for studies investigating the efficacy of infliximab on UC . Data from 1966 to 2006 were collected . The keywords used to search were \" ulcerative colitis \" with \" infliximab \" , \" anti tumor necrosis factor \" , or \" anti tumor necrosis factors \" . The reference lists from the retrieved articles were also reviewed for additional applicable studies . RESULTS : The summary odds ratio ( OR ) for clinical remission in four studies was 3 . 24 with a 95 % CI of 1 . 6 - 6 . 57 and a significant OR . The summary OR for clinical response in three studies was 3 . 93 with a 95 % CI of 2 . 84 - 5 . 45 and a significant OR . CONCLUSIONS : DB00065 is effective in inducing response and remission in patients with ulcerative colitis when administered in combination with corticosteroids .", "Ten years of infliximab : its role in dermatology . Psoriasis is a common chronic inflammatory disease of the skin . Psoriatic arthritis may develop in about 20 % of psoriasis patients while metabolic syndrome is a frequent comorbidity , and risk of cardiovascular disease is increased in psoriasis patients . Classical systemic treatments have not evolved much during the last decades ; biological therapies on the contrary have added most significant progress in systemic treatment during the last 10 years . In particular tumor necrosis factor ( P01375 ) blockade has changed the treatment outcomes in moderate to severe psoriasis patients . With drugs such as infliximab treatment goals of 75 % improvement of psoriasis lesions together with significant improvement of quality of life can be achieved . Furthermore , skin clearance is possible in many patients with continued maintenance treatment with infliximab . More recent pivotal studies have shown that associated nail psoriasis responds well to infliximab , an outcome that was difficult to reach with classical therapies . There is good evidence that infliximab may be useful in other dermatological conditions such as pyoderma gangrenosum and hidradenitis suppurativa . DB00065 is an intravenous administration over a 2 - hour period . Some patients may develop infusion reactions , and dermatologists need to be well aware of any possible adverse events that may be associated with anti - P01375 treatment . Today , dermatologists have collected a broad experience with infliximab treatment of psoriasis and they have thus advanced their clinical practice accordingly .", "Antitumor necrosis factor treatment for pediatric inflammatory bowel disease . DB00065 , adalimumab , and certolizumab are monoclonal antibodies against tumor necrosis factor - α ( TNFα ) , a proinflammatory cytokine with an increased expression in the inflamed tissues of inflammatory bowel disease ( Q9UKU7 ) patients . Currently , infliximab is the only anti - P01375 drug that has been approved for use in refractory pediatric Crohn ' s disease ( CD ) . Nevertheless , adalimumab and certolizumab have been used off - label to treat refractory pediatric Q9UKU7 . Over the past 10 years , anti - P01375 treatment has been of great benefit to many pediatric Q9UKU7 patients , but their use is not without risks ( infections , autoimmune diseases , malignancies ) . Despite the growing experience with these drugs in children with Q9UKU7 , optimal treatment strategies still need to be determined . The purpose of this review is to summarize the current knowledge on the use of anti - P01375 drugs in pediatric Q9UKU7 and to discuss the yet - unsolved issues .", "Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .", "DB00065 inhibits activation and effector functions of peripheral blood T cells in vitro from patients with clinically active ulcerative colitis . Many patients with inflammatory bowel disease ( Q9UKU7 ) are undergoing therapy with infliximab , an antibody specific for P01375 . However , the exact mechanisms of action of infliximab are not completely understood . The aim of this study was to determine the in vitro effects of infliximab on blood T cells derived from anti - P01375 therapy - naïve ulcerative colitis ( UC ) patients with clinically active disease . Peripheral blood mononuclear cells were stimulated polyclonally or by antigen in the presence or absence of infliximab . The T cell phenotype was investigated by flow cytometry , cytokine secretion was determined by ELISA , and cell proliferation was determined by thymidine assay or CFSE dye . Presence of infliximab resulted in reduced expression of CD25 in P01730 (+) and CD8 (+) T cell populations and inhibited secretion of IFN - γ , P35225 , Q16552 , P01375 as well as granzyme A . DB00065 also suppressed P01730 (+) and CD8 (+) T cell proliferation . These effects of infliximab were recorded both in T cells activated by polyclonal and antigen - specific stimulation . The effects of infliximab on T cell apoptosis and induction of Q9BZS1 (+) P01730 (+) T regulatory cells were ambiguous and depended on the originating cellular source and / or the stimulation mode and strength . In conclusion , infliximab is able to reduce T cell activation as measured by CD25 , proliferation and cytokine secretion in vitro from UC patients with clinically active disease . These data suggest that suppression of T cell activity may be important for infliximab - mediated disease remission in patients with UC .", "Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .", "DB00065 induction therapy for patients with severe plaque - type psoriasis : a randomized , double - blind , placebo - controlled trial . BACKGROUND : P01375 - alpha is a key mediator in the pathogenesis of psoriasis . DB00065 is a monoclonal antibody that specifically binds to tumor necrosis factor - alpha , blocking its biologic activity . OBJECTIVE : The purpose of this study was to access the efficacy and safety of infliximab induction therapy for patients with severe plaque psoriasis . METHODS : In this multicenter , double - blind , placebo - controlled trial , 249 patients with severe plaque psoriasis were randomly assigned to receive intravenous infusions of either 3 or 5 mg / kg of infliximab or placebo given at weeks 0 , 2 , and 6 . The primary end point was the proportion of patients who achieved at least 75 % improvement in Psoriasis Area and Severity Index score from baseline at week 10 . At week 26 , patients whose Physician Global Assessment indicated moderate or severe disease were eligible for a single intravenous infusion of their assigned treatment to assess the safety of retreatment after a 20 - week , treatment - free interval . RESULTS : At week 10 , 72 % of patients treated with infliximab ( 3 mg / kg ) and 88 % of patients treated with infliximab ( 5 mg / kg ) achieved a 75 % or greater improvement from baseline in Psoriasis Area and Severity Index score compared with 6 % of patients treated with placebo ( P < . 001 ) . Improvement was observed in both infliximab groups as early as 2 weeks . Overall , 63 % , 78 % , and 79 % of patients in the placebo , 3 - , and 5 - mg / kg groups , respectively , reported one or more adverse events . CONCLUSIONS : DB00065 treatment resulted in a rapid and significant improvement in the signs and symptoms of psoriasis . DB00065 was generally well tolerated .", "P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK6___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .", "Efficacy of infliximab in a patient with refractory idiopathic retroperitoneal fibrosis . Glucocorticoids are the mainstay of treatment of idiopathic retroperitoneal fibrosis ( Q969Q1 ) . However , relapses are frequent upon tapering of the glucocorticoid dose . A variety of traditional immunosuppressants have been proposed as steroid - sparing agents , but some patients fail to adequately respond to combined glucocorticoid and immunosuppressive therapy . We report a patient with Q969Q1 refractory to combined glucocorticoid and methotrexate therapy treated with the anti - P01375 - α monoclonal antibody infliximab . DB00065 was administered at 5 mg / kg / bodyweight at week 0 , 2 , 6 and 8 - weekly thereafter for 3 consecutive years . Drug efficacy and safety were assessed clinically and by laboratory tests at treatment onset and subsequently before each infusion . In addition , 18FFluorodeoxyglucose ( DB09150 ) positron emission computerised tomography ( PET / CT ) and abdominal CT scans were used to monitor disease activity and response to treatment . DB00065 therapy resulted in a satisfactory clinical and laboratory response paralleled by an improvement in imaging findings . No serious adverse events were noted . DB00065 may be an effective and safe treatment for refractory Q969Q1 . A controlled study is required to confirm our findings .", "Cause for controversy ? DB00065 in the treatment of ulcerative colitis : an update . DB00065 is a monoclonal antibody against tumor necrosis factor ( P01375 ) which has become an established therapy for Crohn ' s disease over the last 10 years . Given the similarities between Crohn ' s disease and ulcerative colitis ( UC ) , it is no surprise that gastroenterologists have used infliximab in patients with UC who have failed other therapies . Although the initial controlled trials with infliximab in steroid - refractory disease were unimpressive , subsequent controlled trials have demonstrated the efficacy of infliximab in both moderate to severe disease , and as rescue - therapy to avoid colectomy . The long - term remission rates , colectomy - sparing effects , and the impact of concomitant immunomodulator therapy , remain to be determined in these patients . Whether infliximab is a superior strategy to cyclosporine in patients with steroid - refractory disease is controversial . This review examines the data on the efficacy and safety of infliximab as an induction and maintenance agent for UC .", "DB00065 for the treatment of posterior uveitis with retinal neovascularization in Behçet disease . PURPOSE : To report a case of posterior uveitis with retinal neovascularization in a patient with Behçet disease treated with infliximab . METHODS : A 50 - year - old man with a history of recurrent relapses of ocular inflammation despite immunosuppressive therapy developed retinal neovascularization near the optic disk . The patient was treated with infliximab and followed up for 12 months . RESULTS : Retinal neovascularization regressed 8 months after the first anti - tumor necrosis factor ( P01375 ) treatment and with six infusions of infliximab . The ocular inflammation resolved almost completely . CONCLUSIONS : The result suggests that anti - P01375 therapy may be effective in the treatment of retinal neovascularization caused by panuveitis in Behçet disease .", "Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .", "[ DB00065 ] . DB00065 is a chimeric monoclonal antibody , which specifically binds to tumor necrosis factor ( P01375 ) and blocks its activity . Based on previous evidence that P01375 has been involved in the pathogenesis of psoriasis , multiple controlled trials have shown that infliximab has provided a high degree of clinical benefit in the treatment of psoriasis and psoriatic arthritis allowing a major and rapid improvement in these patients . We review several clinical trials , which have firmly established both efficacy and safety of DB00065 in the treatment of moderate to severe psoriasis and psoriatic arthritis .", "Neurochemical correlates of sympathetic activation during severe alcohol withdrawal . Cerebrospinal fluid ( P04141 ) was obtained from 17 patients during acute alcohol withdrawal . Eight of these 17 patients had a second lumbar puncture a mean of 11 . 9 +/- 8 . 1 ( SD ) days later , when the clinical signs of alcohol withdrawal had subsided . P04141 3 - methoxy - 4 - hydroxyphenylglycol concentrations declined significantly ( p < 0 . 05 ) during the course of alcohol withdrawal from 52 . 0 +/- 22 . 1 ( SD ) to 39 . 6 +/- 12 . 6 pM / ml . In early withdrawal , there was a significant positive correlation between P04141 norepinephrine ( NE ) and corticotropin releasing hormone ( P06850 ) concentrations ( r = 0 . 95 , p < 0 . 001 ) . Both NE and P06850 concentrations correlated positively with diastolic blood pressure ( r = 0 . 88 , p < 0 . 001 and r = 0 . 62 , p < 0 . 05 , respectively ) . In all samples , P04141 5 - hydroxyindole acetic acid concentrations correlated positively with P04141 - homovanillic acid concentrations ( r = 0 . 83 , p < 0 . 001 ) . These findings indicate significant perturbations of the noradrenergic neuronal system and a change in P06850 - NE interactions during acute alcohol withdrawal .", "Effects of biologics on vascular function and atherosclerosis associated with rheumatoid arthritis . Endothelial dysfunction and accelerated atherosclerosis lead to increased cardiovascular morbidity and mortality in rheumatoid arthritis ( RA ) . Sustained inflammation is a major risk factor . Apart from traditional vasculoprotective agents , biologics may also exert favorable effects on the vasculature . Indeed , tumor necrosis factor - alpha ( P01375 ) inhibitors agents may transiently improve endothelial function . There are conflicting data regarding the effects of biologics on atherosclerosis and arterial stiffness . DB00065 stimulates the number and differentiation of endothelial progenitor cells that lead to vascular repair . There may be differences in the effects of P01375 blockers on dyslipidemia , as long - term infliximab therapy may be proatherogenic , while some studies suggest that etanercept and adalimumab may exert beneficial effects on lipids . P01375 blockers may decrease the incidence of cardiovascular events in RA . Preliminary data suggest that rituximab may also improve endothelial function and dyslipidemia . Further studies are needed to determine the net effects of biologics on the vasculature .", "[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK34___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK34___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .", "Protective effects of indomethacin and cyclophosphamide but not of infliximab on liver metabolic changes caused by adjuvant - induced arthritis . In the study , indomethacin , cyclophosphamide , and infliximab were administered to adjuvant - induced arthritic rats to determine if they were able to prevent the abnormalities caused by arthritis on hepatic metabolism . The drugs were administered to arthritic rats , and at the clinical onset of arthritis ( day 14 after adjuvant injection ) , the livers were perfused to evaluate gluconeogenesis , ureagenesis , oxygen uptake , L : - lactate , pyruvate , and ammonia release from L : - alanine . The effects of the drugs on body weight gain and the signs of arthritis ( paw edema , appearance of secondary lesions , and weights of lymphoid tissues ) were also evaluated . Cyclophosphamide could completely prevent liver metabolic changes and the inflammatory response . Indomethacin restored ureagenesis , minimized the decrease in gluconeogenesis , and exerted a partially beneficial effect on inflammatory reactions . DB00065 did not improve arthritis - induced liver metabolic alterations or inflammatory responses . These results suggest the participation of prostaglandins , but not P01375 - α , on arthritis - induced liver metabolic alterations .", "[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK25___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "DB00065 : mechanism of action beyond P01375 neutralization in inflammatory bowel disease . DB00065 , a chimeric antibody to tumour necrosis factor - alpha ( P01375 ) , holds much promise for the treatment of patients with Crohn ' s disease . On the cellular level , infliximab affects survival and , as presented by Agnholt et al . in this issue of the journal , inhibits GM - P04141 ( granulocyte - macrophage colony - stimulating factor ) production by intestinal T lymphocytes . Future studies will reveal whether the pro - apoptotic effect of infliximab is linked to its inhibition of endogenous GM - P04141 expression in T cells . Treatment of Crohn ' s disease , a severe chronic intestinal disorder , may at times be challenging as it can be refractory to routine therapy . Among novel therapeutic strategies , agents that neutralize tumour necrosis factor - alpha ( P01375 ) are of particular interest because of the crucial role of P01375 in sustaining chronic mucosal inflammation . The exact mechanism of the anti - P01375 action , apart from direct activity that neutralizes cytokines , is not fully understood . Cellular effects of P01375 neutralizing treatment include an increased susceptibility to apoptosis of intestinal mucosal T cells . A novel pathway of anti - P01375 interaction with T cells has been presented in the current issue of this journal . Agnholt et al . have found that in - vivo or in - vitro administration of infliximab , a chimeric antibody to P01375 , resulted in a decreased production of GM - P04141 ( granulocyte - macrophage colony - stimulating factor ) by T cells . DB00065 related down - regulation of P01375 induced GM - P04141 expression may be one of the mechanisms by which this drug increases the rate of apoptosis in T cells .", "Differential effects of P01375 ( P01375 ) and IFN - γ on intestinal epithelial cell morphogenesis and barrier function in three - dimensional culture . BACKGROUND : The cytokines P01375 ( P01375 ) and IFNγ are important mediators of inflammatory bowel diseases and contribute to enhanced intestinal epithelial permeability by stimulating apoptosis and / or disrupting tight junctions . Apoptosis and tight junctions are also important for epithelial tissue morphogenesis , but the effect of P01375 and IFNγ on the process of intestinal epithelial morphogenesis is unknown . METHODS / PRINCIPAL FINDINGS : We have employed a three - dimensional cell culture system , reproducing in vivo - like multicellular organization of intestinal epithelial cells , to study the effect of P01375 on intestinal epithelial morphogenesis and permeability . We show that human intestinal epithelial cells in three - dimensional culture assembled into luminal spheres consisting of a single layer of cells with structural , internal , and planar cell polarity . Exposure of preformed luminal spheres to P01375 or IFNγ enhanced paracellular permeability , but via distinctive mechanisms . Thus , while both P01375 and IFNγ , albeit in a distinguishable manner , induced the displacement of selected tight junction proteins , only P01375 increased paracellular permeability via caspase - driven apoptosis and cell shedding . DB00065 and adalumimab inhibited these effects of P01375 . Moreover , we demonstrate that P01375 via its stimulatory effect on apoptosis fundamentally alters the process of intestinal epithelial morphogenesis , which contributes to the de novo generation of intestinal epithelial monolayers with increased permeability . Also IFNγ contributes to the de novo formation of monolayers with increased permeability , but in a manner that does not involve apoptosis . CONCLUSIONS : Our study provides an optimized 3D model system for the integrated analysis of ( real - time ) intestinal epithelial paracellular permeability and morphogenesis , and reveals apoptosis as a pivotal mechanism underlying the enhanced permeability and altered morphogenesis in response to P01375 , but not IFNγ .", "Does weight - adjusted anti - tumour necrosis factor treatment favour obese patients with Crohn ' s disease ? BACKGROUND : DB00051 ( P00813 ) is a subcutaneous anti - tumour necrosis factor ( anti - P01375 ) agent , effective in inducing and maintaining remission in Crohn ' s disease ( CD ) . Unlike DB00065 ( IFX ) , P00813 dosing is not weight adjusted and dose frequency is based on clinical response . AIM : To determine whether obesity is a risk factor for early loss of response ( P23490 ) to anti - P01375 treatment and whether weight - adjusted anti - P01375 treatment is favourable . MATERIALS AND METHODS : A hospital database of CD patients receiving anti - P01375 treatment was analyzed retrospectively . The relationship between time to P23490 and BMI was examined by Kaplan - Meier ( KM ) survival curves and a Cox proportional hazards model . RESULTS : P00813 patients : Of the 54 patients ( 46 BMI < 30 and 8 BMI ≥ 30 ) , KM estimation indicated a significantly shorter time to dose escalation in the BMI of at least 30 ( χ = 6 . 117 , P = 0 . 01 ) . The Cox proportional hazards model showed that an increased hazard of P23490 to P00813 is related to increases in BMI ( P = 0 . 04 ) . IFX patients : Of the 76 patients ( 62 BMI < 30 and 14 BMI ≥ 30 ) , KM estimation showed that the differences in survival curves were not significant ( χ = 1 . 933 , P = 0 . 16 ) for the BMI groups . This was supported by the Cox proportional hazard model ( P = 0 . 36 ) . CONCLUSION : BMI appears to be important in predicting P00813 efficacy ( P23490 ) in CD . IFX appears to overcome this reduction of efficacy in obese patients . A prospective study evaluating the effect of weight on anti - P01375 drug response and serum drug levels is warranted .", "___MASK65___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .", "Genetic polymorphisms of tumour necrosis factor receptor superfamily 1A and 1B affect responses to infliximab in Japanese patients with Crohn ' s disease . BACKGROUND : Tumour necrosis factor alpha is the key inflammatory cytokine involved in the pathogenesis of Crohn ' s disease . DB00065 , a chimaeric monoclonal antibody of tumour necrosis factor - alpha is successfully used for the treatment of Crohn ' s disease , although the response to infliximab therapy differs among patients . The genetic background of the individual may partially explain the differences of the responsiveness . AIM : To investigate whether the polymorphisms in these genes are associated with the response to infliximab treatment as tumour necrosis factor - alpha exerts its biological activity through P01375 receptor superfamily 1A and 1B . METHODS : Eighty Crohn ' s disease patients were enrolled in the study and classified into responder and nonresponder according to the efficacy of infliximab treatment . Single nucleotide polymorphisms of P01375 receptor superfamily 1A ( rs767455 and rs4149570 ) and P01375 receptor superfamily 1B ( rs1061622 , rs1061624 and rs3397 ) were determined . RESULTS : The minor allele carrier of rs767455 showed a significant association with a lack of efficacy compared to the major genotype ( OR = 0 . 26 ; 95 % CI : 0 . 08 - 0 . 91 ) . A P01375 receptor superfamily 1B haplotype inferred by rs1061624 and rs3397 also showed significant differences in the distribution between responder and nonresponder ( P = 0 . 01 ) . CONCLUSION : These results suggest that tumour necrosis factor receptor genotypes may be involved in the different responses to infliximab in Japanese patients with Crohn ' s disease .", "___MASK67___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .", "DB00065 ' s influence on anastomotic strength and degree of inflammation in intestinal surgery in a rabbit model . BACKGROUND : DB00065 , a P01375 - α inhibitor , is a potent anti - inflammatory drug in the treatment of inflammatory bowel diseases . Recent studies have investigated the effect of infliximab treatment on postoperative complications such as anastomotic leakage , however , with conflicting results and conclusions . The purpose of this study was to investigate whether a single dose infliximab has an adverse effect on the anastomotic healing process , observed as reduced anastomotic breaking strength and histopathologically verified lower grade of inflammatory response , in the small intestine of a rabbit . METHODS : Thirty New Zealand rabbits ( median weight 2 . 5 kg ) were allocated to treatment with an intravenous bolus of either 10 mg / kg infliximab ( n = 15 ) or placebo ( n = 15 ) . One week later all rabbits underwent two separate end - to - end anastomoses in the jejunum under general anesthesia . At postoperative day three , the anastomotic breaking strength was determined and histopathological changes were examined . RESULTS : The mean value of anastomotic breaking strength in the placebo group was 1 . 89 ± 0 . 36 N and the corresponding value was 1 . 81 ± 0 . 33 N in the infliximab treated rabbits . There was no statistically significant difference between the groups ( p = 0 . 51 ) . The infliximab - treated rabbits had a significant lower degree of inflammatory infiltration response compared to the placebo group ( p = 0 . 047 ) . CONCLUSIONS : Our conclusion , limited by the small sample sizes in both groups , is that a single dose of infliximab , given one week prior to surgery , does not have an impact on the anastomotic breaking strength on the third postoperative day in the small intestine of rabbits .", "Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK80___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK80___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK80___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK80___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK80___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .", "DB00065 for chronic obstructive pulmonary disease : towards a more specific inflammation targeting ? Chronic obstructive pulmonary disease ( P48444 ) is a predominantly smoking - related condition in which chronic progressive airways obstruction results because of inflammation that is triggered and maintained by the causative agent and enhanced during exacerbations . Inflammation is dominated by neutrophils , and macrophages and their mediators . P01375 is a proinflammatory cytokine involved in P48444 pathogenesis . Treatment of the stable disease is mainly inhalatory with anticholinergics , beta ( 2 ) agonsists and inhaled corticosteroids being involved in various stages of the disease . Novel therapeutic agents are currently under investigation for P48444 treatment and some of them target various inflammation mediators . DB00065 is a monoclonal anti - P01375 antibody with demonstrated efficacy in other autoimmune diseases , such as Crohn ' s disease and rheumatoid arthritis . The current study assesses the scientific rationale for the use of infliximab in P48444 patients .", "P01375 inhibitors in dermatology . To date , the US FDA has approved three tumor necrosis factor ( P01375 ) - a inhibitors for use in dermatology . DB00005 ( Enbrel , Amgen - Wyeth ) , a fully human fusion protein of P01375 receptor II bound to the Fc component of human IgG1 , is approved for use in psoriasis ( 2004 ) and psoriatic arthritis ( 2002 ) . DB00065 ( Remicade , Centocor ) is a chimeric monoclonal antibody that is approved for use in psoriasis ( 2006 ) and psoriatic arthritis ( 2005 ) , and adalimumab ( Humira , Abbott Laboratories ) , a fully human monoclonal antibody , is approved for use in psoriatic arthritis ( 2005 ) . While data regarding the efficacy and safety of these therapies is abundant , it proves nearly impossible to objectively compare and contrast agents as there are no head - to - head trials . Clinical experience and post - marketing reporting has allowed dermatologists to identify the relative strengths and limitations of each agent . The well - founded enthusiasm for these agents , because of their excellent initial efficacy and safety profile , is reasonably tempered by concerns about declining efficacy over time , the risk of infection , lymphoma and demyelinating disorders , and cost . The distinct and targeted mechanism of action of the P01375 inhibitors allows dermatologists to customize therapy to match the individual needs and characteristics of patients who are candidates for systemic or phototherapy .", "Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK85___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .", "The murine chemokine receptor P61073 is tightly regulated during T cell development and activation . We have characterized the murine homolog of the HIV - co - receptor P61073 during T cell development and activation . Our data demonstrate that this chemokine receptor , although highly conserved between human and mouse , is differently expressed and regulated in both species . Mitogenic activation resulted in an increase of surface P61073 on murine T cells within 2 days , whereas the receptor was strongly down - regulated on human T cells during this period . Furthermore , intraperitoneal immunization of mice resulted in a strong increase of splenic and mesenteric cytotoxic T cells co - expressing P61073 . It is interesting that , on thymocytes , expression of P61073 is restricted to P01730 + CD8 + cells . Stromal cell - derived factor - 1alpha , a natural ligand of P61073 , induced chemotaxis of thymocytes and was found to counteract dexamethasone - induced apoptosis to a certain extent in these cells . Thus , our data show that expression of P61073 is tightly controlled on murine T cells and indicate that this highly conserved chemokine receptor might serve different functions in humans and mice .", "Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .", "Inorganic lead enhances cytokine - induced elevation of matrix metalloproteinase P14780 expression in glial cells . Inorganic lead ( Pb ) is a ubiquitous environmental contaminant that produces a variety of deleterious effects in the central nervous system ( CNS ) . Matrix metalloproteinases ( MMPs ) , specifically P14780 , induced by inflammatory cytokines , are increasingly being implicated in CNS pathology . The present study demonstrates that low concentrations of either pro - inflammatory cytokines ( P01375 and IL - 1beta ) or Pb did not influence the P14780 expression in a glial cell line ( P13671 ) when added separately . However , combined administration of Pb and cytokines induced a marked synergized elevation of P14780 expression in spite of a reduction in the number of glial cells . These results demonstrate a possible new mechanism by which Pb may induce neuropathological processes .", "Successful Treatment of Ulcerative Colitis With DB09033 in a Patient With an DB00065 - Associated Psoriasiform Rash . Psoriatic skin lesions associated with anti - tumor necrosis factor ( P01375 ) agents are well - described in the medical literature . However , the etiology and optimal management of this condition remain unclear . DB09033 is a novel , gut - specific , anti - integrin agent used for the treatment of inflammatory bowel disease ( Q9UKU7 ) . We report a case of infliximab - associated psoriasiform lesions in an ulcerative colitis patient . Transition to vedolizumab resulted in resolution of the cutaneous lesions without recurrence and remission of his ulcerative colitis .", "DB00065 counteracts tumor necrosis factor - α - enhanced induction of matrix metalloproteinases that degrade claudin and occludin in non - pigmented ciliary epithelium . DB00065 , a monoclonal antibody directed against human tumor necrosis factor - alpha ( P01375 - α ) , effectively treats anterior uveitis , which can accompany Behçet ' s disease . Here , we investigated the underlying mechanism of this action . We examined human , non - pigmented ciliary epithelial cells ( HNPCECs ) , which make up the blood - aqueous barrier ( BAB ) in the uvea . We measured the expression levels of matrix metalloproteinases ( MMPs ) and tissue inhibitors of MMPs in the presence or absence of P01375 - α using quantitative , real - time polymerase chain reaction and enzyme - linked immunosorbent assays . The expression of P03956 , P08254 , and P14780 increased in the presence of P01375 - α , and the addition of infliximab reversed the increase . The P01375 - α effects were more attenuated when infliximab was added before than when it was added after P01375 - α exposure . Gelatin zymography demonstrated that the protease activity of these MMPs was also increased in the presence of P01375 - α and attenuated with infliximab . Immunostaining showed that P03956 , P08254 , and P14780 degraded claudin - 1 and occludin in HNPCECs and in non - pigmented ciliary epithelial cells of the swine ciliary body . In a monolayer of HNPCECs , we found that permeability was significantly increased with MMP treatment . Thus , P01375 - α increased levels of MMPs in cells that form the BAB , and MMPs degraded components of the tight junctions in the BAB , which increased permeability through the cellular barrier . Furthermore , infliximab effectively attenuated the P01375 - α - induced increases in MMP expression in cells that make up the BAB . These findings might suggest a basis for the clinical prevention of anterior uveitis ." ]

[ "___MASK25___", "___MASK30___", "___MASK34___", "___MASK63___", "___MASK65___", "___MASK67___", "___MASK6___", "___MASK80___", "___MASK85___" ]

[ "Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK21___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .", "DB05773 : a P04626 - positive targeted antibody - drug conjugate . OBJECTIVE : To review the pharmacology , pharmacokinetics , efficacy , adverse effects , drug - drug interactions , dosage and administration , and formulary considerations for ado - trastuzumab emtansine . DATA SOURCES : Sources of information were identified through a PubMed search ( 1966 to June 2014 ) using the key terms ado - trastuzumab emtansine , trastuzumab - DM1 , trastuzumab - MCC - DM1 , and DB05773 . Other information was obtained from clinicaltrials . gov , product labeling , and press releases . STUDY SELECTION AND DATA EXTRACTION : All English - language clinical trials and abstracts evaluating ado - trastuzumab emtansine in humans were reviewed for inclusion . DATA SYNTHESIS : Overexpression or amplification of human epidermal growth factor receptor 2 ( P04626 ) occurs in approximately 20 % of breast cancers and is associated with more aggressive tumors and poorer prognosis in the absence of treatment . Although effective therapies for the initial management of P04626 - positive metastatic breast cancer ( MBC ) exist , many patients will experience disease progression . Most second - line therapies are associated with either significant toxicities or limited improvements in overall survival ( OS ) . DB05773 is a P04626 - positive directed antibody drug conjugate ( ADC ) approved in February 2013 . In phase III clinical trials comparing the efficacy and safety of ado - trastuzumab emtansine with lapatinib - capecitabine or physician ' s choice , ado - trastuzumab emtansine had a better tolerability profile and improved progression - free survival compared with lapatinib - capecitabine or physician ' s choice and increased OS compared with lapatinib - capecitabine . CONCLUSION : DB05773 is a novel ADC effective for P04626 - positive MBC in patients previously treated with trastuzumab , lapatinib , and a taxane . Further studies will determine its use in the adjuvant and neoadjuvant setting and in combination with pertuzumab .", "Regulation of osteoclasts by membrane - derived lipid mediators . Osteoclasts are bone - resorbing cells of monocytic origin . An imbalance between bone formation and resorption can lead to osteoporosis or osteopetrosis . Osteoclastogenesis is triggered by O14788 - and IP3 - induced Ca ( 2 +) influx followed by activation of O95644 , a master transcription factor for osteoclastogenic gene regulation . During differentiation , osteoclasts undergo cytoskeletal remodeling to migrate and attach to the bone surface . Simultaneously , they fuse with each other to form multinucleated cells . These processes require P19957 - kinase - dependent cytoskeletal protein activation to initiate cytoskeletal remodeling , resulting in the formation of circumferential podosomes and fusion - competent protrusions . In multinucleated osteoclasts , circumferential podosomes mature into stabilized actin rings , which enables the formation of a ruffled border where intensive membrane trafficking is executed . Membrane lipids , especially phosphoinositides , are key signaling molecules that regulate osteoclast morphology and act as second messengers and docking sites for multiple important effectors . We examine the critical roles of phosphoinositides in the signaling cascades that regulate osteoclast functions .", "A mechanistic pharmacokinetic model elucidating the disposition of trastuzumab emtansine ( DB05773 ) , an antibody - drug conjugate ( ADC ) for treatment of metastatic breast cancer . DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate ( ADC ) therapeutic for treatment of human epidermal growth factor receptor 2 ( P04626 ) - positive cancers . The DB05773 dose product contains a mixture of drug - to - antibody ratio ( DAR ) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody . The pharmacokinetics ( PK ) underlying this system and other ADCs are complex and have not been elucidated . Accordingly , we have developed two PK modeling approaches from preclinical data to conceptualize and understand DB05773 PK , to quantify rates of DM1 deconjugation , and to elucidate the link between trastuzumab , DB05773 , and DAR measurements . Preclinical data included PK studies in rats ( n = 34 ) and cynomolgus monkeys ( n = 18 ) at doses ranging from 0 . 3 to 30 mg / kg and in vitro plasma stability . DB05773 and total trastuzumab ( TT ) plasma concentrations were measured by enzyme - linked immunosorbent assay . Individual DAR moieties were measured by affinity capture liquid chromatography - mass spectrophotometry . Two PK modeling approaches were developed for DB05773 using NONMEM 7 . 2 software : a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and DB05773 concentrations . DAR moieties were well described with a three - compartmental model and DM1 deconjugation in the central compartment . DM1 deconjugated fastest from the more highly loaded trastuzumab molecules ( i . e . , DAR moieties that are ≥ 3 DM1 per trastuzumab ) . DB05773 clearance ( CL ) was 2 - fold faster than TT CL due to deconjugation . The two modeling approaches provide flexibility based on available analytical measurements for DB05773 and a framework for designing ADC studies and PK - pharmacodynamic modeling of ADC efficacy - and toxicity - related endpoints .", "P04626 - directed therapy for metastatic breast cancer . Human epidermal growth factor receptor 2 ( P04626 ) overexpression drives the biology of 20 % of breast cancers , and predicts a poor prognosis for patients . P04626 - targeted therapies significantly improve outcomes for P04626 - positive patients with both early and metastatic breast cancer . Currently three P04626 - targeted agents , trastuzumab ( Herceptin ) , lapatinib ( DB01259 ) , and pertuzumab ( Perjeta ) , are available for the treatment of P04626 - positive metastatic breast cancer ( MBC ) . Numerous studies have attempted to optimize their use by combining them with each other , or with endocrine and cytotoxic therapies . Most recently , the FDA approved the combination of trastuzumab , pertuzumab , and docetaxel as first - line treatment for MBC , and in late February 2013 approved a fourth P04626 - targeted agent , trastuzumab emtansine ( DB05773 , Kadcyla ) , for accelerated approval . These advances create a number of clinical dilemmas , including identification of the optimal sequence of P04626 - targeted agents and the best drug combinations to use , as well as the recognition of primary and acquired drug resistance . In this article , we review clinical data informing the effective management of P04626 - positive MBC .", "Targeting androgen receptor in estrogen receptor - negative breast cancer . Endocrine therapies for breast cancer that target the estrogen receptor ( ER ) are ineffective in the 25 % - 30 % of cases that are ER negative ( ER - ) . P10275 ( AR ) is expressed in 60 % - 70 % of breast tumors , independent of ER status . How androgens and AR regulate breast cancer growth remains largely unknown . We find that AR is enriched in ER - breast tumors that overexpress P04626 . Through analysis of the AR cistrome and androgen - regulated gene expression in ER -/ P04626 + breast cancers we find that AR mediates ligand - dependent activation of Wnt and P04626 signaling pathways through direct transcriptional induction of P56706 and P21860 . Specific targeting of AR , Wnt or P04626 signaling impairs androgen - stimulated tumor cell growth suggesting potential therapeutic approaches for ER -/ P04626 + breast cancers .", "A multimarker model to predict outcome in tamoxifen - treated breast cancer patients . PURPOSE : This study was designed to produce a model to predict outcome in tamoxifen - treated breast cancer patients based on clinicopathologic features and multiple molecular markers . EXPERIMENTAL DESIGN : This was a retrospective study of 324 stage I to III female breast cancer patients treated with tamoxifen for whom standard clinicopathologic data and tumor tissue microarrays were available . Nine molecular markers were studied by semiquantitative immunohistochemistry and / or fluorescence in situ hybridization . Cox proportional hazards analysis was used to determine the contributions of each variable to disease - specific and overall survival , and machine learning was used to produce a model to predict patient outcome . RESULTS : On a univariate basis , the following features were significantly associated with worse survival : high pathologic tumor or nodal class , histologic grade , epidermal growth factor receptor , P04626 , MYC , or P04637 ; absent estrogen receptor ( ER ) or progesterone receptor ; and low P10415 . P24385 and P46527 did not reach statistical significance . On a multivariate basis , nodal class , ER , and MYC were statistically significant as independent factors for survival . However , the benefit of ER - positive status was moderated by P10415 , P04626 , and progesterone receptor . P10415 and P04637 also interacted as an independent risk factor . A kernel partial least squares polynomial model was developed with an area under the receiver operating characteristic curve of 0 . 90 . CONCLUSIONS : Our data show the predictive value of P10415 , P04626 , MYC , and P04637 in addition to the standard hormone receptors and clinicopathologic features , and they show the importance of conditional interpretation of certain molecular markers . Our multimarker predictive model performed significantly better than standard guidelines .", "Breast cancer brain metastases responding to lapatinib plus capecitabine as second - line primary systemic therapy . Brain metastases ( BM ) are diagnosed in up to 40 % of P04626 - positive breast cancer patients . Standard treatment includes local approaches such as whole - brain radiotherapy ( WBRT ) , radiosurgery , and neurosurgery . The landscape trial established primary systemic therapy as an effective and safe alternative to WBRT in selected patients with Her2 - positive BM . We aim to further focus on the role of systemic therapy in oligosymptomatic patients by presenting this case report . We report on a 50 - year - old patient diagnosed with multiple BM 5 years after early breast cancer diagnosis . As the patient was asymptomatic and had a favorable diagnosis - specific P02724 score , she received primary systemic treatment with DB05773 . She achieved partial remission within the brain for eight treatment cycles and then progressed despite stable extracranial disease . As the patient remained asymptomatic and refused WBRT , we decided upon trastuzumab , lapatinib plus capecitabine as second - line therapy . Another partial remission of BM was observed ; to date , she has received 11 treatment cycles without any sign of disease progression . In this case , WBRT was delayed by at least 14 months , again indicating the activity of systemic treatment in BM . Apparently , in selected patients , BM can be controlled with multiple lines of systemic therapy similar to extracranial disease . Further investigation of systemic treatment approaches is therefore warranted .", "Tyrosine phosphorylation of Q92835 promotes its proteasomal degradation . OBJECTIVE : The activity of the SH2 - containing - phosphatidylinositol - 5 '- phosphatase ( Q92835 , also known as Q92835 ) , a critical hematopoietic - restricted negative regulator of the P19957 kinase ( PI3K ) pathway , is regulated in large part via its protein levels . We sought to determine the mechanism ( s ) involved in its downregulation by P11274 - P00519 and by interleukin ( IL ) - 4 . MATERIALS AND METHODS : We used Ba / P13726 ( Q92817 - tetOFF ) cells to study the downregulation of Q92835 by P11274 - P00519 and bone marrow - derived macrophages to study Q92835 ' s downregulation by P05112 . RESULTS : We show herein that P11274 - P00519 downregulates Q92835 , but not O15357 or P60484 , and this can be blocked with the Src kinase inhibitor Q99463 , which inhibits the tyrosine phosphorylation of Q92835 , or with the proteasomal inhibitor MG - 132 . We also show , using anti - Q92835 immunoprecipitates , that c - Cbl and Cbl - b are associated with Q92835 and that P11274 - P00519 induces Q92835 ' s polyubiquitination . This ubiquitination can be blocked with Q99463 , consistent with the tyrosine phosphorylation of Q92835 acting as a signal for its ubiquitination . In bone marrow - derived macrophages , P05112 also leads to the proteasomal degradation of Q92835 but , unlike in Ba / P13726 ( Q92817 - tetOFF ) cells , O15357 is also proteasomally degraded and the degradation of both inositol phosphatases can be prevented with Q99463 or MG - 132 . CONCLUSION : Our results suggest that Q92835 protein levels can be reduced via P11274 - P00519 and / or Src family member - induced tyrosine phosphorylation of Q92835 because this triggers its polyubiquitination and degradation within the proteasome .", "Next - generation cDNA screening for oncogene and resistance phenotypes . There is a pressing need for methods to define the functional relevance of genetic alterations identified by next - generation sequencing of cancer specimens . We developed new approaches to efficiently construct full - length cDNA libraries from small amounts of total RNA , screen for transforming and resistance phenotypes , and deconvolute by next - generation sequencing . Using this platform , we screened a panel of cDNA libraries from primary specimens and cell lines in cytokine - dependent murine Ba / P13726 cells . We demonstrate that cDNA library - based screening can efficiently identify DNA and RNA alterations that confer either cytokine - independent proliferation or resistance to targeted inhibitors , including RNA alterations and intergenic fusions . Using barcoded next - generation sequencing , we simultaneously deconvoluted cytokine - independent clones recovered after transduction of 21 cDNA libraries . This approach identified multiple gain - of - function alleles , including P01116 G12D , P01111 Q61K and an activating splice variant of P04626 . This approach has broad applicability for identifying transcripts that confer proliferation , resistance and other phenotypes in vitro and potentially in vivo .", "Treating metastatic breast cancer with systemic chemotherapies : current trends and future perspectives . Treatment selection for metastatic breast cancer ( MBC ) is guided by multiple factors , most importantly hormone receptor ( HR ) or P04626 expression , treatment history , and prognostic factors such as short disease - free interval , presence of visceral metastases , performance status , and degree of symptoms . Chemotherapy is indicated as initial therapy for patients with HR - negative disease and following failure of hormonal therapies in HR - positive disease . Patients treated with an anthracycline or a taxane in early - stage settings may no longer be candidates for those drugs in MBC , thus underscoring the need for alternative options . Sequential single - agent therapy or combination therapy are viable strategies . Trials have shown that ixabepilone plus capecitabine significantly improves progression - free survival compared with capecitabine alone in anthracycline - or taxane - pretreated or - resistant patients , and single - agent eribulin improves survival compared with the physician ' s choice of treatment in patients treated previously with at least two regimens for MBC . Regardless of the regimen , proactive management to detect treatment - related adverse events in a timely manner remains important for ensuring effective delivery of treatment . Many promising investigational agents are in development , including DB05773 ( trastuzumab emtansine ) and pertuzumab for P04626 - positive disease , as well as P09874 ( poly [ adenosine diphosphate ribose ] polymerase - 1 ) inhibitors and cetuximab for triple - negative disease . In addition , new options for the treatment of MBC following failure of an anthracycline and a taxane promise to improve patient outcomes . Nurses should remain vigilant for adverse events and remember that the goal of treatment remains control of the disease and palliation .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "Optimal sequencing of anti - P04626 therapy throughout the continuum of P04626 - positive breast cancer : evidence and clinical considerations . With the advent of the monoclonal antibody trastuzumab over 2 decades ago for breast cancer therapy , the outcome of patients with human epidermal growth factor receptor ( HER ) 2 - positive disease has improved dramatically . Based on its substantial efficacy and good tolerability , trastuzumab has become the therapeutic gold standard for early as well as advanced breast cancer . Nevertheless , despite adjuvant trastuzumab , patients do experience recurrence and require further anti - P04626 - targeted therapy . Next to the small molecule tyrosine kinase inhibitor lapatinib , which was the first approved therapy option after trastuzumab failure , several new anti - P04626 agents are currently already available for clinical use [ i . e . pertuzumab , DB05773 ( trastuzumab emtansine ) ] or are still being evaluated ( e . g . afatinib , neratinib ) . Recent evidence from neoadjuvant as well as metastatic therapy suggests that dual blockade may be superior to single - agent P04626 blockade . While the number of available or potential therapies has increased considerably , no additional predictive biomarkers beyond P04626 have been validated for the use of the different anti - P04626 therapies . Moreover , novel therapeutic concepts such as the antibody - drug conjugate DB05773 warrant excellent determination methodology for P04626 and suggest re - evaluation of tumor biology upon first metastasis . The clinical challenge remains to optimally choose , utilize , and sequence anti - P04626 therapy in early as well as metastatic breast cancer . This article will provide evidence - based guidance for sequencing anti - P04626 therapy throughout the continuum of breast cancer therapy .", "Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator - activated receptor / retinoid X receptor heterodimers in the absence and presence of ligand . In a global approach combining fluorescence recovery after photobleaching ( P42345 ) , fluorescence correlation spectroscopy ( FCS ) , and fluorescence resonance energy transfer ( FRET ) , we address the behavior in living cells of the peroxisome proliferator - activated receptors ( PPARs ) , a family of nuclear receptors involved in lipid and glucose metabolism , inflammation control , and wound healing . We first demonstrate that unlike several other nuclear receptors , PPARs do not form speckles upon ligand activation . The subnuclear structures that may be observed under some experimental conditions result from overexpression of the protein and our immunolabeling experiments suggest that these structures are subjected to degradation by the proteasome . Interestingly and in contrast to a general assumption , PPARs readily heterodimerize with retinoid X receptor ( RXR ) in the absence of ligand in living cells . Q07869 diffusion coefficients indicate that all the receptors are engaged in complexes of very high molecular masses and / or interact with relatively immobile nuclear components . PPARs are not immobilized by ligand binding . However , they exhibit a ligand - induced reduction of mobility , probably due to enhanced interactions with cofactors and / or chromatin . Our study draws attention to the limitations and pitfalls of fluorescent chimera imaging and demonstrates the usefulness of the combination of FCS , P42345 , and FRET to assess the behavior of nuclear receptors and their mode of action in living cells .", "A RANTES - antibody fusion protein retains antigen specificity and chemokine function . The successful eradication of cancer cells in the setting of minimal residual disease may require targeting of metastatic tumor deposits that evade the immune system . We combined the targeting flexibility and specificity of mAbs with the immune effector function of the chemokine RANTES to target established tumor deposits . We describe the construction of an Ab fusion molecule with variable domains directed against the tumor - associated Ag P04626 / neu , linked to sequences encoding the chemokine RANTES ( RANTES . her2 . IgG3 ) . RANTES is a potent chemoattractant of T cells , NK cells , monocytes , and dendritic cells , and expression of RANTES has been shown to enhance immune responses against tumors in murine models . RANTES . her2 . IgG3 fusion protein bound specifically to P04626 / neu Ag expressed on EL4 cells and on SKBR3 breast cancer cells as assayed by flow cytometry . RANTES . her2 . IgG3 could elicit actin polymerization of THP - 1 cells and transendothelial migration of primary T lymphocytes . RANTES . her2 . IgG3 prebound to SKBR3 cells also facilitated migration of T cells . RANTES . her2 . IgG3 bound specifically to the P51681 chemokine receptor , as demonstrated by flow cytometry , and inhibited HIV - 1 infection via the P51681 coreceptor . RANTES . her2 . IgG3 , alone or in combination with other chemokine or cytokine fusion Abs , may be a suitable reagent for recruitment and activation of an expanded repertoire of effector cells to tumor deposits .", "[ Antibody - drug conjugates in oncology : from the concept to trastuzumab emtansine ( DB05773 ) ] . DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate ( ADC ) which associates the selective intracellular targeting of the cytotoxic agent , DM1 ( maytansine derivative ) to the antitumor activity of trastuzumab . DB05773 targets the epidermal growth factor receptor 2 ( P04626 ) , highly expressed in the most aggressive forms of breast cancer . Current standard of care in P04626 - positive advanced or metastatic breast cancers has its limitations , particularly after progression on P04626 - targeted approved therapies . DB05773 showed a significant antitumor activity in vitro and in vivo , and in experimental models resistant to P04626 - targeted agents . Phase I and II studies showed that the maximum tolerated dose for DB05773 is 3 . 6 mg / kg given intravenously every three weeks . At this recommended dose , DB05773 provided objective tumor responses and favourable safety profile . A phase II randomised study , evaluating DB05773 in first line vs trastuzumab plus docetaxel , the current standard of care in advanced or metastatic breast cancers , showed improved tolerability and efficacy . Recently , the results of EMILIA , a phase III randomised study assessing , after prior treatment with trastuzumab and a taxane , the efficacy and the safety of DB05773 vs lapatinib plus capecitabine , confirmed the therapeutic benefit . DB05773 appears to be an effective therapeutic option to treat patients with P04626 - positive metastatic breast cancer .", "___MASK77___ for joints and bones . ___MASK77___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK77___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK77___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .", "Population pharmacokinetics of trastuzumab emtansine ( DB05773 ) , a P04626 - targeted antibody - drug conjugate , in patients with P04626 - positive metastatic breast cancer : clinical implications of the effect of covariates . PURPOSE : DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1 , a highly potent cytotoxic agent . A population pharmacokinetic ( PK ) analysis was performed to estimate typical values and interindividual variability of DB05773 PK parameters and the effects of clinically relevant covariates . METHODS : Serum samples were collected from 671 patients with human epidermal growth factor receptor 2 - positive locally advanced or metastatic breast cancer ( MBC ) who received single - agent DB05773 in five phase I to phase III studies . Nonlinear mixed - effects modeling with the first - order conditional estimation method was used . RESULTS : A linear two - compartment model with first - order elimination from the central compartment described DB05773 PKs in the clinical dose range . DB05773 elimination clearance was 0 . 676 L / day , volume of distribution in the central compartment ( V c ) was 3 . 127 L , and terminal elimination half - life was 3 . 94 days . Age , race , region , and renal function did not influence DB05773 PK . Given the low - to - moderate effect of all statistically significant covariates on DB05773 exposure , none of these covariates is expected to result in a clinically meaningful change in DB05773 exposure . CONCLUSIONS : DB05773 PK properties are consistent and predictable in patients . A further refinement of dose based on baseline covariates other than body weight for the current 3 . 6 mg / kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC .", "Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK40___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .", "Emerging therapeutic targets in bladder cancer . Treatment of muscle invasive urothelial bladder carcinoma ( BCa ) remains a major challenge . Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets . This manuscript discusses relevant molecular drivers of the malignant phenotype and agents with therapeutic potential in BCa . Small molecule pan - FGFR inhibitors have shown encouraging efficacy and safety results especially among patients with activating FGFR mutations or translocations . P42345 inhibitors for patients with Q92574 mutations and concomitant targeting of PI3K and MEK represent strategies to block PI3K / AKT / P42345 pathway . Encouraging preclinical results with ado - trastuzumab emtansine ( DB05773 ) exemplifies a new potential treatment for P04626 - positive BCa along with innovative bispecific antibodies . Inhibitors of cell cycle regulators ( aurora kinase , polo - like kinase 1 , and cyclin - dependent kinase 4 ) are being investigated in combination with chemotherapy . Early results of clinical studies with anti - P16410 and anti - Q9NZQ7 are propelling immune modulating drugs to the forefront of emerging treatments for BCa . Collectively , these novel therapeutic targets and treatment strategies hold promise to improve the outcome of patients afflicted with this malignancy .", "Exposure - response relationship of DB05773 : insight into dose optimization for patients with P04626 - positive metastatic breast cancer . Exposure - response ( E - R ) analyses for ado - trastuzumab emtansine ( DB05773 , Kadcyla ) were performed using data from a randomized , active control ( lapatinib plus capecitabine ) trial in patients with human epidermal growth factor 2 - positive metastatic breast cancer . Kaplan - Meier survival analyses stratified by DB05773 trough concentration on day 21 of cycle 1 ( Cmin , C1D21 ) were performed for overall survival ( OS ) and progression - free survival ( PFS ) . E - R analyses indicated that after adjusting for baseline risk factors , higher DB05773 exposure is associated with improved efficacy . DB05773 - treated patients with Cmin , C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm . The percentage of patients who received DB05773 dose adjustments was similar across the exposure range and was lower than that of the active control arm . Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low DB05773 exposure for improved efficacy with acceptable tolerability .", "Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK8___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .", "Update on denosumab treatment in postmenopausal women with osteoporosis . ___MASK77___ , a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor - κB ligand ( O14788 ) , blocks binding of O14788 to the Q9Y6Q6 receptor , found on the surface of osteoclasts and osteoclast precursors , resulting in decreased bone resorption . Subcutaneous denosumab administration once every 6 months increases bone mineral density at the lumbar spine , total hip , and / or femoral neck , and reduces markers of bone turnover significantly in postmenopausal women with osteoporosis . Relative to placebo , denosumab treatment reduces the risk of vertebral , nonvertebral , and hip fractures significantly . The benefits of denosumab treatment are generally obvious after the first dose and were continued for up to 8 years of treatment in an extension study . The tolerability profile of denosumab during this extension phase was consistent with that observed during the initial 3 - year FREEDOM trial . Postmarketing safety surveillance has not shown any unexpected findings . Ongoing safety surveillance will more fully define the long - term safety of denosumab . The benefits of denosumab would seem to be greater than its risks . ___MASK77___ is an important choice in the treatment of postmenopausal women with osteoporosis at increased risk of fractures , including older patients who have difficulty with oral bisphosphonate intake and patients who are intolerant of , or unresponsive to , other therapies .", "Characterization of P04626 status by fluorescence in situ hybridization ( Q5TCZ1 ) and immunohistochemistry ( IHC ) . The use of human epidermal growth factor receptor type 2 ( P04626 ) gene amplification and overexpression as a molecular predictive marker has become critically important for proper selection of breast cancer patients for treatment with targeted therapeutic agents such as trastuzumab , lapatinib , pertuzumab , and DB05773 . A high level of sensitivity and specificity of molecular tests for this alteration is desirable . The American Society of Clinical Oncology and College of American Pathology have jointly established consensus guidelines to standardize characterization of this alteration in breast cancers . This chapter provides a brief overview of pre - analytic and analytical processing of breast specimens as well as subsequent molecular evaluation for P04626 status .", "DB00072 emtansine : the first targeted chemotherapy for treatment of breast cancer . DB00072 emtansine ( DB05773 ) is a novel antibody - drug conjugate , comprised of a potent cytotoxic drug connected via a stable linker to the anti - P04626 antibody , trastuzumab , thereby primarily targeting chemotherapy delivery to cells overexpressing the P04626 receptor . A Phase II randomized trial of DB05773 in the front - line metastatic breast cancer setting revealed promising activity and improved safety compared with standard chemotherapy plus trastuzumab . Subsequently , a Phase III trial in patients with trastuzumab - pretreated metastatic breast cancer showed DB05773 to be associated with prolonged progression - free and overall survival compared with lapatinib plus capecitabine . DB05773 represents a major shift in the treatment of patients with breast cancer as it replaces traditional nontargeted chemotherapy with a ' smart ' medication that directs the cytotoxic therapy to cancer cells by using a known biomarker .", "DB09301 glycosaminoglycans as major P16109 ligands on metastatic breast cancer cell lines . The metastatic breast cancer cell line , 4T1 , abundantly expresses the oligosaccharide sialylated Lewis x ( sLe ( x ) ) . SLe ( x ) oligosaccharide on tumor cells can be recognized by E - and P16109 , contributing to tumor metastatic process . We observed that both selectins reacted with this cell line . However , contrary to the P16581 reactivity , which was sLe ( x ) dependent , P16109 reactivity with this cell line was sLe ( x )- independent . The sLe ( x )- Neg variant of the 4T1 cell line with markedly diminished expression of sLe ( x ) and lack of sLe ( a ) , provided a unique opportunity to characterize P16109 ligands and their contribution to metastasis in the absence of overlapping selectin ligands and P16581 binding . We observed that P16109 binding was Ca ( 2 +)- independent and sulfation - dependent . We found that P16109 reacted primarily with cell surface chondroitin sulfate ( CS ) proteoglycans , which were abundantly and stably expressed on the surface of the 4T1 cell line . P16109 binding to the 4T1 cells was inhibited by heparin and CS glycosaminoglycans ( GAGs ) . Moreover , ___MASK15___ administration significantly inhibited experimental lung metastasis . In addition , the data suggest that surface CS GAG chains were involved in P16109 mediated adhesion of the 4T1 cells to murine platelets and human umbilical vein endothelial cells . The data suggest that CS GAGs are also the major P16109 - reactive ligands on the surface of human MDA - MET cells . The results warrant conducting clinical studies on the involvement of cell surface CS chains in breast cancer metastasis and evaluation of various CS types and their biosynthetic pathways as target for development of treatment strategies for antimetastatic therapy of this disease .", "Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK18___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .", "Preclinical safety profile of trastuzumab emtansine ( DB05773 ) : mechanism of action of its cytotoxic component retained with improved tolerability . DB00072 emtansine ( DB05773 ) is the first antibody - drug conjugate ( ADC ) approved for patients with human epidermal growth factor receptor 2 ( P04626 ) - positive metastatic breast cancer . The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non - targeted delivery , where poor tolerability can limit efficacious doses . Here , we present results from preclinical studies characterizing the toxicity profile of DB05773 , including limited assessment of unconjugated DM1 . DB05773 binds primate ErbB2 and human P04626 but not the rodent homolog c - neu . Therefore , antigen - dependent and non - antigen - dependent toxicity was evaluated in monkeys and rats , respectively , in both single - and repeat - dose studies ; toxicity of DM1 was assessed in rats only . DB05773 was well tolerated at doses up to 40 mg / kg ( ~ 4400 μg DM1 / m ( 2 ) ) and 30 mg / kg ( ~ 6000 μg DM1 / m ( 2 ) ) in rats and monkeys , respectively . In contrast , DM1 was only tolerated up to 0 . 2mg / kg ( 1600 μg DM1 / m ( 2 ) ) . This suggests that at least two - fold higher doses of the cytotoxic agent are tolerated in DB05773 , supporting the premise of ADCs to improve the therapeutic index . In addition , DB05773 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 ( i . e . , microtubule disruption ) . Findings included hepatic , bone marrow / hematologic ( primarily platelet ) , lymphoid organ , and neuronal toxicities , and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest . These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in DB05773 - treated patients to date .", "Recent advances in the development of anti - P04626 antibodies and antibody - drug conjugates . Human epidermal growth factor receptor 2 ( P04626 ) - targeted therapies have revolutionized the treatment of P04626 - positive breast cancer , both in the metastatic and early stage settings . While trastuzumab and lapatinib had been the mainstays of treatment in combination with chemotherapy , innate and acquired resistance to these therapies occur . More recently , two additional P04626 - directed therapies have been approved for P04626 - positive breast cancer . DB06366 is a humanized monoclonal antibody that binds to the extracellular portion of the receptor on a domain distinct from the binding site of trastuzumab . The addition of pertuzumab to trastuzumab results in synergistic tumor cell inhibition and has been shown to significantly improve clinical outcomes for patients with P04626 - positive metastatic breast cancer ( MBC ) compared to trastuzumab plus chemotherapy alone . In addition , ado - trastuzumab emtansine ( DB05773 ) , a novel antibody - drug conjugate linking trastuzumab with the cytotoxic maytansinoid , DM1 , is an effective treatment for P04626 - positive breast cancer that has progressed on other P04626 - directed therapies . Both pertuzumab and DB05773 are relatively well tolerated . This review presents the mechanisms of action as well as phase I , II and III clinical data describing the safety and efficacy of pertuzumab and DB05773 for P04626 - positive breast cancer .", "Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine , a P04626 - targeted antibody - drug conjugate , in patients with P04626 - positive metastatic breast cancer . DB00072 emtansine ( DB05773 ) is a P04626 - targeted antibody - drug conjugate in development for treatment of P04626 - positive cancers . DB05773 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer ( MBC ) , with the maximum tolerated dose established at 3 . 6 mg / kg intravenously for every - 3 - week dosing . The authors present results from the population pharmacokinetics analysis for DB05773 . Population pharmacokinetics for DB05773 were characterized using a clinical database of 273 patients from the 3 studies . Pharmacokinetics was best described by a linear 2 - compartment model . Population estimates ( interindividual variability [ IIV ] ) for pharmacokinetic parameters were clearance , 0 . 7 L / d ( 21 . 0 % ) ; central compartment volume ( V ( c ) ) , 3 . 33 L ( 13 . 2 % ) ; peripheral compartment volume ( V ( p ) ) , 0 . 89 L ( 50 . 4 % ) ; and intercompartmental clearance , 0 . 78 L / d . Body weight , albumin , tumor burden , and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in DB05773 pharmacokinetics , with body weight having a greater effect on IIV of clearance and V ( c ) than other covariates . DB05773 exposure was relatively consistent across the weight range following body weight - based dosing . This analysis suggests no further DB05773 dose adjustments are necessary in heavily pretreated patients with MBC .", "Synthesis of novel spiropyrazoline oxindoles and evaluation of cytotoxicity in cancer cell lines . A series of novel spiropyrazoline oxindole derivatives was synthesized by 1 , 3 - dipolar cycloaddition reaction . The compounds were screened for their in vitro cytotoxic activity against MCF - 7 breast cancer cell line ( estrogen receptor positive ( ER + ) and human epidermal growth factor receptor 2 negative ( P04626 - ) ) . Of the nineteen spiropyrazoline oxindoles tested , six compounds have a GI50 below 12 μM The most potent compounds in this series were also evaluated against MDA - MB - 231 breast cancer cell line ( ER - and P04626 - ) . Two spiropyrazoline oxindoles were highly selective between MCF - 7 tumor cells and MDA - MB - 231 tumor cells . More importantly , they were noncytotoxic against P29320 293T non tumor derived cell lines .", "DB05773 ( Kadcyla ) for P04626 - positive metastatic breast cancer .", "Overcoming treatment resistance in P04626 - positive breast cancer : potential strategies . Human epidermal growth factor receptor ( HER ) - 2 overexpression or amplification occurs in about 20 % of all breast cancers and results in a worse prognosis . Nevertheless , anti - P04626 treatments have recently been developed , resulting in dramatic improvements in the clinical outcome of patients with P04626 - positive breast cancer . DB00072 has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease . Other anti - P04626 agents are being investigated . Mechanisms of resistance to trastuzumab treatment include crosstalk with heterologous receptors and amplification of P04626 signalling ; amplification of the phosphoinositide 3 - kinase ( PI3K ) / AKT pathway ; alteration in binding of trastuzumab to P04626 ; and loss of P04626 expression . Proposed mechanisms of resistance to lapatinib involve derepression and / or activation of compensatory survival pathways through increased PI3K / AKT or estrogen receptor ( ER ) signalling . Several strategies to overcome resistance to anti - P04626 treatment are in different phases of development and include treatment with pertuzumab , DB05773 and mammalian target of rapamycin ( P42345 ) inhibitors .", "Peroxisome proliferator - activated receptors ( Q07869 ) agonists affect cell viability , apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors . The nuclear receptors PPARs ( peroxisome proliferator - activated receptors ) are transcription factors activated by specific ligands . PPARs play an important role in carcinogenesis , inflammation , atherosclerosis , lipid metabolism and diabetes . There is evidence that activation of PPARs by specific ligands is able to suppress the growth of different types of human cancer by mechanisms including the growth arrest , apoptosis and induction of differentiation , although the detailed signalling pathways have not been completely elucidated to date . The aim of our study was to determine whether synthetic ligands of PPARalpha and PPARgamma could affect the viability , proliferation , differentiation , apoptosis and expression of some cell cycle related proteins in glial tumor cell lines . The study was performed on human glioblastoma cell lines U - 87 MG , T98G , A172 and U - 118 MG . Cell lines were treated by ligands of PPARalpha ( bezafibrate , gemfibrozil ) and PPARgamma ( ciglitazone ) . MTT , flow cytometry , TUNEL assay and immunoblotting were used for detection of changes in cell viability , proliferation , differentiation and apoptosis . ___MASK8___ , ciglitazone and gemfibrozil inhibited viability of glioblastoma cell lines . The synthetic ligands significantly reduced or induced the expression of cyclins , P46527 , p21Waf1 / Cip1 , MDM - 2 , Bcl - 2 , Bax , PARP , Caspase 3 , androgen receptors , etc . and did not affect the expression of the differentiation marker P14136 . Flow cytometry confirmed arrest of the cell cycle although the detection of apoptosis was controversial . Apart from hypolipidemic and hypoglycaemic effects , Q07869 ligands may also have significant cytostatic effects of potential use in anticancer treatment .", "DB05773 for the treatment of human epidermal growth factor receptor 2 - positive metastatic breast cancer . PURPOSE : An update on completed and ongoing clinical trials of ado - trastuzumab emtansine for the treatment of metastatic breast cancer ( MBC ) is presented . SUMMARY : DB05773 ( Kadcyla , Genentech ) , the first U . S .- approved antibody - drug conjugate for MBC , is indicated for use as a single - agent therapy in patients with human epidermal growth factor receptor 2 ( P04626 ) - positive MBC who have received prior treatment with unconjugated trastuzumab and a taxane - based regimen . The standard dosage of ado - trastuzumab is 3 . 6 mg / kg i . v . every three weeks . In completed Phase II or III clinical trials , ado - trastuzumab was found to confer significant survival and quality - of - life benefits . The largest of those trials ( the EMILIA study , n = 991 ) showed that ado - trastuzumab was superior to a regimen of lapatinib plus capecitabine in terms of progression - free survival ( 9 . 6 months versus 6 . 4 months , p < 0 . 001 ) and overall survival ( 30 . 9 months versus 25 . 1 months , p < 0 . 001 ) ; it also had a more favorable tolerability profile , with lower rates of treatment - limiting adverse effects . The most common adverse effects of ado - trastuzumab are thrombocytopenia ( reported in about 12 % of clinical trial participants overall ) and increased transaminase levels . Two ongoing Phase III trials - the TH3RESA study ( slated for completion in June 2015 ) and the MARIANNE study ( estimated completion in 2016 ) - may help determine the optimal role of ado - trastuzumab relative to other P04626 - targeted agents and its potential use as a front - line therapy for both heavily pretreated and treatment - naive patients with MBC . CONCLUSION : With a novel targeted mechanism of action , ado - trastuzumab is an effective treatment option for P04626 - positive MBC in previously treated patient populations .", "Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK46___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .", "Q14242 and P42345 regulate translation of ROCK - 1 and physiological functions of macrophages . Rho - associated kinases ( ROCKs ) are critical molecules involved in the physiological functions of macrophages , such as chemotaxis and phagocytosis . We demonstrate that macrophage adherence promotes rapid changes in physiological functions that depend on translational upregulation of preformed ROCK - 1 mRNA , but not ROCK - 2 mRNA . Before adherence , both ROCK mRNAs were present in the cytoplasm of macrophages , whereas ROCK proteins were undetectable . Macrophage adherence promoted signaling through P16109 glycoprotein ligand - 1 ( Q14242 ) / Akt / P42345 that resulted in synthesis of ROCK - 1 , but not ROCK - 2 . Following synthesis , ROCK - 1 was catalytically active . In addition , there was a rapamycin / sirolimus - sensitive enhanced loading of ribosomes on preformed ROCK - 1 mRNAs . Inhibition of P42345 by rapamycin abolished ROCK - 1 synthesis in macrophages resulting in an inhibition of chemotaxis and phagocytosis . Macrophages from Q14242 - deficient mice recapitulated pharmacological inhibitor studies . These results indicate that receptor - mediated regulation at the level of translation is a component of a rapid set of mechanisms required to direct the macrophage phenotype upon adherence and suggest a mechanism for the immunosuppressive and anti - inflammatory effects of rapamycin / sirolimus .", "Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine ( DB05773 ) : an emphasis on preclinical and clinical catabolism . DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 ( P04626 ) - positive cancers . Herein , we describe a series of studies to assess DB05773 absorption , distribution , metabolism , and excretion ( ADME ) in rats as well as to assess human exposure to DB05773 catabolites . Following administration of unlabeled and radiolabeled DB05773 in female Sprague Dawley rats as a single dose , plasma , urine , bile and feces were assessed for mass balance , profiling and identification of catabolites . In rats , the major circulating species in plasma was DB05773 , while DM1 concentrations were low ( 1 . 08 to 15 . 6 ng / mL ) . The major catabolites found circulating in rat plasma were DM1 , [ N - maleimidomethyl ] cyclohexane - 1 - carboxylate - DM1 ( MCC - DM1 ) , and DB00123 - MCC - DM1 . These catabolites identified in rats were also detected in plasma samples from patients with P04626 - positive metastatic breast cancer who received single - agent DB05773 ( 3 . 6 mg / kg every 3 weeks ) in a phase 2 clinical study . There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing . In rats , DB05773 was distributed nonspecifically to the organs without accumulation . The major pathway of DM1 - containing catabolite elimination in rats was the fecal / biliary route , with up to 80 % of radioactivity recovered in the feces and 50 % in the bile . The rat DB05773 ADME profile is likely similar to the human profile , although there may be differences since trastuzumab does not bind the rat P04626 - like receptor . Further research is necessary to more fully understand the DB05773 ADME profile in humans .", "DB00072 emtansine in breast cancer . INTRODUCTION : DB00072 emtansine ( DB05773 ) is a human epidermal growth factor receptor 2 ( P04626 ) - targeted antibody - drug conjugate ( ADC ) composed of trastuzumab , a stable linker ( MCC ) , and the cytotoxic agent DM1 ( derivative of maytansine ) . Administration of DB05773 leads to limited systemic exposure of free DM1 , with no evidence of DM1 accumulation after repeated dosing . AREAS COVERED : Phase I and Phase II clinical trials with DB05773 as a single agent and in combination with paclitaxel , docetaxel , and pertuzumab have shown substantial clinical activity and a favorable safety profile . A randomized , open - label , first - line trial comparing trastuzumab and docetaxel with single agent DB05773 showed a significant improved progression - free survival for DB05773 . EXPERT OPINION : DB05773 has successfully completed second - line Phase III development for advanced P04626 - positive breast cancer . The Phase III EMILIA study demonstrated an overall survival benefit for DB05773 compared to the combination of lapatinib and capecitabine in taxane - trastuzumab pretreated patients . DB05773 may offer delivery on a personalized basis of very potent cytotoxic agents in a cellular selective manner .", "Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .", "DB05773 ( Kadcyla ) for P04626 - positive metastatic breast cancer .", "P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK38___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .", "Metastasis and the Tumor Microenvironment : A Joint Metastasis Research Society - AACR Conference - Research on Metastasis : part 2 . The Metastasis and the Tumor Microenvironment Conference , held in Philadelphia , included topics covering new research developments in the field of metastasis and tumor microenvironment . This conference report highlights selected presentations on translation targets from a clinical perspective , antibody inhibitors of TGFβ for metastasis suppression , metastasis in bladder and lung cancer , c - ErbB2 / P04626 expression in ductal carcinomas in situ and breast cancer , targeting Hsp90 chaperones in solid cancers , peritoneal carcinomas , and the discovery and exploitation of Q9Y6Q6 ligands in bone metastasis . Investigational drugs discussed include the humanized antibody against TGFβ fresolimumab ( GC - 1008 ; Genzyme ) , the anti - P17948 antibody icrucumab ( IMC - 18F1 ; ImClone Systems ) and the novel Hsp90 inhibitor DB00238 - AUY - 922 ( AUY - 922 , VER - 52296 ; Novartis ) .", "Updates on the treatment of human epidermal growth factor receptor type 2 - positive breast cancer . PURPOSE OF REVIEW : To review the most recent developments in the treatment of human epidermal growth factor receptor type 2 ( P04626 ) - positive breast cancer with novel P04626 - targeting agents and combinations that have significantly improved clinical outcomes . RECENT FINDINGS : Since the approval of trastuzumab 15 years ago , the natural history of P04626 - positive breast cancer has been altered with improvements in survival for both early and advanced disease with the addition of this agent to standard chemotherapy . The P04626 receptor pathway drives breast cancer growth and aggressiveness , and P04626 - targeted agents can improve survival in early and advanced disease . In the advanced setting , two new drugs have been approved since 2012 , pertuzumab and ado - trastuzumab emtansine ( DB05773 ) , both of which improve survival without any reciprocal increase in toxicity . However , resistance almost always ensues , pointing to the need to understand the driving mechanisms and to biomarkers that will help individualize therapy and point to newer signal transduction and other modulators . SUMMARY : P04626 - positive breast cancer represents a distinct subtype with more aggressive clinical characteristics . P04626 - targeted therapies , usually in combination with chemotherapy , are the standard of care , improving the cure rate in early - stage breast cancer and lengthening survival in the advanced setting .", "Molecular weight and biochemical profile of a chemically modified heparin derivative , Suleparoide . Recently , a new chemically modified derivative of heparin ( Suleparoide , Syntex Laboratories Buenos Aires , Argentina ) was introduced for the prophylaxis of thrombosis and treatment of vascular disorders . This agent is claimed to contain a depolymerized , chemically modified , heparin derivative with similar biologic actions as heparan sulfate . To study the pharmacologic profile of this agent , we have defined its molecular weight distribution profile , utilizing a computerized gel permeation chromatographic system equipped with ultraviolet and refractive index detectors . Suleparoide exhibited a normal molecular distribution profile with no contaminants . It exhibited a weight average of 9 . 3 K DA and an apparent peak MW of 8 . 0 K DA . Approximately 50 % of the molecular components were < 5 . 0 K DA and 40 % > 5 . 0 K DA . The results from these studies on the mechanisms show that Suleparoide has anticoagulant activity primarily mediated through ___MASK15___ Cofactor - II ( P05546 ) and because of its novel mechanism of action , further investigations on the biochemical profile of Suleparoide are carried out . Global clotting tests such as Activated Partial P13726 Time ( APTT ) , Heptest and Thrombin Time ( TT ) revealed a concentration dependent effect in all assays . Plasma samples supplemented with Suleparoide exhibited no significant anti - Xa and anti - IIa activities . However , in the P05546 mediated inhibitory assay for IIa , Suleparoide exhibited significant activity . In contrast , the P01008 ( DB11598 ) mediated inhibition of IIa was much weaker .", "Circulating apoptotic proteins are increased in long - term disease - free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis - related proteins and inflammation markers are increased in long - term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF - receptor ( sTNF - R ) 1 and 2 , sFas , sFas ligand , sTNF - related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High - sensitivity P02741 ( HS - CRP ) , fibrinogen , plasma B - type and N - terminal atrial natriuretic peptide ( NT - P01160 and DB04899 ) were also determined . Thirty - four patients with median 6 . 0 years follow - up and 12 healthy age - matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high - dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high - dose than in the standard - dose group . In conclusion , we observed increased circulating apoptotic protein levels in long - term disease - free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .", "Delta ( 9 )- DB00470 enhances MCF - 7 cell proliferation via cannabinoid receptor - independent signaling . We recently reported that Delta ( 9 )- tetrahydrocannabinol ( Delta ( 9 )- THC ) has the ability to stimulate the proliferation of human breast carcinoma MCF - 7 cells . However , the mechanism of action remains to be clarified . The present study focused on the relationship between receptor expression and the effects of Delta ( 9 )- THC on cell proliferation . RT - PCR analysis demonstrated that there was no detectable expression of CB receptors in MCF - 7 cells . In accordance with this , no effects of cannabinoid 1 / 2 ( P21554 / 2 ) receptor antagonists and pertussis toxin on cell proliferation were observed . Although MCF - 7 cell proliferation is suggested to be suppressed by Delta ( 9 )- THC in the presence of CB receptors , it was revealed that Delta ( 9 )- THC could exert upregulation of living cells in the absence of the receptors . Interestingly , Delta ( 9 )- THC upregulated human epithelial growth factor receptor type 2 ( P04626 ) expression , which is known to be a predictive factor of human breast cancer and is able to stimulate cancer cells as well as MCF - 7 cells . DB00970 - treatment interfered with the upregulation of P04626 and cell proliferation by cannabinoid . Taken together , these studies suggest that , in the absence of CB receptors , Delta ( 9 )- THC can stimulate the proliferation of MCF - 7 cells by modulating , at least in part , P04626 transcription .", "P04626 - family signalling mechanisms , clinical implications and targeting in breast cancer . Approximately 20 % of human breast cancers ( BC ) overexpress P04626 protein , and P04626 - positivity is associated with a worse prognosis . Although P04626 - targeted therapies have significantly improved outcomes for P04626 - positive BC patients , resistance to trastuzumab - based therapy remains a clinical problem . In order to better understand resistance to P04626 - targeted therapies in P04626 - positive BC , it is necessary to examine HER family signalling as a whole . An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in P04626 - positive BC and response to P04626 - targeted therapy . Known mechanisms of trastuzumab resistance include reduced receptor - antibody binding ( Q99102 , p95HER2 ) , increased signalling through alternative HER family receptor tyrosine kinases ( RTK ) , altered intracellular signalling involving loss of P60484 , reduced p27kip1 , or increased PI3K / AKT activity and altered signalling via non - HER family RTKs such as P08069 . Emerging strategies to circumvent resistance to P04626 - targeted therapies in P04626 - positive BC include co - targeting P04626 / PI3K , pan - HER family inhibition , and novel therapies such as DB05773 . There is evidence that immunity plays a key role in the efficacy of HER - targeted therapy , and efforts are being made to exploit the immune system in order to improve the efficacy of current anti - HER therapies . With our rapidly expanding understanding of P04626 signalling mechanisms along with the repertoire of HER family and other targeted therapies , it is likely that the near future holds further dramatic improvements to the prognosis of women with P04626 - positive BC .", "The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer : latest evidence and ongoing studies . The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 ( P04626 ) has been drastically improved by the development of P04626 - targeted therapies including trastuzumab and lapatinib . While outcomes for patients diagnosed with P04626 - positive breast cancer have been greatly impacted by these therapies , treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge . DB00072 emtansine ( DB05773 ) is a novel antibody drug conjugate that consists of the P04626 - targeted monoclonal antibody , trastuzumab , joined via a stable linker to a derivative of maytansine , a highly potent cytotoxic chemotherapy . While other antibody drug conjugates have been developed clinically , this is the first in its class that maintains the antitumor properties of the P04626 - targeted antibody , trastuzumab , and also avoids release of the chemotherapy until the molecule is taken up inside the P04626 - overexpressing cancer cell . Several phase I studies have shown DB05773 is safe , tolerable and has activity in trastuzumab - and lapatinib - pretreated breast cancer . Moreover , phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings . Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the P04626 - positive metastatic breast cancer setting . This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action , efficacy and safety of DB05773 for the treatment of P04626 - positive breast cancer .", "Treatment of P04626 - overexpressing breast cancer . The HER family of receptors consists of four closely related type 1 transmembrane TK receptors : P00533 ( P00533 ) , P04626 , P21860 and Q15303 . Signalling via the HER family of receptors underpins the majority of the intricate array of cellular activities on which cell survival and functionality depend . Aberrant P04626 expression and / or functionality have been implicated in the evolution of breast cancer and this receptor has proved to be a potent target for anticancer therapies , including antibody - based therapies to prevent ligand binding , dimer formation or the recruitment of antibody - dependent cell - mediated cytotoxicity , and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners . Novel strategies against P04626 include HER tyrosine kinase inhibitors , HSP90 inhibitors and antibody - chemotherapy conjugates . This latter approach is exemplified by DB05773 , a potent antibody that has a good safety profile and that has shown remarkable activity in patients with advanced disease . In addition , pertuzumab , an mAb that directly inhibits the formation of P04626 dimers including the P04626 : P21860 dimer , offers a unique mechanism of P21860 inhibition . All these approaches have shown substantial clinical activity in patients refractory to trastuzumab . It is anticipated that with the increased availability of novel anti - P04626 agents together with a better understanding of the mechanisms of resistance to anti - P04626 agents we should be able to further improve the outcome of patients with P04626 breast cancer . There will also be an increasing tendency towards moving the study of these agents to earlier stages of the disease , namely in the adjuvant and neoadjuvant setting .", "DB06366 protects the achilles ' heel of trastuzumab -- emtansine . DB00072 emtansine ( DB05773 ) represents a significant advancement in the treatment of P04626 (+) breast cancers . Its clinical efficacy however will be limited by the development of therapeutic resistance . In this report , the P21860 ligand neuregulin is shown to mediate DB05773 resistance , which was overcome by administration of pertuzumab , a steric inhibitor of P04626 dimerization .", "DB05773 ( DB05773 ) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer . DB00072 ( Herceptin (®) ) is currently used as a treatment for patients whose breast tumors overexpress P04626 / ErbB2 . DB05773 ( DB05773 , trastuzumab emtansine ) is designed to combine the clinical benefits of trastuzumab with a potent microtubule - disrupting drug , DM1 ( a maytansine derivative ) . Currently DB05773 is being tested in multiple clinical trials . The mechanisms of action for trastuzumab include inhibition of PI3K / AKT signaling pathway , inhibition of HER - 2 shedding and Fcγ receptor mediated engagement of immune cells , which may result in antibody - dependent cellular cytotoxicity ( ADCC ) . Here we report that DB05773 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors .", "DB05773 ( DB05773 ) in human epidermal growth factor receptor 2 ( P04626 ) - positive metastatic breast cancer : latest evidence and clinical potential . In February 2013 , ado - trastuzumab emtansine ( DB05773 , Kadcyla ® ) received regulatory approval in the United States for treatment - refractory human epidermal growth factor receptor 2 ( P04626 ) positive metastatic or locally advanced breast cancer based on results from EMILIA , a large phase III trial that compared standard of care lapatinib plus capecitabine to DB05773 . Several other studies have been reported in the metastatic setting and multiple trials are ongoing or planned in the neoadjuvant , adjuvant and advanced disease settings . Here we provide an updated and comprehensive review of clinical trials evaluating DB05773 , discuss management of toxicity associated with this drug , propose potential mechanisms of resistance and offer practical considerations for the treating oncologist .", "AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK63___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .", "New therapies in P04626 - positive breast cancer : a major step towards a cure of the disease ? Overexpression of the human epidermal growth factor receptor 2 ( P04626 ) predicts a poor prognosis in metastatic breast cancer . While the introduction of P04626 - targeted therapies , such as the monoclonal antibody trastuzumab and the small - molecule tyrosine kinase inhibitor lapatinib , has significantly improved outcomes in P04626 + breast cancer compared with previously available therapies , use of these targeted therapies is often limited by the development of drug resistance and tolerability issues . These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways . Recently , several agents have demonstrated promising activity in P04626 + metastatic breast cancer , either as monotherapy or in combination therapy , including the tyrosine - kinase inhibitors neratinib ( HKI - 272 ) and afatinib ( BIBW - 2992 ) and the anti - P04626 monoclonal antibodies pertuzumab and trastuzumab - DM1 ( DB05773 ) . Agents that target other molecular pathways , such as the vascular endothelial growth factor receptor , mammalian target of rapamycin , P19957 - kinases , insulin - like growth factor ( IGFR ) , HSP - 90 , and other kinases also have potential , in combination with anti - P04626 and / or other systemic therapies , to be active in this subtype of breast cancer . Innovative clinical studies are required in well - characterized patient populations to define the true clinical value of these emerging new approaches .", "Safety and efficacy of the combination of DB05773 with radiotherapy of the central nervous system in a patient with P04626 - positive metastatic breast cancer : case study and review of the literature . Approximately 35 % of patients with confirmed P04626 breast cancer progress to metastases of the central nervous system ( CNS ) . Total cerebral radiotherapy is considered as standard treatment for these cases ; however , studies have shown that some chemotherapy drugs can be used during radiotherapy without significantly increasing its toxicity . In this article , we report the case of a patient with P04626 - positive breast cancer who showed isolated progression of the illness in the CNS , which was observed during the treatment period using DB05773 concomitantly with radiotherapy of the CNS without apparent toxicity of the combination and keeping the illness controlled . Through a review of the literature on the use of radiotherapy and chemotherapy with DB05773 for the treatment of cerebral metastases in P04626 - positive breast cancer , we describe the efficacy and tolerance of the concomitant application of these treatments ." ]

[ "___MASK15___", "___MASK18___", "___MASK21___", "___MASK38___", "___MASK40___", "___MASK46___", "___MASK63___", "___MASK77___", "___MASK8___" ]

[ "Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .", "Attenuated P08908 receptor signaling in brains of suicide victims : involvement of adenylyl cyclase , phosphatidylinositol 3 - kinase , Akt and mitogen - activated protein kinase . Positron emission tomography studies in major depression show reduced serotonin ( 5 - HT ) 1A receptor antagonist - binding potentials in many brain regions including occipital cortex . The functional meaning of this observation in terms of signal transduction is unknown . We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of P08908 receptor activation . The diagnosis was established by means of psychological autopsy using Diagnostic and Statistical Manual of Mental Disorders ( DSM ) III - R criteria . Measurements of [ 35S ] GTPgammaS binding to Galphai / o in the occipital cortex of suicide victims and matched controls revealed a blunted response in suicide subjects and a decrease in the coupling of P08908 receptor to adenylyl cyclase . No significant group differences were detected in the expression levels of Galphai / o , Galphaq / 11 or Galphas proteins , or in the activity of DB02527 - dependent protein kinase A . Studies of a parallel transduction pathway downstream from P08908 receptor activation demonstrated a decrease in the activity of phosphatidylinositol 3 - kinase and its downstream effector Akt , as well as an increase in P60484 ( phosphatase and tensin homolog deleted on chromosome 10 ) , the phosphatase that hydrolyzes phosphatidylinositol 3 , 4 , 5 - triphosphate . Finally , the activation of extracellular signal - regulated kinases 1 and 2 was attenuated in suicide victims . These data suggest that the alterations in agonist - stimulated P08908 receptor activation in depressed suicide victims are also manifest downstream from the associated G protein , affecting the activity of second messengers in two P08908 receptor transduction pathways that may have implications for cell survival .", "Effect of progesterone on intracellular Ca2 + homeostasis in human myometrial smooth muscle cells . Although it is well known that progesterone alters uterine contractility and plays an important role in maintenance of pregnancy , the biochemical mechanisms by which progesterone alters uterine contractility in human gestation are less clear . In this investigation we sought to identify progesterone - induced adaptations in human myometrial smooth muscle cells that may alter Ca2 + signaling in response to contractile agents . Cells were treated with vehicle or the progesterone analog medroxyprogesterone acetate ( ___MASK51___ ) for 5 days , and intracellular free Ca2 + concentration ( [ Ca2 +] i ) was quantified after treatment with oxytocin ( OX ) or endothelin ( ET ) - 1 . OX - and ET - 1 - induced increases in [ Ca2 +] i were significantly attenuated in cells pretreated with ___MASK51___ in a dose - dependent manner . P06401 antagonists prevented the attenuated Ca2 + transients induced by ___MASK51___ . P25101 and ETB receptor subtypes were expressed in myometrial cells , and treatment with ___MASK51___ resulted in significant downregulation of P25101 and ETB receptor binding . ___MASK51___ did not alter ionomycin - stimulated increases in [ Ca2 +] i and had no effect on inositol trisphosphate - dependent or - independent release of Ca2 + from internal Ca2 + stores . We conclude that adaptations of Ca2 + homeostasis in myometrial cells during pregnancy may include progesterone - induced modification of receptor - mediated increases in [ Ca2 +] i .", "Melatonin receptor potentiation of cyclic AMP and the cystic fibrosis transmembrane conductance regulator ion channel . We have used the cystic fibrosis transmembrane conductance regulator ( P13569 ) Cl - channel as a model system to study the DB02527 signal transduction pathways coupled to the Xenopus melatonin receptor . During forskolin ( Fsk ) stimulation , melatonin reduced the amplitude of the P13569 currents in oocytes injected with in vitro transcribed cRNAs for the Xenopus melatonin receptor and P13569 . Pertussis toxin ( Ptx ) treatment eliminated melatonin inhibition of Fsk stimulated P13569 currents . In oocytes injected with cRNA for melatonin receptors , serotonin receptors ( P34969 ) , and P13569 Cl - channels , application of melatonin together with serotonin ( 5 - HT ) activated an additional inward current showing potentiation of adenylyl cyclases by melatonin receptors . Subthreshold activation of P34969 receptors was sufficient and necessary to permit activation of P13569 channels by melatonin . Preexposure to melatonin desensitized the melatonin receptor mediated response . Therefore , based on this model system , the effects of melatonin in vivo could be either positive or negative modulation of other neuronal inputs , depending on the mode of adenylyl cyclase stimulation .", "Involvement of P08908 and 5 - HT2 receptor in cisplatin induced emesis in dogs . The effect of drug acting on P08908 , 5 - HT2 and 5 - Q9H205 receptors were studied against cisplatin and apomorphine induced emesis in dogs . Buspirone , P08908 receptor partial agonist significantly reduced the emetic episodes though it had no significant effect on emetic latency . DB06148 , 5 - HT2 receptor antagonist exhibited significant reduction in emetic episodes and in latency . Buspirone prevented the apomorphine induced emesis while mianserin had no effect . The antiemetic activity of buspirone may be attributable to its agonistic activity at P08908 receptor and antagonistic activity at dopamine receptors . These findings further confirm the involvement of P08908 and 5 - HT2 receptor in cytotoxic drug induced emesis , though the species difference in their antiemetic action can not be ruled out .", "Activating mutations of the serotonin P28335 receptor . Site - directed mutagenesis was performed to create a mutant serotonin P28335 receptor that would mimic the active conformation of the native receptor . Structural alteration of receptor conformation was achieved by changing amino acid no . 312 from serine to phenylalanine ( S312F ) or lysine ( S312K ) . After expression in COS - 7 cells , the binding affinity of 5 - HT for [ 3H ] mesulergine - labeled P28335 receptors increased from 203 nM ( native ) to 76 nM for S312F and 6 . 6 nM for S312K mutant receptors . 5 - HT potency for stimulation of phosphatidylinositol ( PI ) hydrolysis increased from 70 nM ( native ) to 28 nM for S312F and 2 . 7 nM for S312K mutant receptors . The mutant receptors were constitutively active , stimulating PI hydrolysis in the absence of agonist . S312F and S312K mutations resulted in twofold and five - fold increases , respectively , in basal levels of PI hydrolysis . DB06148 and mesulergine displayed inverse agonist activity by decreasing basal levels of PI hydrolysis stimulated by S312K mutant receptors . [ 3H ] 5 - HT and [ 3H ] mesulergine labeled the same number of S312K mutant receptors and 5 '- guanylylimidodiphosphate had no effect on [ 3H ] 5 - HT binding . These results indicate that serine --> lysine mutation at amino acid no . 312 produces an agonist high - affinity state of the P28335 receptor that spontaneously couples to G proteins and stimulates PI hydrolysis in the absence of agonist .", "Redistribution of membrane glycoproteins in platelets activated under flow conditions . A reduction in the ability of GPIb to bind specific MoAbs or ligands ( P04275 ) has been reported in platelets exposed to thrombin in suspension . We have analyzed modifications in the presence of glycoproteins ( GPs ) on platelets activated under flow conditions in a system which allows limited thrombin and fibrin generation . Normal blood anticoagulated with low molecular weight heparin ( LMWH , ___MASK86___ 20 IU / ml ) was recirculated for up to 10 min at 800 s - 1 through annular chambers containing denuded arterial segments . Aliquots of blood were removed from the reservoir at 0 , 1 , 5 and 10 min and immediately mixed with paraformaldehyde . Membrane glycoproteins : GPIb ( CD42b ) , P08514 - IIIa ( CD41a ) , P16671 ( P16671 ) ; and activation dependent antigens : P16109 ( CD62P ) and lysosomal glycoprortein ( P08962 ) , were detected in whole blood by dual color flow cytometry . Circulation of through the perfusion system resulted in platelet activated as demonstrated by the increased percentage of platelets positive for antigens CD62P and P08962 . A gradual increase in the binding of MoAbs directed against GPIb , P08514 - IIIa , and P16671 epitopes was noted during the entire perfusion period . Observed differences in mean fluorescence intensities at all the observation times were statistically significant ( P < 0 . 001 ) . Our results obtained on platelets in an experimental thrombosis system indicate that GPIb , P08514 - IIIa and P16671 remain on the surface of activated platelets and actually increase their expression . Alterations detected at the level of GPIb in platelets activated by thrombin in suspension may not take place under in vivo situations .", "Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )", "___MASK46___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK46___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .", "Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK100___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .", "Statins exhibit anticancer effects through modifications of the pAkt signaling pathway . Statins are cholesterol lowering drugs that exhibit antitumor effects in several in vitro and in vivo models , and epidemiological studies indicate that statins prevent cancer . However , the molecular mechanism underlying the effects of statins still needs to be elucidated . We previously demonstrated that single doses of different statins rapidly affect Akt signaling via the purinergic receptor Q99572 . In particular , statins down - regulated nuclear pAkt . Here , we report that long - term treatment of A549 cells with high concentrations of statins ( 15 - 75 µM ) selects cell sub - populations exhibiting altered P2X receptor expression , signs of increased P60484 activity , enhanced Q6ZVD8 , decreased PI3K p110β and inhibited downstream pAkt signaling . Furthermore , the nuclear accumulation of pAkt in response to insulin was inhibited in selected cells . Statin - selected cells displayed reduced proliferation rate and were more vulnerable to etoposide - and 5 - fluorouracil - elicited cytotoxic effects . The stability of a selected phenotype ( 50 µM ) was tested for three weeks in the absence of statins . This resulted in a reversal of some , but not all alterations . Importantly , the truncated nuclear insulin response was retained . We conclude that long - term treatment with high doses of statins selects cells exhibiting stable alterations in insulin - Akt signaling and which are vulnerable to DNA damage . Our studies strengthen the hypothesis that an altered Akt signaling has a role in chemopreventive effects of statins .", "Desmopressin ( ___MASK32___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK32___ ) also has strong vasodilatory effects . ___MASK32___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK32___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK32___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK32___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK32___ - induced vasodilation .", "___MASK86___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK86___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .", "[ Molecular pharmacogenetic studies of drug responses to obsessive - compulsive disorder and six functional genes ] . OBJECTIVE : To investigate the associations between the drug responses to obsessive - pulsive disorder ( OCD ) and six functional genes related with serotonin and dopamine . METHODS : One hundred and thirteen OCD nuclear families were collected . The OCD patients were treated with serotonin reuptake inhibitors ( SRIs ) for 8 weeks and the drug responses were assessed using the Yale - Brown obsessive - compulsive scale ( Y - BOCS ) . The patients were divided into drug responders group and non - responders group according to the reducing rate of Y - BOCS score . The genotypes of six genes were determined with the Amp - DB00712 and Amp - RFLP techniques and analyzed by transmission disequilibrium test ( P04053 ) . The six genes are serotonin 2A receptor ( 5 - Q13049 ) , serotonin transporter ( 5 - HTT ) , dopamine D2 receptor ( P14416 ) , dopamine D4 receptor ( P21917 ) , catechol - O - methyltransferase ( P21964 ) and monoamine oxidase A ( P21397 ) . RESULTS : No association was found between the six genes and different drug responses groups . However , there was significant difference between the drug responders and non - responders in homozygosity at the 5 - Q13049 - 1438G / A locus ( chi ( 2 )= 4 . 69 , P = 0 . 03 ) . CONCLUSION : The results suggested that the 5 - Q13049 may play some roles in the effects of drug treatment on OCD .", "Mediation by 5 - hydroxytryptamine2B receptors of endothelium - dependent relaxation in rat jugular vein . 1 . An ' atypical ' 5 - HT2 receptor which is located on the endothelium of rat jugular vein has been described . In the present study we have further defined the nature of the 5 - HT2 receptor subtype present in this preparation . 2 . In experiments conducted in the presence of ketanserin to preclude involvement of 5 - HT2 receptors , the mixed P41595 / 2C antagonist , SB 200646 , acted as an antagonist of 5 - HT at the endothelial 5 - HT receptor ( pA2 = 7 . 2 ) . Yohimbine , which exhibits negligible affinity for rat P28335 receptors but has high P41595 receptor affinity , acted as a potent but non - surmountable antagonist ( pA2 > or = 7 . 3 ) in rat jugular vein . Neither yohimbine nor SB 200646 affected endothelium - dependent relaxations induced by carbachol . 3 . DB06148 also acted as a surmountable antagonist ( pA2 = 7 . 3 ) and the P41595 agonist , BW 723C86 , acted as a potent partial agonist ( pEC50 [ 95 % C L ] , intrinsic activity +/- s . e . mean = 7 . 9 [ 7 . 6 - 8 . 3 ] , 0 . 84 +/- 0 . 04 ) . Responses to BW 723C86 were antagonized by SB 200646 ( 0 . 3 microM ) yielding an ' apparent ' pA2 [ 95 % CL ] of 7 . 03 [ 6 . 76 - 7 . 32 ] . 4 . These data are consistent with the presence of P41595 receptors mediating endothelium - dependent relaxation of rat jugular vein .", "Association testing of panic disorder candidate genes using Q13308 challenge in healthy volunteers . Despite continuing efforts to determine genetic vulnerability to panic disorder ( PD ) , the studies of candidate genes in this disorder have produced inconsistent or negative , results . Laboratory panic induction may have a potential in testing genetic substrate of PD . In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin - tetrapeptide ( Q13308 ) challenge in healthy subjects . The study sample consisted of 110 healthy volunteers ( 47 males and 63 females , mean age 22 . 2 +/- 5 . 2 ) who participated in Q13308 challenge test . Nine gene - candidates , including 5 - HTTLPR , P21397 VNTR , Q8IWU9 rs1386494 , 5 - P08908 - 1019C - G , 5 - P28223 102T - C , CCKR1 246G - A , CCKR2 - 215C - A , P21728 - 94G - A and P21964 Val158Met , were selected for genotyping based on previous positive findings from genetic association studies in PD . After Q13308 challenge , 39 ( 35 . 5 % ) subjects experienced a panic attack , while 71 subjects were defined as non - panickers . We detected significant differences for both genotypic and allelic frequencies of 1386494A / G polymorphism in Q8IWU9 gene between panic and non - panic groups with the frequencies of G / G genotype and G allele significantly higher in panickers . None of the other candidate loci were significantly associated with Q13308 - induced panic attacks in healthy subjects . In line with our previous association study in patients with PD , we detected a possible association between Q8IWU9 rs1386494 polymorphism and susceptibility to panic attacks . Other polymorphisms previously associated with PD were unrelated to Q13308 - induced panic attacks , probably due to the differences between complex nature of PD and laboratory panic model .", "Expression of serotonergic system components during early Xenopus embryogenesis . Despite abundant research studies on the physiological and biochemical nature of embryonic neurotransmitter function , little is known about the molecular genetic mechanisms involved . The expression of the main components of the serotonergic system during early Xenopus embryogenesis was investigated using RT - PCR , real time PCR and in situ hybridization . Transcripts encoding the serotonin receptors P28335 and P34969 , as well as the vesicular monoamine transporter Q05940 , the serotonin transporter ( P31645 ) and the serotonin synthesis enzymes tryptophan hydroxylase ( Q8IWU9 ) and aromatic amino acid decarboxylase ( AAAD ) were found to be expressed during the cleavage division stages , whereas the degradation enzyme monoamine oxidase A ( P21397 ) was absent . The main components of the serotonergic system were found to be expressed during the earliest stages of embryonic development . The embryonic transmitter mechanism , its complexity , and its variability among various species are discussed .", "Supramolecular signalling complexes in the nervous system . It is now apparent that multiprotein signalling complexes or \" signalling machines \" are responsible for orchestrating many complex signalling pathways in the cell . The synapse is a sub - cellular specialisation which transmits and converts patterns of electrical activity into cellular memory . This processing of electrical information is mediated by the protein components of the synapse . The organisation of synaptic proteins has been investigated over the last number of years using proteomic methods and with the application ofbioinformatics ; a landscape of modular protein complexes at the synapse is emerging . Many share a common organisation centred on a receptor / channel , a protein scaffold , ( in which the signalling molecules are localised ) and membrane to cytoskeleton interactions . The use of PDZ - domain based protein scaffolds is a particularly common feature in the construction of neuronal protein complexes and the differential presence of these proteins in complexes can have functional consequences . Here we overview current proteomic methodologies for the analysis of multiprotein complexes . In addition , we describe the characterisation of a number of multiprotein complexes associated with ion channels ( NMDAR , Q99572 and Kir2 ) and GPCRs ( 5 - Q13049 / P28335 , D2 and P41594 ) and discuss common their common components and organisation .", "5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .", "Genetic dissection of atypical antipsychotic - induced weight gain : novel preliminary data on the pharmacogenetic puzzle . Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia , particularly regarding extrapyramidal symptoms . Despite their benefits , use is limited by the occurrence of adverse reactions such as sedation and weight gain . This article provides a comprehensive review and discussion of obesity - related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment . Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine - induced weight gain . There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain . Genetic predisposition to clozapine - induced weight gain has been suggested . Therefore , genetic variation in these candidate molecules may predict patient susceptibility to clozapine - induced weight gain . This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes , including the serotonin 2C , 2A , and 1A receptor genes ( P28335 / 2A / 1A ) ; the histamine H1 and H2 receptor genes ( P35367 / P25021 ) ; the cytochrome P450 1A2 gene ( P05177 ) ; the beta3 and alpha , alpha - adrenergic receptor genes ( P13945 / ADRAIA ) ; and tumor necrosis factor alpha ( P01375 ) . Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial . Trends were observed for P13945 , ADRA1A , P01375 , and P28335 ; however , replication in larger , independent samples is required . Although in its infancy , psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects , such as antipsychotic - induced weight gain , and minimize the current \" trial and error \" approach to prescribing .", "5 - hydroxytryptamine and its receptors in systemic vascular walls . 5 - hydroxytryptamine ( 5 - HT ) in the bloodstream is largely contained in platelets and circulates throughout the entire vascular system . 5 - HT released from activated platelets dramatically changes the function of vascular smooth muscle cells ( VSMCs ) and endothelial cells ( ECs ) . In VSMCs , 5 - HT induces proliferation and migration via 5 - Q13049 receptors . These effects are further enhanced by vasoactive substances such as thromboxane A2 and angiotensin II . 5 - Q13049 receptor activation in VSMCs also causes both enhancement of prostaglandin I2 production by inducing cyclooxygenase - 2 and reduction of nitric oxide ( NO ) by suppressing inducible NO synthase . Evidence showing that 5 - HT in ECs plays a principal role in angiogenesis now exists . Stimulation of 5 - HT1 and / or 5 - HT2 receptors has been implicated in the angiogenic effect of 5 - HT . The extracellular signal - regulated kinase and endothelial NO synthase ( P29474 ) activation - dependent pathways are involved in the mechanisms . Moreover , Q13639 receptors in ECs have been shown to also regulate angiogenesis . Recent reports show sarpogrelate , a selective antagonist of the 5 - Q13049 receptor , indirectly enhances the function of P28222 receptors in ECs via inhibition of 5 - Q13049 receptors in VSMCs or platelets . This indirect action of P28222 receptors in ECs may increase NO production derived from P29474 and a vasodilator response . Furthermore , sarpogrelate and other 5 - Q13049 receptor antagonists have been shown to reduce the constitutive activity of 5 - Q13049 receptors . It is believed that increasing evidence on the role of 5 - HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate , and to the development of new 5 - HT receptor - related drugs for treating cardiovascular diseases .", "5 - HT2 receptor involvement in conditioned olfactory learning in the neonate rat pup . These experiments addressed the role of 5 - HT2 receptors in conditioned olfactory learning . Ritanserin , a 5 - Q13049 / 2C antagonist , was injected subcutaneously into postnatal day ( P01160 ) 7 pups before or after conditioned olfactory training to a peppermint odor . When the pups were tested for olfactory preference on P01160 8 , those injected with ritanserin before training failed to acquire an odor preference whereas those injected after training learned . This suggested that the 5 - HT2 receptor is required only in the acquisition of conditioned olfactory learning . Injection of ritanserin directly into the olfactory bulb before training also blocked preference for the peppermint odor . In pups that had depletion of the 5 - HT input to the bulb , subcutaneous injection of a 5 - Q13049 / 2C agonist was sufficient to maintain conditioned olfactory learning , confirming the importance of 5 - HT in learning .", "Effects of antidepressants on intracellular Ca2 + mobilization in CHO cells transfected with the human P28335 receptors . Serotonin P28335 receptor - mediated intracellular Ca2 + mobilization was investigated in P28335 receptors expressed in Chinese hamster ovary ( CHO ) cells ; and fura - 2 / AM was used to investigate the regulation of P28335 receptor function . CHO cells , transfected with a cDNA clone for the P28335 receptor , expressed 287 fmol / mg of the receptor protein as determined by mianserin - sensitive [ 3H ] - mesulergine binding ( kd = 0 . 49 nM ) . The addition of 5 - HT mobilized intracellular Ca2 + in a dose - dependent fashion , ranging from basal level of 99 +/- 1 . 8 nM up to 246 +/- 21 . 2 nM , with an EC50 value for 5 - HT of . 015 microM . Exposure to 5 - HT , a 5 - HT receptor agonist , mCPP [ 1 -( 3 - chlorophenyl ) piperazine dihydrochloride ] , a P28335 agonist , and DOI [ 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane ] , a P28335 and 5 - HT2 agonist , resulted in increased intracellular Ca2 + levels . DB06148 , mesulergine , ritanserin , and ketanserin each blocked 5 - HT - mediated intracellular Ca2 + mobilization more effectively than spiperone . DB06148 and amoxapine inhibited 5 - HT - mediated intracellular Ca2 + mobilization completely ; amitriptyline , nortriptyline , and imipramine reduced it about 50 % . These results suggest that antagonism in CHO cells transfected with human P28335 receptors is a component of the serotonergic properties of a number of established antidepressants .", "Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds . Using radioligand binding assays and post - mortem normal human brain tissue , we obtained equilibrium dissociation constants ( K ( d ) s ) for nine new antipsychotic drugs ( iloperidone , melperone , olanzapine , ORG 5222 , quetiapine , risperidone , sertindole , ziprasidone , and zotepine ) , one metabolite of a new drug ( 9 - OH - risperidone ) , and three older antipsychotics ( clozapine , haloperidol , and pimozide ) at nine different receptors ( alpha1 - adrenergic , alpha2 - adrenergic , dopamine D2 , histamine H1 , muscarinic , and serotonin P08908 , P28221 , 5 - Q13049 , and P28335 receptors ) . ___MASK75___ was the most potent drug at the two adrenergic receptors . ORG 5222 was the most potent drug at dopamine D2 and 5 - HT2c receptors , while ziprasidone was the most potent compound at three serotonergic receptors ( P08908 , P28221 , and 5 - Q13049 ) . At the remaining two receptors , olanzapine was the most potent drug at the histamine H1 receptor ( Kd = 0 . 087 nM ) ; clozapine at the muscarinic receptor ( Kd = 9 nM ) . Certain therapeutic and adverse effects , as well as certain drug interactions can be predicted from a drug ' s potency for blocking a specific receptor . These data can provide guidelines for the clinician in the choice of antipsychotic drug .", "___MASK75___ binding to human and rat dopamine and 5 - HT receptors . ___MASK75___ ( ___MASK75___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK75___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK75___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK75___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .", "Discriminative stimulus properties of mCPP : evidence for a P28335 receptor mode of action . Previous drug discrimination studies with the serotonergic drug m - chlorophenylpiperazine ( mCPP ) showed conflicting results , with some authors concluding that the cue was mediated by P28335 receptors , but others that it was definitively not . We further examined the discriminative stimulus properties of mCPP in rats and reviewed previously published data . We trained rats to discriminate mCPP ( 2 . 0 mg / kg , PO ) from water . We found that the mCPP cue generalized to m - trifluoromethyl - phenylpiperazine ( TFMPP ) and 6 - chloro - 2 -( 1 - piperazinyl )- pyrazine ( MK - 212 ) , and partially to eltoprazine , 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane ( DOI ) , fenfluramine and trazodone . A moderate level of generalization was obtained with quipazine , 1 -( m - chlorophenyl ) biguanide and clonidine . No generalization was found with flesinoxan , methiothepin , idazoxan and haloperidol . DB06148 and methysergide antagonized the mCPP stimulus , whereas ketanserin antagonized it partially . Metergoline , methiothepin and clozapine only marginally antagonized the mCPP stimulus . These results show that the discriminative stimulus effects of mCPP are predominantly mediated by P28335 receptors , and to some extent by P28222 receptors . When considering our results and other research together , the substitution tests clearly point to a P28335 receptor mediated stimulus , with an additional role for P28222 receptors . Antagonism studies are less clearcut , but are also suggestive of a P28335 receptor mediated effect . A definitive answer as to whether other receptors , e . g . P41595 and P34969 , are of any importance in mCPP ' s discriminative stimulus properties has to wait for more selective ligands .", "Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK11___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .", "Thermoregulatory responses to serotonin ( 5 - HT ) receptor stimulation in the rat . Evidence for opposing roles of 5 - HT2 and P08908 receptors . The effects of serotonergic agonists and antagonists on the body temperatures of rats were investigated . The administration of the serotonin ( 5 - HT ) agonist 6 - chloro - 2 ( 1 - piperazinyl )- pyrazine ( MK - 212 ) produced a dose - related increase in body temperature . A maximal increase in body temperature of approx . 1 . 1 degrees C was observed 30 min after the administration of 3 mg / kg of MK - 212 . In contrast , administration of the putative P08908 agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) resulted in marked , dose - related hypothermic responses . Body temperatures were decreased approx . 3 degrees C 30 min after an injection of 0 . 3 mg / kg of 8 - OH - DPAT . Body temperatures were affected differentially by 5 - methoxy - N , N - dimethyltryptamine ( 5 - MeODMT ) . Large doses ( 3 - 10 mg / kg ) of 5 - MeODMT elicited hyperthermic responses , whereas small doses ( 0 . 5 - 1 . 0 mg / kg ) produced hypothermic responses . Treatment of rats with ketanserin ( 3 mg / kg ) completely prevented the hyperthermic effects of 5 - MeODMT , and , in fact , converted a hyperthermic response to 5 - MeODMT into a marked hypothermic response . Ketanserin ( 0 . 1 - 1 . 0 mg / kg ) selectively antagonized the hyperthermic response to MK - 212 but did not alter the hypothermic effect of 8 - OH - DPAT . DB06148 ( 10 mg / kg ) and pirenperone ( 0 . 03 mg / kg ) also selectively antagonized hyperthermia induced by MK - 212 . In contrast , pindolol ( 0 . 03 - 0 . 1 mg / kg ) and methiothepin ( 10 mg / kg ) selectively antagonized hypothermia induced by 8 - OH - DPAT but did not alter hyperthermia induced by MK - 212 . Spiperone ( 0 . 1 - 3 mg / kg ) and pizotifen ( 10 mg / kg ) attenuated the effects of both 8 - OH - DPAT and MK - 212 . Xylamidine , a peripheral 5 - HT antagonist , had no significant effect on hyperthermia induced by MK - 212 or hypothermia induced by 8 - OH - DPAT . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK11___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .", "Differential display RT - PCR reveals genes associated with lithium - induced neuritogenesis in SK - N - MC cells . DB01356 is shown to be neurotrophic and protective against variety of environmental stresses both in vitro as well as in vivo . In view of the wider clinical applications , it is necessary to examine alterations in levels of expression of genes affected by lithium . DB01356 induces neuritogenesis in human neuroblastoma cell line SK - N - MC . Our aim was to elucidate genes involved in lithium - induced neuritogenesis using SK - N - MC cells . The differential display reverse transcriptase polymerase chain reaction ( DD - RT - PCR ) technique was used to study gene expression profiles in SK - N - MC cells undergoing lithium - induced neuritogenesis . Differential expression of genes in control and lithium ( 2 . 5 mM , 24 h ) - treated cells was compared by display of cDNAs generated by reverse transcription of mRNA followed by PCR using arbitrary primers . Expression of four genes was altered in lithium - treated cells . Real - time PCR was done to confirm the levels of expression of each of these genes using specific primers . DB01356 significantly up - regulated P13591 , a molecule known to stimulate neuritogenesis , occludin , a molecule participating in tight junctions and PKD2 , a molecule known to modulate calcium transport . P01160 32c , a gene whose function is not fully known yet , was found to be down - regulated by lithium . This is the first report demonstrating altered levels of expression of these genes in lithium - induced neuritogenesis and contributes four hitherto unreported candidates possibly involved in the process .", "Platelet derived serotonin drives the activation of rat cardiac fibroblasts by 5 - Q13049 receptors . Platelet activation occurs in different acute and chronic heart diseases including myocardial infarction , obstructive hypertrophic cardiomyopathy and valve stenosis . Recent studies suggested that some factors secreted by activated platelets may participate in cardiac remodeling . In the present study , we investigated whether platelets and platelet - released serotonin ( 5 - HT ) are directly involved in the functional regulation of cardiac fibroblasts . Treatment of neonatal rat cardiac fibroblasts with platelet lysate , 5 - HT and the 5 - Q13049 receptor agonist DOI increased the expression of alpha - SMA protein , a marker of fibroblast differentiation into myofibroblasts . Platelet lysate , 5 - HT and DOI also induced a time - dependent stimulation of cardiac fibroblast migration that was inhibited by the 5 - Q13049 receptor antagonist ketanserin . Finally , incubation of cardiac fibroblasts with platelet lysate or 5 - HT enhanced secretion of TGF - beta1 and expression of P08254 and P45452 . As observed for fibroblast migration , these effects were prevented by ketanserin . These results demonstrated for the first time that factors released from platelet directly regulate cardiac fibroblasts by enhancing secretion of TGF - beta1 and MMPs and promoting their migration and differentiation . 5 - HT released by platelets appears to be a major contributor of platelet effects which are mediated through 5 - Q13049 receptors .", "Effects of antidepressants on the exploration , spontaneous motor activity and isolation - induced aggressiveness in mice . OBJECTIVE : To study the role of different antidepressants on exploration , spontaneous motor activity and isolation - induced aggressiveness in mice , further to discuss different mechanisms of their anti - aggression . METHODS : With an aggressive model induced by isolation housing in mice , antagonism of different antidepressants against isolation - induced aggression was evaluated . In the group - housed mice given the same treatment as aggressive test , exploration and spontaneous motor activity were measured . RESULTS : ( 1 ) DB06148 ( 0 . 5 - 5 mg / kg - 1 ) , buspirone ( 2 . 5 - 10 mg . kg - 1 ) and meclobemide ( 2 . 5 - 10 mg . kg - 1 ) significantly inhibited the exploration in the group - housed mice , but not fluoxetine ( 2 . 5 - 10 mg . kg - 1 ) , imipramine ( 2 . 5 - 10 mg . kg - 1 ) and DOI ( 0 . 5 - 2 mg . kg - 1 ) ; ( 2 ) Both mianserin and buspirone , but not fluoxetine , imipramine , meclobemide and DOI , obviously reduced spontaneous motor activity ; ( 3 ) DB00472 , miaserin , imipramine and buspirone significantly and dose - dependently antagonized isolation - induced aggressive behavior , whereas meclobemide failed to attenuate aggression . DOI dual - regulated aggressiveness in isolation mice . CONCLUSION : Our findings suggest that the effects of fluoxetine , mianserin , buspirone , imipramine , meclobemide and DOI on exploration , spontaneous motor activity and isolation - induced aggression in mice are different , which may involve different pharmacological mechanisms underlying their anti - aggression in isolation mice . P08908 and 5 - Q13049 / 2C receptors may mediate isolation - induced aggressive behavior in mice . The involvement of 5 - HT receptor subtypes needs further clarification .", "Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK51___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK51___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK51___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK51___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .", "Differential involvement of Galpha12 and Galpha13 in receptor - mediated stress fiber formation . The ubiquitously expressed heterotrimeric guanine nucleotide - binding proteins ( G - proteins ) G12 and Q99941 have been shown to activate the small GTPase Rho . Rho stimulation leads to a rapid remodeling of the actin cytoskeleton and subsequent stress fiber formation . We investigated the involvement of G12 or Q99941 in stress fiber formation induced through a variety of Gq / P49842 - coupled receptors . Using fibroblast cell lines derived from wild - type and Galphaq / Galpha11 - deficient mice , we show that agonist - dependent activation of the endogenous receptors for thrombin or lysophosphatidic acid and of the heterologously expressed bradykinin B2 , vasopressin V1A , endothelin P25101 , and serotonin P28335 receptors induced stress fiber formation in either the presence or absence of Galphaq / Galpha11 . Stress fiber assembly induced through the muscarinic M1 and the metabotropic glutamate subtype 1alpha receptors was dependent on Gq / P49842 proteins . The activation of the Gq / P49842 - coupled endothelin ETB and angiotensin AT1A receptors failed to induce stress fiber formation . Lysophosphatidic acid , B2 , and P28335 receptor - mediated stress fiber formation was dependent on Galpha13 and involved epidermal growth factor ( P01133 ) receptors , whereas thrombin , P25101 , and V1A receptors induced stress fiber accumulation via Galpha12 in an P01133 receptor - independent manner . Our data demonstrate that many Gq / P49842 - coupled receptors induce stress fiber assembly in the absence of Galphaq and Galpha11 and that this involves either a Galpha12 or a Galpha13 / P01133 receptor - mediated pathway .", "Vascular endothelial growth factor and basic fibroblast growth factor in exudative age - related macular degeneration and diffuse diabetic macular edema . BACKGROUND : To evaluate the concentrations of vascular endothelial growth factor ( P15692 ) and basic fibroblast growth factor ( P09038 ) in neovascular or edematous retinal diseases . METHODS : In the clinical comparative interventional study , P15692 and P09038 concentrations in aqueous humor samples of 35 patients with exudative age - related macular degeneration ( AMD ) , 21 patients with diabetic macular edema and 24 patients of a control group were measured using a solid - phase chemiluminescence immunoassay . RESULTS : Concentrations of P15692 and P09038 , respectively , were significantly higher in the diabetic group ( 184 . 7 +/- 107 . 0 and 5 . 0 +/- 10 . 2 pg / l ) than in the AMD group ( 107 . 7 +/- 73 . 0 pg / l , p = 0 . 002 ; 2 . 2 +/- 7 . 4 pg / l , p = 0 . 002 ) and the control group ( 71 . 5 +/- 94 . 7 pg / l , p = 0 . 001 ; 0 . 00 pg / l , p = 0 . 001 ) . The two latter groups did not vary significantly ( p = 0 . 10 ) . CONCLUSIONS : P15692 and P09038 are present in considerably higher concentrations in eyes with diabetic macular edema than in eyes with exudative AMD or normal eyes . The differences were more marked for P15692 than for P09038 .", "Modulation of antipsychotic - induced extrapyramidal side effects by medications for mood disorders . Antipsychotic drugs are widely used not only for schizophrenia , but also for mood disorders such as bipolar disorder and depression . To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects ( EPS ) , we examined the effects of antidepressants and mood - stabilizing drugs on haloperidol ( P42357 ) - induced bradykinesia and catalepsy in mice and rats . The selective serotonin reuptake inhibitors ( SSRIs ) , fluoxetine and paroxetine , and the tricyclic antidepressant ( TCA ) clomipramine , which showed no EPS by themselves , significantly potentiated P42357 - induced bradykinesia and catalepsy in a dose - dependent manner . In contrast , the noradrenergic and specific serotonergic antidepressant ( NaSSA ) mirtazapine failed to augment , but rather attenuated P42357 - induced bradykinesia and catalepsy . DB06148 also tended to reduce the EPS induction . In addition , neither treatment with lithium , sodium valproate nor carbamazepine potentiated P42357 - induced EPS . Furthermore , treatment of animals with ritanserin ( 5 - Q13049 / 2C antagonist ) , ondansetron ( 5 - Q9H205 antagonist ) , and SB - 258585 ( P50406 antagonist ) significantly antagonized the EPS augmentation by fluoxetine . Intrastriatal injection of ritanserin or SB - 258585 , but not ondansetron , also attenuated the EPS induction . The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction . In addition , 5 - Q13049 / 2C , 5 - Q9H205 and P50406 receptors seem to be responsible for the augmentation of antipsychotic - induced EPS by serotonin reuptake inhibitors .", "Synaptic vesicular monoamine transporter expression : distribution and pharmacologic profile . The human vesicular monoamine transporter ( hSVMT ) cDNA predicts a protein of 515 amino acids that shares 92 % amino acid identity with the rat cDNA . Northern analyses reveal expression of 4 . 3 kb Q05940 mRNAs in rat hypothalamus , midbrain and brainstem , a 3 kb hSVMT mRNA in human brainstem and a 4 . 8 kb hSVMT mRNA in human hypothalamus . In situ hybridization documents significant Q05940 expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers . COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine , micromolar affinities for haloperidol , GBR12909 , serotonin , mazindol , nomifensin and ___MASK72___ , while dopamine , epinephrine , norepinephrine and histamine each displayed millimolar affinities . These observations extend the pharmacological characterization of hSVMT and studies of its distribution , and indicate likely physiological roles for Q05940 in packaging monoamine transmitters including histamine .", "Presence of a P34969 receptor positively coupled to adenylate cyclase activation in human granulosa - lutein cells . Although serotonin ( 5 - HT ) has been shown to stimulate progesterone production by human granulosa - lutein cells ( hGLC ) , the receptor type and associated signaling pathway remain uncharacterized . We report here that 5 - HT receptors in these cells are positively coupled to adenylate cyclase activity . Formation of DB02527 was stimulated by 5 - HT and its agonists in a dose - and time - dependent manner . DB06148 , amoxapine , and loxapine were equipotent in antagonizing 5 - HT - induced DB02527 formation . For both DB02527 formation in cells and adenylate cyclase assay using membrane fractions , the rank order of potency for agonists of 5 - HT were : 5 - carboxy - aminotryptamine > 5 - HT > or = 5 - methoxytryptamine , consistent with a typical pharmacological profile of human 5 - ht7 ( h5 - ht7 ) receptor . Sequence data of amplified complementary DNA fragments reverse transcribed from hGLC RNA revealed complete identity with published sequence of h5 - ht7 receptor complementary DNA . Northern analysis showed the presence of 2 . 8 - kb h5 - ht7 transcripts in hGLC . The three variants h5 - ht7A , h5 - ht7B , and h5 - ht7D were also detected in hGLC . Preincubation of hGLC with 5 - HT ( 10 (- 8 )- 10 (- 6 ) M ) resulted in a marked reduction in the DB02527 response when the cells were subsequently stimulated with gonadotropin , and this heterologous desensitization could be reversed by 5 - ht7 receptor antagonist clozapine . These data demonstrate that h5 - ht7 receptor is present and stimulate DB02527 formation in hGLC . In addition , the h5 - ht7 receptor seems to be implicated in the heterologous down - regulation hCG - stimulated DB02527 response in hGLC , with a possible ramification for luteal insufficiency .", "Cholecystokinin - induced satiety depends on activation of P28335 receptors . To investigate the dependence of the satiating action of cholecystokinin on serotonergic function in rats , we examined the effects of systemic pretreatment with serotonin ( 5 - HT ) antagonists of varying selectivity for 5 - HT receptor subtypes on suppression of food intake induced by systemic administration of cholecystokinin octapeptide ( CCK - 8 ) . DB06148 , a P28335 / 2 - selective antagonist , significantly attenuated the satiating action of CCK - 8 . Ketanserin , a 5 - HT2 antagonist , and three 5 - Q9H205 antagonists , MDL - 72222 , ICS 205 - 930 , and ondansetron , however , had no effect on the satiating action of CCK - 8 . These results demonstrate that the satiating action of exogenous CCK depends on activation of 5 - HT1 ( probably P28335 ) receptors and that activation of 5 - HT2 or 5 - Q9H205 receptors is not required .", "___MASK42___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .", "Beneficial effect of low - dose mianserin on fluvoxamine - induced akathisia in an obsessive - compulsive patient . Extrapyramidal side effects induced by some selective serotonin reuptake inhibitors ( SSRIs ) , i . e . fluoxetine and sertraline , have been previously reported in patients with depression and obsessive - compulsive disorder ( OCD ) . However , the occurrence and management of akathisia induced by fluvoxamine have not been described . In the presented case fluvoxamine - induced akathisia in an OCD patient was partially resistant to the anticholinergic agent biperiden , and was successfully treated with the 5 - Q13049 / P28335 antagonist mianserin . DB06148 ( 15 mg / day at 21 . 00 h ) was discontinued and then reinstituted ( off - on - off - on design ) . DB00810 was transiently effective in the acute akathisia , while the more persistent akathisia was alleviated by mianserin . Discontinuation of mianserin resulted in recurrence of akathisia , while full amelioration of the symptoms of akathisia was noted when mianserin was reinstituted . No aggravation of OCD symptoms was noted during mianserin administration .", "Role of monoamine oxidases in the exaggerated 5 - hydroxytryptamine - induced tension development of human isolated preeclamptic umbilical artery . We investigated the role ( s ) of monoamine oxidases ( MAOs ) on the altered 5 - hydroxytryptamine ( 5 - HT , serotonin ) - induced tension development of the isolated umbilical artery of preeclamptic pregnancy of Chinese women . An enhanced 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy was observed when compared with that of normal pregnancy . The enhanced component of 5 - HT - induced tension development was eradicated by clorgyline ( a P21397 inhibitor ) . Blockade of P29474 ( endothelial isoform nitric oxide synthase ) ( N ( omega )- nitro - L - arginine methyl ester ) , 5 - HT transporter ( citalopram ) , 5 - HT receptor subtypes ( 5HT2B , SB 204741 ; P28335 , RS 102221 ; P34969 , SB 269970 ) , and endothelium denudation of the umbilical artery of normal pregnancy mimicked the enhanced 5 - HT - induced tension development as observed in the preeclamptic tissues . In contrast , no apparent changes in 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy were observed with the same pharmacological manipulations . A decreased protein expression levels of P21397 and P29474 ( no P35228 and P27338 expression was detected ) and no change in caveolin - 1 and 5 - HT transporter expression were demonstrated in the umbilical artery ( endothelium intact ) lysate of preeclamptic pregnancy , compared to that of the umbilical artery of normal pregnancy . Thus , in the umbilical artery of preeclamptic pregnancy , a decrease of P21397 and P29474 protein expression levels are probably associated with , or responsible for , the exaggerated 5 - HT - induced tension development .", "Putative selective P28223 antagonists block serotonin 5 - HT - 1c receptors in the choroid plexus . The binding of [ 3H ] mianserin to rat choroid plexus was characterized and compared with two other radioligands that label the 5 - HT ( serotonin )- 1c receptor ( [ 3H ] mesulergine and [ 125I ] lysergic acid diethylamide ) . [ 3H ] DB06148 binding to a crude membrane preparation of choroid plexus from rat brain was rapid , saturable and of high affinity ( Kd = 1 nM ) . The density of sites labeled by [ 3H ] mianserin and [ 3H ] mesulergine was equal . Furthermore , an excellent correlation was found between the potencies of drugs in competing for [ 3H ] mianserin binding and for [ 125 ] lysergic acid diethylamide binding . Based on these data , it was concluded that [ 3H ] mianserin labels the 5 - HT - 1c binding site . Using this ligand , the binding of the putative selective P28223 antagonist ritanserin to the 5 - HT - 1c site was evaluated . Ritanserin was a potent inhibitor of [ 3H ] mianserin binding with a Ki value of 0 . 2 nM . Functional studies of 5 - HT - stimulated phosphoinositide hydrolysis , the transmembrane signaling pathway for the 5 - HT - 1c receptor , showed that ritanserin blocks the effect of 5 - HT and that it functions as a competitive antagonist of the 5 - HT - 1c receptor in intact choroid plexus . The potencies of ritanserin and several other drugs , including other P28223 antagonists , at the 5 - HT - 1c binding site correlated with their potencies at blocking 5 - HT - stimulated phosphoinositide hydrolysis . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Tissue specificity of methylation and expression of human genes coding for neuropeptides and their receptors , and of a human endogenous retrovirus K family . The purpose of the present study was to understand the tissue specificity of DNA methylation and the relationship between methylation and expression of genes with essential roles in neurodevelopment and brain function . We chose dopamine receptor genes ( P21728 and P14416 ) , P13591 , and P21964 as examples of genes with CpG islands around the promoter region , and serotonin receptor genes ( P28223 and P46098 ) , O43612 , and P35462 as genes without CpG islands . Methylation states were investigated in fetal brain , fetal liver , placenta , and in adult peripheral leukocytes from three individuals by Southern blot and bisulfite - modified DNA sequencing . A repetitive sequence , human endogenous retrovirus ( HERV ) - K was also examined . All genes examined were almost completely unmethylated in brains . The genes with CpG islands were unmethylated regardless of their expression state . In contrast , genes without CpG islands showed various methylation patterns , which did not necessarily reflect the transcriptional activity of the genes . Most HERV - K loci were methylated , but some loci showed relatively low methylation in the placenta and liver . Interestingly , we found inter - individual differences in methylation levels in P28223 and O43612 in the placenta and in some loci of HERV - K in the placenta and liver . The sample with the lowest methylation levels in the two unique genes showed higher methylation of HERV - K loci than the other samples . These results provide detailed information about the methylation states of the genes analyzed and evidence for inter - individual variations in methylation in both unique and repetitive sequences .", "Maxi - anion channel as a candidate pathway for osmosensitive DB00171 release from mouse astrocytes in primary culture . In the present study , we aimed to evaluate the pathways contributing to DB00171 release from mouse astrocytes during hypoosmotic stress . We first examined the expression of mRNAs for proteins constituting possible DB00171 - releasing pathways that have been suggested over the past several years . In RT - PCR analysis using both control and osmotically swollen astrocytes , amplification of cDNA fragments of expected size was seen for connexins ( P08034 , P35212 , P17302 ) , pannexin 1 ( Px1 ) , the Q99572 receptor , MRP1 and P08183 , but not P13569 . Inhibitors of exocytotic vesicular release , gap junction hemi - channels , P13569 , MRP1 , P08183 , the Q99572 receptor , and volume - sensitive outwardly rectifying chloride channels had no significant effects on the massive DB00171 release from astrocytes . In contrast , the hypotonicity - induced DB00171 release from astrocytes was most effectively inhibited by gadolinium ( 50 muM ) , an inhibitor of the maxi - anion channel , which has recently been shown to serve as a pathway for DB00171 release from several other cell types . Thus , we propose that the maxi - anion channel constitutes a major pathway for swelling - induced DB00171 release from cultured mouse astrocytes as well .", "Chronic mianserin or eltoprazine treatment in rats : effects on the elevated plus - maze test and on limbic P28335 receptor levels . Rats were chronically treated with mianserin ( 10 mg / kg i . p . ) or eltoprazine ( 1 mg / kg i . p . ) and were tested in the elevated plus - maze test for anxiety . P28335 ( previously P28335 , see Humphrey et al . , 1993 , Trends Pharmacol . Sci . 14 , 223 ) binding sites and their mRNA were evaluated in limbic structures ( i . e . , amygdala , hippocampus , septum ) of a sample of these rats by autoradiographic binding studies and in situ hybridization histochemistry . DB06148 and eltoprazine displayed opposite effects in the elevated plus - maze : mianserin induced anxiolytic - like effects , while eltoprazine showed anxiogenic - like ones . Within the amygdala , but not in other structures , the quantitative autoradiographic analysis of the P28335 binding sites showed a differential effect : mianserin treatment induced a decrease in the number of these sites , while eltoprazine treatment resulted in an increase . In spite of this , neither mianserin - nor eltoprazine - treated rats displayed an alteration in the P28335 receptor mRNA levels in the brain regions examined . Our results are suggestive of a relation between anxiolytic / anxiogenic - like effects and the level of P28335 binding sites in the amygdala .", "Identification of multiple binding sites for [ 3H ] 5 - hydroxytryptamine in the rat CNS . Recent studies indicate that there may be multiple subtypes of [ 3H ] 5 - hydroxytryptamine ( [ 3H ] 5 - HT ) binding sites . DB06148 and spiperone inhibited the specific binding of [ 3H ] 5 - HT ( 2 - 3 nM ) to rat brain cortical membranes with shallow displacement curves . The displacement data for spiperone were best described by the presence of three independent binding sites , for which spiperone had high , medium , and low affinities . The displacement data for mianserin were best fitted by two independent , high - and low - affinity sites . The inclusion of mianserin ( 250 nM ) to inhibit [ 3H ] 5 - HT binding to the mianserin - sensitive site selectively blocked one of the sites discriminated by spiperone . These results suggest the presence of three binding sites for [ 3H ] 5 - HT , one blocked by low concentrations of spiperone ( P08908 ) , one blocked by low concentrations of mianserin ( P28335 ) , and one blocked only by high concentrations of both mianserin and spiperone ( P28222 ) . Regional differences in the relative densities of the three sites were observed . The hippocampus was rich in P08908 sites , whereas the striatum contained mainly P28222 and P28335 sites . Selective degeneration of 5 - HT - containing nerve terminals induced by the neurotoxin 5 , 7 - dihydroxytryptamine increased binding to all three sites in the cerebral cortex . Binding of [ 3H ] 5 - HT to the three sites was differentially modulated by CaCl2 and guanylimidodiphosphate . The present data suggest the presence of three independent 5 - HT1 binding sites having different affinities for mianserin and spiperone and having different regional distributions .", "Alteration of contractile properties to serotonin in gastric fundus smooth muscle isolated from streptozotocin ( Q11206 ) - induced diabetic rats . Contractile responses to serotonin ( 5 - HT ) of fundic smooth muscle strips isolated from both control and streptozotocin ( Q11206 ) - induced diabetic rats were investigated . Contrary to carbachol ( CCh ) which causes contractile hyperactivity in DM , 5 - HT response tended to decrease in DM compared to that of the control . Pindolol ( 10 (- 5 ) M ) increased the value of EC50 of the concentration - response to 5 - HT about 2 . 5 times in both the control and DM . After treatment with pindolol , the maximal tension to 5 - HT in DM significantly decreased compared to that of the control . Pindolol showed no effect on the contractile response to CCh . Pindolol significantly inhibited the relaxation caused by isoproterenol in DM more than in the control . DB06148 ( 10 (- 5 ) M ) increased the EC50 of the response to 5 - HT about 2 - 2 . 5 times in both groups , but did not cause a significant difference between the control and DM . The Ca ( 2 +)- induced contraction caused hyperreactivity in DM in the presence of 10 (- 6 ) M CCh , but that in DM was not significantly different from the control in the presence of 10 (- 6 ) M 5 - HT . Pretreatment of phorbol 12 - myristate 13 - acetate ( PMA , 10 (- 5 ) M ) significantly attenuated the response to 5 - HT in the control , but not in DM . Results suggest that the contractile response to 5 - HT in DM is related to the altered Ca2 + signal transduction system via disturbed protein kinase C ( PKC ) activity , and that there are alterations of receptor characteristics and of the density in 5 - HT receptor subtypes , especially P08908 , during DM development .", "Ectopic DB01285 syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing ' s disease . A 75 - year - old woman was admitted to our hospital because of a poor glycemic control . She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma DB01285 and cortisol levels , lack of their circadian rhythm , non - suppressibility to high - dose dexamethasone , responsiveness to P06850 , but not to ___MASK32___ , and suppression to octreotide . Pituitary Q9BWK5 showed an equivocal small lesion . CT scan of the chest showed two nodular lesions in the right lung ( S5 , S7 ) , while a mild uptake was noted only in S5 lesion by DB09150 - PET , but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy ( SRS ) . Inferior petrosal sinus sampling revealed a gradient of plasma DB01285 after P06850 stimulation , consistent with the diagnosis of Cushing ' s disease . She underwent middle and inferior lobectomy of the right lung . The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive DB01285 immunoreactivity , while that of S5 was cryptococcal granuloma . RT - PCR revealed abundant expressions of P01189 and SSTR ( - 1 , - 2 , - 5 ) , but not of P34998 and P47901 . Postoperatively , abnormal endocrine data were normalized along with improvement of hypertension and diabetes . This was a diagnostic challenging case with ectopic DB01285 syndrome indistinguishable from Cushing ' s disease by various endocrine and imaging tests , among which SRS successfully localized the tumor responsible for ectopic DB01285 secretion .", "\" In vitro \" postnatal expression of P34969 receptors in the rat hypothalamus : an immunohistochemical analysis . The neurotransmitter serotonin ( 5 - HT ) is involved in various physiological functions via multiple receptor subtypes . These have been classified in seven receptor families ( 5 - HT1 - 7 ) on the basis of their structures and functional characteristics . In this study , we examined the expression of P34969 receptors in the rat hypothalamic neurons cultured \" in vitro \" during postnatal development . Neuronal cultures were prepared from postnatal pups P2 , P09131 and Q15084 , were treated with P09038 and processed by means of immunofluorescence technique using a polyclonal P34969 receptor antibody . In P2 , we found a low density of P34969 labeled hypothalamic P09038 - treated neurons and no P34969 immunolabeling in control cultures ; in P09131 , a moderate number of P09038 - treated neurons were observed but they were not bright . No P34969 immunolabeling was found in controls . In Q15084 , a heavy labeling of small sized bipolar neurons was seen in P09038 - treated neurons , while in control cultures , few labeled neurons with a low stained density were observed . These results suggest that P34969 receptors in hypothalamic neurons begin to appear at Q15084 and then could be involved in many physiological implications that are not exerted at P2 and P09131 . This indicates that P34969 receptors have a potential significance in the rat hypothalamus during early postnatal development .", "A novel class of 5 - Q13049 receptor antagonists : aryl aminoguanidines . Local delivery of serotonin ( 5 - HT ) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5 - HT2 antagonists such as ketanserin or mianserin . Here we report the effects of a new class of aminoguanidine 5 - HT2 antagonists , with relative selectivity for 5 - Q13049 receptors which are potent inhibitors of 5 - HT - induced paw edema in the rat . Radioligand binding studies with 125I DOI on human 5 - Q13049 and P28335 receptors and with 3H - 5 - HT on human P41595 receptors demonstrated that , LY314228 , and LY320954 displayed some selectivity for the 5 - Q13049 receptor . When compared to binding at other 5 - HT2 receptor subtypes , LY314228 had an 18 . 6 - fold greater affinity for the 5 - Q13049 site over the P41595 site , and 2 . 6 fold greater at the P28335 site . LY320954 displayed similar preference for 5 - Q13049 sites . Both compounds also inhibited 5 - HT - induced paw swelling in rats , with ED50 ' s of 6 . 4 and 4 . 8 mg / kg ( for LY314228 and LY320954 , respectively ) . These studies offer evidence for a novel class of pharmacophores for the 5 - HT2 receptor family which show greater relative affinities for the 5 - Q13049 receptor subclass .", "Cloning , after cloning , knock - out mice , and physiological functions of MAO A and B . Cloning of MAO A and B has demonstrated clearly that MAO A and B are coded by different proteins with 70 % amino acid identity . With the MAO A and B cDNA clones , we showed the tissue distribution and genomic structure of MAO A and B , the latter suggesting that they are derived from the same ancestral gene . The active sites , the role of cysteine residues , the three - dimensional models and the mitochondria targeting domains of both isoenzymes have been established . The transcriptional regulation of MAO A and B has been studied . MAO A KO mice showed increased levels of serotonin ( 5 - HT ) , norepinephrine ( NE ) , dopamine ( DA ) whereas MAO B KO mice showed increased phenylethylamine ( PEA ) levels only . Both MAO A and B KO mice showed increased response to stress . MAO A KO mice showed increased emotional learning and memory and aggressive behavior , but the vesicular monoamine transporter ( Q05940 ) , P08908 , 5 - Q13049 and P28335 receptors were down regulated . 5 - Q13049 antagonist , ketanserin and MDL100907 were able to abolish the aggression , suggesting that the aggressive behavior may be mediated by 5 - Q13049 receptor . In contrast , MAO B KO mice are resistant to MPTP , a toxin which induces Parkinson ' s syndromes . Studies of these mice suggest that MAO A and B have distinct biochemical and physiological functions .", "Serotonin as a homeostatic regulator of lactation . Serotonin ( 5 - HT ) , a neurotransmitter produced in mammary epithelial cells ( MECs ) , acts via autocrine - paracrine mechanisms on MECs to regulate milk secretion in a variety of species . Recent studies in dairy cows reported that 5 - HT ligands affect milk yield and composition . We determined the mRNA expression of bovine 5 - HT receptor ( 5 - HTR ) subtypes in bovine mammary tissue ( BMT ) and cultured bovine MECs . We then used pharmacologic agents to evaluate functional activities of 5 - HTR subtypes . The mRNAs for five receptor isoforms ( 5 - P28222 , 5 - P28223 , 5 - P41595 , 5 - Q13639 , and 5 - P34969 ) were identified by conventional reverse transcription PCR , real - time PCR , and in situ hybridization in BMT . In addition to luminal Q9NRJ3 expression , 5 - Q13639 was expressed in myoepithelium , and 5 - P28222 , P28223 , and P41595 were expressed in small mammary blood vessels . Studies to date report that there are multiple 5 - HTR isoforms in mammary tissue of rodents , humans , and cattle . Inhibition of the 5 - HT reuptake transporter with selective 5 - HT reuptake inhibitors ( SSRIs ) disrupted tight junctions and decreased milk protein mRNA expression in mouse , human , and bovine mammary cells . Selective 5 - HT reuptake inhibitors act to increase the cellular exposure to 5 - HT by preventing reuptake of 5 - HT by the cell and eventual degradation . Increasing 5 - HT concentration in milk via inhibiting its reuptake ( SSRI ) , or by increasing the precursor for 5 - HT synthesis 5 - hydroxytryptophan , accelerated decline in milk synthesis at dry - off . We conclude that the 5 - HT system in mammary tissue acts as a homeostatic regulator of lactation .", "The interaction of antidepressant drugs with enteric P34969 receptors . In this study the functional interaction of the antidepressant drugs amitriptyline , mianserin , maprotiline , imipramine , fluoxetine and the putative antidepressant drug flibanserin has been studied on P34969 - mediated responses to 5 - carboxamidotryptamine ( 5 - CT ) in the guinea - pig ileum . 5 - CT induced a concentration - dependent inhibition of the contractile response to DB05875 ( 100 nM ) . Except for fluoxetine and flibanserin , all the antidepressants antagonized by different degrees the 5 - CT inhibitory response with the following rank affinity order : mianserin > maprotiline > imipramine > amitriptyline . DB06148 was the only antidepressant to show a profile of competitive antagonism at P34969 receptors in a tenfold range of concentrations ( 0 . 1 - 1 microM ) , with an affinity ( pA2 ) value of 8 . 1 +/- 0 . 6 . The antagonism of the other antidepressants was not concentration - dependent ( amitriptyline ) or was associated with slight or moderate reduction of the maximal 5 - CT response ( imipramine or maprotiline ) . The apparent affinity ( pKB ) values were : amitriptyline , 7 . 0 +/- 0 . 2 ; maprotiline , 7 . 3 +/- 0 . 6 ; imipramine , 7 . 2 +/- 0 . 4 . Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric P34969 receptors through competitive or allosteric mechanisms . This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5 - HT receptors , namely 5 - Q9H205 and Q13639 receptors .", "DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK100___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .", "Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .", "( N ) - methanocarba - 2MeSADP ( MRS2365 ) is a subtype - specific agonist that induces rapid desensitization of the P47900 receptor of human platelets . DB00640 diphosphate ( ADP ) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq - coupled P47900 receptor and the Gi - coupled Q9H244 receptor . We recently described the synthesis and P47900 receptor - specific agonist activity of ( N ) - methanocarba - 2MeSADP ( MRS2365 ) . Consequences of selective activation of the P47900 receptor by MRS2365 have been further examined in human platelets . Whereas MRS2365 alone only induced shape change , addition of MRS2365 following epinephrine treatment , which activates the Gi / z - linked , alpha2A - adrenergic receptor , resulted in sustained aggregation that was indistinguishable from that observed with ADP . Conversely , the platelet shape change promoted by ADP in the presence of the P08514 / IIIa antagonist eptifibatide was similar to that promoted by MRS2365 . Preaddition of the high affinity P47900 receptor antagonist MRS2500 inhibited the effect of MRS2365 , whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365 - induced shape change . Preactivation of the P47900 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20 - fold rightward shift in the concentration effect curve of ADP . This inhibitory effect of P47900 receptor activation was dependent on the concentration of MRS2365 ( EC50 = 34 nm ) . The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq - coupled 5 - Q13049 receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq - coupled P47900 receptor . The time course of MRS2365 - induced loss of aggregation response to epinephrine was similar to that observed with ADP . These results further demonstrate the P47900 receptor selectivity of MRS2365 and illustrate the occurrence of agonist - induced desensitization of the P47900 receptor of human platelets studied in the absence of Q9H244 receptor activation .", "A 3 - D model for P08908 - receptor agonists based on stereoselective methyl - substituted and conformationally restricted analogues of 8 - hydroxy - 2 -( dipropylamino ) tetralin . The enantiomers of cis - and trans - 1 , 2 , 3 , 4 , 4a , 5 , 10 , 10a - octahydro - 9 - hydroxy - 1 - propylbenzo [ g ] quinolines ( 10 and 11 , respectively ) and the enantiomers of trans - 1 , 2 , 3 , 4 , 4a , 5 , 6 , 10b - octahydro - 10 - hydroxy - 4 - propylbenzo [ f ] quinoline ( 12 ) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X - ray crystallography and molecular mechanics ( P08253 ) calculations . The compounds , which are conformationally restricted analogues of the potent 5 - hydroxytryptamine ( 5 - HT ) receptor agonist 8 - hydroxy - 2 - ( dipropylamino ) tetralin ( 8 - OH - DPAT ; 1 ) have been evaluated for central 5 - HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats . In addition , we have evaluated the ability of these compounds and a number of previously reported analogues to displace [ 3H ] - 8 - OH - DPAT from P08908 - binding sites . The enantiomers of 12 behave as potent P08908 - receptor agonists , whereas the octahydrobenzo [ g ] quinoline derivatives are much less potent or inactive . In general , the affinities of the compounds correlate well with their agonist potencies . The set of compounds under study is accommodated by a novel computer - graphics - derived model for P08908 - receptor agonism . The model consists of a flexible pharmacophore and a partial receptor - excluded volume .", "Rapid desensitization of serotonin P28335 receptor - stimulated intracellular calcium mobilization in CHO cells transfected with cloned human P28335 receptors . Serotonin P28335 receptor - mediated intracellular Ca2 + mobilization was investigated in Chinese hamster ovary ( CHO ) cells transfected with P28335 receptors . Fura - 2 acetoxymethyl ester was used to investigate the regulation of P28335 receptor function . CHO cells , transfected with a cDNA clone for the P28335 receptor , expressed 287 fmol / mg of the receptor protein as determined by mianserin - sensitive [ 3H ] mesulergine binding ( KD = 0 . 49 nM ) . The addition of 5 - HT mobilized intracellular Ca2 + in a dose - dependent fashion , ranging from a basal level of 99 +/- 1 . 8 up to 379 +/- 18 nM , with an EC50 value for 5 - HT of 0 . 029 microM . Exposure to 5 - HT , 1 -( 3 - chlorophenyl ) piperazine dihydrochloride ( a P28335 agonist ) , and 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane ( a P28335 and 5 - Q13049 agonist ) resulted in increased intracellular Ca2 + levels . DB06148 , mesulergine , ritanserin , and ketanserin each blocked 5 - HT - mediated intracellular Ca2 + mobilization more effectively than spiperone . The receptor was rapidly desensitized by preexposure to 5 - HT in a time - and concentration - dependent manner . Mezerein and phorbol 12 - myristate 13 - acetate , protein kinase C activators , weakly inhibited the intracellular Ca2 + mobilization induced by 10 microM 5 - HT . Furthermore , the protein kinase C inhibitor H - 7 partially prevented the protein kinase C activator - induced inhibition of the 5 - HT - mediated increase in intracellular Ca2 + concentration . The desensitization induced by pretreatment with 5 - HT was blocked by W - 7 , added in conjunction with 5 - HT , and partially inhibited by W - 5 , a nonselective inhibitor of protein kinases and weak analogue of W - 7 . ( ABSTRACT TRUNCATED AT 250 WORDS )", "DB06148 - induced down - regulation of human 5 - hydroxytryptamine2A and 5 - hydroxytryptamine2C receptors stably expressed in the human neuroblastoma cell line SH - SY5Y . We have assessed the ability of the serotonergic antagonist mianserin to modulate the number and functional activity of human 5 - hydroxytryptamine2A ( 5 - Q13049 ) and P28335 receptors stably expressed in the human neuroblastoma cell line SH - SY5Y . Incubation of cells expressing the 5 - Q13049 receptor with mianserin ( 100 nM ) for 24 h caused a significant decrease ( 48 % ) in the binding capacity of [ 3H ] ketanserin . This receptor down - regulation was associated with a corresponding decrease in the maximal production of inositol phosphates induced by 5 - HT but not by carbachol . Exposure of cells expressing the P28335 receptor to mianserin ( 100 nM ) for 72 h but not for 24 h similarly resulted in a significant reduction ( 44 % ) in [ 3H ] mesulergine binding . Corresponding analysis of inositol phosphate production by 5 - HT at the P28335 receptor after incubation with mianserin showed no change in maximal response after 24 h . No change in the binding capacity of either radioligand was seen after incubation with mianserin for 1 h . A decrease in the binding affinity of both radioligands was also observed after mianserin treatment , but this decrease was similar after 1 h of incubation to that seen after 24 or 72 h , and was probably due to the retention of mianserin within the tissue . We conclude that antagonist down - regulation is evident at human 5 - Q13049 and P28335 receptors stably expressed in a human neuroblastoma cell line and is probably mediated by a direct action of mianserin at the receptor .", "Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development ." ]

[ "___MASK100___", "___MASK11___", "___MASK32___", "___MASK42___", "___MASK46___", "___MASK51___", "___MASK72___", "___MASK75___", "___MASK86___" ]

[ "TSII toxin isolated from Tityus serrulatus scorpion venom : behavioral , electroencephalographic , and histopathologic studies . We have reported earlier that intrahippocampal administration of the C - pool from Tityus serrulatus scorpion venom induces convulsions in rats . Here we report the effects of seven toxins isolated from the C - pool . The strongest effects were seen after toxin 5C , which was sequenced and identified as TSII , a beta - type toxin that affects Na + channel activation . Unilateral injection of TSII in the rat hippocampus ( 1 . 7 microg / microl ) induced clusters of spikes and epileptic discharges of mainly moderate intensity , convulsion - related behavioral changes ( wet dog shakes , staring , masticatory jaw movements , facial automatisms , orofacial movements , intense sniffing , blinking , and forelimb clonus with rearing and falling ) and a massive neuronal loss of pyramidal cells in the ipsilateral P00915 , P07451 , and P22748 subfields and of granulate cells of the ipsilateral dentate gyrus . Toxins P01024 , C4 , and P13671 induced weaker changes in the EEG and behavioral changes and failed to induce cell death , and toxins C1 , P06681 , and P10643 had no effects . The similarities in the effects of TsTx , a alpha - type toxin that affects Na + channel , suggest that the loss of modulation of activation of the sodium channel caused by TSII increases glutamate release , leading to long - lasting increases in intracellular Ca2 + and cell death .", "Neurotoxicant - induced elevation of adrenomedullin expression in hippocampus and glia cultures . Adrenomedullin ( AM ) , a vasoactive peptide first isolated from pheochromocytoma , has been reported to be present in neurons in the central nervous system and in tumors of neural and glial origin . In this study , we investigated AM expression both in the hippocampus and in glial cell cultures using a chemical - induced model of injury . An acute intraperitoneal injection of the organometal trimethyltin ( Q9NRR2 ) results in neurodegeneration of the hippocampal P07451 - 4 pyramidal cell layer . Within 4 days of injection , sparse , punctate staining for AM and lectin was evident in the P07451 - 4 region ; by 10 days , a minimal level of P07451 - 4 neuronal degeneration was evident , with an increase in glial fibrillary acidic protein ( P14136 ) - positive astrocytes throughout the hippocampus . Degeneration progressed in severity until 30 days post - Q9NRR2 , with distinct positive immunoreactivity for AM in the P22748 region . mRNA levels for tumor necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 1alpha , P14136 , and AM in the hippocampus were increased over control levels within 4 days following Q9NRR2 . In cultured glial cells , a 6 hr exposure to Q9NRR2 ( 10 microM ) produced a morphological response of the cells and increased immunoreactivity for vimentin , P14136 , and AM . mRNA levels for TNFalpha , IL - 1alpha , P14136 , vimentin , and AM were elevated within 3 - 6 hr of exposure . In culture , neutralizing antibodies to IL - 1alpha and TNFalpha were effective in inhibiting the Q9NRR2 - induced elevation of AM mRNA . These data suggest an interaction between the proinflammatory cytokines and glia response in the regulation of AM in response to injury .", "Autoradiographic analyses of the effects of restraint - induced stress on P08908 , P28335 and 5 - HT2 receptors in the dorsal hippocampus of male and female rats . Quantitative autoradiography was used to evaluate the effects of sex and either 1 or 5 daily 2 - hour sessions of restraint stress on binding at P08908 , P28335 and 5 - HT2 receptors in the rat dorsal hippocampus . Neither sex nor restraint stress were found to have effects on binding at P28335 or 5 - HT2 receptors . However , restraint stress increased binding of [ 3H ] 8 - hydroxy - 2 -( di - n - propylamino ) tetralin at P08908 receptors in the P22748 region and in the infrapyramidal dentate gyrus . In addition , levels of binding at P08908 receptors in the oriens and lacunosum moleculare layers of the P00915 region were significantly higher in female rats . Neither estradiol benzoate nor estradiol benzoate plus progesterone had effects on binding at hippocampal P08908 receptors in ovariectomized rats , making it unlikely that the sex differences were related to stages of the estrous cycle . Stress - induced levels of corticosterone ( O00230 ) were higher in females . Although O00230 levels in blood obtained during restraint decreased from session 1 to session 5 in both male and female rats , the decrease became significant in females only . Female rats also displayed higher levels of activity in the open field . Although activity in the open field was reduced in male and female rats after restraint , these decreases were not significant . Results are discussed in relation to anxiety and depression .", "Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK70___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .", "Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK36___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .", "P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK24___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK24___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .", "[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK25___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .", "P22748 is expressed on P05113 - activated murine eosinophils . Eosinophilia and its cellular activation are hallmark features of asthma , as well as other allergic / Th2 disorders , yet there are few , if any , reliable surface markers of eosinophil activation . We have used a FACS - based genome - wide screening system to identify transcriptional alterations in murine lung eosinophils recruited and activated by pulmonary allergen exposure . Using a relatively stringent screen with false - positive correction , we identified 82 candidate genes that could serve as eosinophil activation markers and / or pathogenic effector markers in asthma . P22748 ( Car4 ) was a top dysregulated gene with 36 - fold induction in allergen - elicited pulmonary eosinophils , which was validated by quantitative PCR , immunohistochemistry , and flow cytometry . Eosinophil CAR4 expression was kinetically regulated by P05113 , but not P35225 . P05113 was both necessary and sufficient for induction of eosinophil CAR4 . Although CAR4 - deficient mice did not have a defect in eosinophil recruitment to the lung , nor a change in eosinophil pH - buffering capacity , allergen - challenged chimeric mice that contained Car4 (-/-) hematopoietic cells aberrantly expressed a series of genes enriched in biological processes involved in epithelial differentiation , keratinization , and anion exchange . In conclusion , we have determined that eosinophils express CAR4 following P05113 or allergen exposure , and that CAR4 is involved in regulating the lung transcriptome associated with allergic airway inflammation ; therefore , CAR4 has potential value for diagnosing and monitoring eosinophilic responses .", "The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK97___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK97___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK97___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK97___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .", "PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells . Dendritic cells ( DCs ) expressing CD1d , a molecule responsible for lipid antigen presentation , are capable of enhancing natural killer T ( iNKT ) cell proliferation . The signals controlling CD1 expression and lipid antigen presentation are poorly defined . We have shown previously that stimulation of the lipid - activated transcription factor , peroxisome proliferator - activated receptor ( Q07869 ) gamma , indirectly regulates CD1d expression . Here we demonstrate that PPARgamma , turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 ( O94788 ) . PPARgamma - regulated expression of these enzymes leads to an increase in the intracellular generation of all - trans retinoic acid ( ___MASK15___ ) from retinol . ___MASK15___ regulates gene expression via the activation of the retinoic acid receptor ( RAR ) alpha in human DCs , and RARalpha acutely regulates CD1d expression . The retinoic acid - induced elevated expression of CD1d is coupled to enhanced iNKT cell activation . Furthermore , in vivo relevant lipids such as oxidized low - density lipoprotein can also elicit retinoid signaling leading to CD1d up - regulation . These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma - controlled transcriptional events in DCs . The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression .", "Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK44___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK44___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .", "___MASK8___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK8___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .", "Long - lasting decreases of type II calmodulin kinase expression in kindled rat brains . The kindling model of epilepsy is associated with long - lasting changes in type II calmodulin kinase ( P62158 kinase ) activity and immunoreactivity . In order to determine the mechanism of these alterations , we measured gene expression of P62158 kinase using in situ hybridization in septally kindled rat brains and paired controls using a 35S - labeled riboprobe for the beta subunit of the enzyme . We found P62158 kinase mRNA concentrated in the hippocampus and other limbic structures . Kindling decreased hippocampal P62158 kinase mRNA by 30 % in P00915 , 34 % in P00918 , 35 % in P07451 41 % in P22748 , and 29 % in the dentate gyrus . Hybridization was also decreased by 21 % in the cerebral cortex but not in the lateral septum . These changes are similar in distribution and direction to those previously measured by immunohistochemistry . These data suggest that altered P62158 kinase activity and immunoreactivity associated with kindling reflect long - lasting alterations in gene expression of this important synaptic protein , and provide further evidence for its possible importance in the kindling phenomenon .", "Localization of the peroxisome proliferator - activated receptor in the brain . This paper describes the localization of the alpha - type peroxisome proliferator - activated receptor ( Q07869 alpha ) in the rat brain using immunocytochemistry and in situ hybridization . Expression of Q07869 alpha mRNA was highest in the granular cells of the cerebellar cortex and in the dentate gyrus , with a somewhat lower expression in areas P00915 - P22748 of the hippocampus . Q07869 alpha mRNA was also found in some neurones of the cerebral cortex ( layers II - IV ) and the molecular layer of the cerebellar cortex , and in the olfactory tubercle . Immunocytochemistry revealed nuclear Q07869 alpha - immunoreactivity ( - IR ) in the same areas as seen with the in situ hybridization . Furthermore , Q07869 alpha - IR was also localized in oligodendrocytes , whereas the other glial cell types appeared to lack Q07869 alpha . These results suggest that peroxisome proliferators and chemicals acting similarly have effects on discrete populations of neurones . The presence of Q07869 alpha in oligodendrocytes lends further support to the suggestion that peroxisomes are important in the assembly and degradation of myelin .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK6___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .", "Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide : molecular basis of isozyme - drug discrimination . P22748 ( CAIV ) is a membrane - associated enzyme anchored to plasma membrane surfaces by a phosphatidylinositol glycan linkage . We have determined the 2 . 8 - angstroms resolution crystal structure of a truncated , soluble form of recombinant murine CAIV . We have also determined the structure of its complex with a drug used for glaucoma therapy , the sulfonamide inhibitor brinzolamide ( DB01194 ) . The overall structure of murine CAIV is generally similar to that of human CAIV ; however , some local structural differences are found in the active site resulting from amino acid sequence differences in the \" 130 ' s segment \" and the residue - 63 loop ( these may affect the nearby catalytic proton shuttle , DB00117 - 64 ) . Similar to human CAIV , the C - terminus of murine CAIV is surrounded by a substantial electropositive surface potential that may stabilize the interaction with the phospholipid membrane . Binding interactions observed for brinzolamide rationalize the generally weaker affinity of inhibitors used in glaucoma therapy toward CAIV compared with CAII .", "Localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain . The cytokine interleukin 6 ( P05231 ) has several effects on the central nervous system in addition to the well established regulation of the acute phase inflammatory response . Therefore , the distribution of P05231 - and P05231 receptor mRNA in the rat brain has been investigated by in situ hybridization using [ 35S ] - labeled oligonucleotides . The messages of both genes were found in the P00915 - P22748 regions as well as in the dentate gyrus of the hippocampus , in the habenulae , the dorsomedial and the ventromedial hypothalamus , in the internal capsule , the optic tract and in the piriform cortex . These data indicate both neuronal and glial localization of P05231 and P05231 receptor and their involvement in an autocrine or paracrine action of the cytokine in centrally regulated functions including neuroendocrine control ." ]

[ "___MASK15___", "___MASK24___", "___MASK25___", "___MASK36___", "___MASK44___", "___MASK6___", "___MASK70___", "___MASK8___", "___MASK97___" ]

[ "Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . ___MASK16___ non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .", "Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .", "P00797 - angiotensin system revisited . New components and functions of the renin - angiotensin system ( DB01367 ) are still being unravelled . The classical DB01367 as it looked in the middle 1970s consisted of circulating renin , acting on angiotensinogen to produce angiotensin I , which in turn was converted into angiotensin II ( Ang II ) by angiotensin - converting enzyme ( P12821 ) . Ang II , still considered the main effector of DB01367 was believed to act only as a circulating hormone via angiotensin receptors , AT1 and P50052 . Since then , an expanded view of DB01367 has gradually emerged . Local tissue DB01367 systems have been identified in most organs . Recently , evidence for an intracellular DB01367 has been reported . The new expanded view of DB01367 therefore covers both endocrine , paracrine and intracrine functions . Other peptides of DB01367 have been shown to have biological actions ; angiotensin 2 - 8 heptapeptide ( Ang III ) has actions similar to those of Ang II . Further , the angiotensin 3 - 8 hexapeptide ( Ang IV ) exerts its actions via insulin - regulated amino peptidase receptors . Finally , angiotensin 1 - 7 ( Ang 1 - 7 ) acts via mas receptors . The discovery of another Q9BYF1 was an important complement to this picture . The recent discovery of renin receptors has made our view of DB01367 unexpectedly complex and multilayered . The importance of DB01367 in cardiovascular disease has been demonstrated by the clinical benefits of P12821 inhibitors and AT1 receptor blockers . Great expectations are now generated by the introduction of renin inhibitors . Indeed , DB01367 regulates much more and diverse physiological functions than previously believed .", "Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK59___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .", "[ Association study of renin - angiotensin system genes and hemostasis system genes with ischemic stroke among Russians of Central Russia ] . The analysis of alleles and genotypes frequencies of 14 SNP in genes of rennin - angiotensin system ( REN , AGT , P30556 , P50052 , P30411 , P07550 ) and hemostasis system ( P02675 , F2 , P12259 , P08709 , P05106 , P05121 , P42898 ) , as well as P12821 insertion - deletion polymorphism in patients with stroke comparing to healthy controls matched by age , sex and ethnicity has been carried out . The genotyping procedure included the amplification of selected gene sequences following by hybridization of fluorescently labeled fragments with SNP - specific DNA probes . The analysis of allele frequencies of each gene separately revealed no statistically significant differences between groups of patients with stroke and healthy donors . Also the complex study has been performed to estimate the contribution of rennin - angiotensin system and hemostasis system genes to the genetic susceptibility to ischemic stroke among Russians from Central Russia using method MDR ( Multifactor Dimensionality Reduction ) . The combination with increased risk for development of ischemic stroke was presented by complex genotype P02675 G /- x P12821 I /- x P42898 C /- x P05121 5G / 5G ( p = 0 . 03 , OR = 2 . 4 , 95 % CI 1 . 1 - 5 . 3 ) , which frequency was statistically significant higher in patients with stroke compared to healthy control .", "[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .", "P10275 - mediated repression of novel target genes . BACKGROUND : The androgen receptor ( AR ) plays a pivotal role in prostate cancer ( PCa ) initiation and progression . To date , studies have focused disproportionately on androgen - stimulated genes such as prostate - specific antigen ( PSA ) , while repressed genes have gained little attention , even though they too may be involved in regulating cell growth , differentiation , and apoptosis . METHODS : ChIP Display was used to identify putative AR target genes in the ablation - resistant human PCa cell line , C4 - 2B . Quantitative real - time reverse transcription - PCR analysis was used to measure gene expression in cells subjected to dihydrotestosterone ( ___MASK73___ ) timecourse and dose - response , as well as AR knock - down and bicalutamide - treatments . RESULTS : We report on three genes , Q5T5P2 , P11229 , and Q6UE05 , which were newly identified in a screen for AR - occupied regions in C4 - 2B PCa cells , and which were repressed by treatment with ___MASK73___ . AR knock - down resulted in increased Q5T5P2 , P11229 , and Q6UE05 mRNA , indicating that , like PSA stimulation , AR represses these three genes even in the absence of added ligand . ___MASK73___ decreased Q5T5P2 and P11229 pre - mRNA levels , suggesting AR - mediated transcriptional inhibition . Cycloheximide attenuated ___MASK73___ - mediated repression of P11229 , suggesting the requirement of new protein synthesis . Furthermore , bicalutamide treatment did not mimic , but rather antagonized ___MASK73___ - mediated Q5T5P2 repression . Unlike the handful of androgen - repressed genes studied thus far , AR occupancy at Q5T5P2 , P11229 , and Q6UE05 was mapped outside their respective 5 '- promoter regions . CONCLUSIONS : Many more genes likely share AR - mediated gene repression through distal regulatory elements . Further study of such targets and their transcriptional regulation may help explain the receptor ' s tumorigenicity in PCa .", "Polymorphisms of the beta2 adrenoreceptor gene in chronic obstructive pulmonary disease . BACKGROUND : The beta2 - adrenergic receptors are cell surface receptors playing a central role in the pharmacological targeting asthma and chronic obstructive pulmonary disease [ P48444 ] . Recent studies suggest that patients who are homozygous for one of the two important polymorphisms of the beta2 - adrenergic receptor [ P07550 ] gene at codon 16 ( arginine to glycine ) and 27 ( glutamine to glutamate ) may have a reduced response to ss2 - agonists . Since smoking patients who are Gly16 homozygotes have an increased risk of airway obstruction we hypothesized that beta2 - adrenoreceptor gene polymorphisms may be also a cofounder for P48444 development and disease severity . METHODS : We investigated 190 P48444 patients and 172 healthy volunteers in a case - control study . DNA was isolated from whole blood and beta2 - AR gene polymorphisms DB00125 / Gly16 and Gln / Glu27 were determined using allele - specific polymerase chain reaction [ PCR ] . RESULTS : In P48444 patients with DB00145 / Gly16 was found more frequently than in healthy smokers [ 29 . 47 % P48444 versus 18 . 18 % controls , p = 0 . 026 ] . All other gene polymorphisms of the P07550 gene at codon 16 were equally distributed between groups . ss2 - adrenoreceptor gene polymorphisms were neither a cofounder for P48444 exacerbations [ > or = 3 hospitalizations within the last 3 years ] nor for disease severity [ FEV1 < or = 30 % predicted ] . CONCLUSION : Our study suggests that the Gly16 allele of the beta2 - AR gene predisposes to P48444 development but not for exacerbation rates and disease severity . In contrast , Gln / Glu27 polymorphism was irrelevant in our P48444 cohort .", "P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK40___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK28___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders . There is a hypothesis that autoimmune abnormalities in neurotransmitter receptors might cause some psychiatric disorders . Using a sensitive radioligand assay , we detected serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 ( P11229 , 34 . 4 % ) , mu - opioid receptor ( P35372 , 13 . 1 % ) , P08908 ( P08908 , 7 . 4 % ) , and dopamine receptor D2 ( P14416 , 4 . 9 % ) in 122 psychiatric patients . Positive antibodies to P11229 were found in 34 . 1 % , 34 . 9 % , 33 . 3 % , and 9 . 1 % of patients with schizophrenic disorders ( n = 44 ) , mood disorders ( n = 63 ) , other psychiatric disorders ( n = 15 ) and autoimmune diseases ( n = 33 ) , respectively . All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to P11229 , P35372 , and / or P08908 . Our data suggest that autoimmunity to neurotransmitter receptors might be associated with the induction of psychiatric symptoms and have some relation to neuroleptic malignant syndrome .", "Genetics of idiopathic disseminated bronchiectasis . Bronchiectasis is an abnormal dilation of bronchi , consequent to the destruction of their walls . It is included in the category of obstructive pulmonary diseases , along with chronic obstructive pulmonary disease ( P48444 ) , asthma , and cystic fibrosis . In approximately 50 % of cases , bronchiectasis is associated with underlying conditions ; in the remainder , known causes are not ascertainable ( idiopathic bronchiectasis ) . A search for genetic determinants of this phenotype , with the cystic fibrosis gene as a candidate , has been performed by three independent groups . The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms . The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis . A few other genes have been investigated in idiopathic bronchiectasis , with negative results . Idiopathic bronchiectasis is , therefore , to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases ( or P13569 - opathies ) , whose pathogenesis is influenced by environmental factors and other undetermined genes .", "Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . ___MASK16___ is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK66___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .", "Beta2 - adrenergic receptor signaling in P01730 + Foxp3 + regulatory T cells enhances their suppressive function in a PKA - dependent manner . Beta2 - adrenergic receptor ( P07550 ) signaling is known to impair Th1 - cell differentiation and function in a DB02527 - dependent way , leading to inhibition of cell proliferation and decreased production of P60568 and IFN - γ . P01730 (+) Foxp3 (+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self - tolerance . Nevertheless , very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function . Here we show that Foxp3 (+) Treg cells express functional P07550 . P07550 activation in Treg cells leads to increased intracellular DB02527 levels and to protein kinase A ( PKA ) - dependent CREB phosphorylation . We also found that signaling via P07550 enhances the in vitro suppressive activity of Treg cells . P07550 - mediated increase in Treg - cell suppressive function was associated with decreased P60568 mRNA levels in responder P01730 (+) T cells and improved Treg - cell - induced conversion of P01730 (+) Foxp3 (-) cells into Foxp3 (+) induced Treg cells . Moreover , P07550 signaling increased P16410 expression in Treg cells in a PKA - dependent way . Finally , we found that PKA inhibition totally prevented the P07550 - mediated increase in Treg - cell suppressive function . Our data suggest that sympathetic fibers are able to regulate Treg - cell suppressive activity in a positive manner through P07550 signaling .", "The neuroendocrine impact of chronic stress on cancer . Behavioral processes have long been suspected to influence many health processes including effects on cancer . However , mechanisms underlying these observations are not fully understood . Recent work has demonstrated that chronic behavioral stress results in higher levels of tissue catecholamines , greater tumor burden , and a more invasive pattern of ovarian cancer growth in an orthotopic mouse model . These effects are mediated primarily through the beta ( 2 ) adrenergic receptor ( P07550 ) activation of the tumor cell cyclic AMP ( DB02527 ) - protein kinase A ( PKA ) signaling pathway . Additionally , tumors in stressed animals have increased vascularization and enhanced expression of vascular endothelial growth factor ( P15692 ) and matrix metalloproteinases ( MMPs ) - 2 and - 9 . In this review , we highlight the importance of the neuroendocrine stress response in tumor biology and discuss mechanisms by which the beta - adrenergic receptors on ovarian cancer cells enhance angiogenesis and tumor growth .", "Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK2___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .", "Additive role of tiotropium in severe asthmatics and Arg16Gly in P07550 as a potential marker to predict response . BACKGROUND : Recent findings have raised new interests about the use of anticholinergics , especially tiotropium , for the treatment of asthma . This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics , and to identify factors capable of predicting the response to tiotropium , using a pharmacogenetic approach . METHODS : A total of 138 severe asthmatics on conventional medications and with decreased lung function were randomly recruited . DB01409 18 microg was added once a day and lung functions were measured every 4 weeks . Responders were defined as those with an improvement of > or = 15 % ( or 200 ml ) in the forced expiratory volume in 1 s ( FEV1 ) that was maintained for at least 8 successive weeks . Eleven single nucleotide polymorphisms ( SNPs ) in P11229 - 3 ( coding muscarinic receptors one to three ) which were identified by re - sequencing , and Arg16Gly and Gln27Glu in P07550 ( coding beta ( 2 ) adrenoreceptor ) were scored in 80 of the 138 asthmatics . RESULTS : Forty - six of the 138 asthmatics ( 33 . 3 % ) responded to tiotropium treatment . Logistic regression analyses ( controlled for age , gender , and smoking status ) showed that Arg16Gly in P07550 [ P = 0 . 003 , OR ( 95 % CI ) = 0 . 21 ( 0 . 07 - 0 . 59 ) in a minor allele - dominant model ] was significantly associated with response to tiotropium . CONCLUSIONS : As many as 30 % of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium . The presence of Arg16Gly in P07550 may predict response to tiotropium .", "___MASK78___ : An orally active renin inhibitor . P00797 inhibitors are antihypertensive drugs that block the first step in the renin - angiotensin system . Their mechanism of action differs from that of the angiotensin - converting enzyme inhibitors and angiotensin - receptor antagonists , but like these drugs , renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion . The renin - angiotensin - aldosterone system ( RAAS ) has long been recognized to play a significant role in hypertension pathophysiology . Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes . Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug . ___MASK78___ is the first of a new class of antihypertensive agents . ___MASK78___ is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once - daily oral dosing . In short - term studies , it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide , and had a low incidence of serious adverse effects . It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives . Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin - receptor blocker . The most common adverse effects reported in clinical trials were headache , fatigue , dizziness , diarrhea , and nasopharyngitis . ___MASK78___ has not been studied in patients with moderate renal dysfunction ; as an RAAS - acting drug , it should be prescribed for such patients only with caution .", "DB09280 - ___MASK52___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 ." ]

[ "___MASK16___", "___MASK28___", "___MASK2___", "___MASK40___", "___MASK52___", "___MASK59___", "___MASK66___", "___MASK73___", "___MASK78___" ]

[ "Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK68___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK68___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK68___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK68___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK68___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .", "Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK90___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .", "P04150 and histone deacetylase - 2 mediate dexamethasone - induced repression of P98088 gene expression . Airway occlusion in obstructive airway diseases is caused in part by the overproduction of secretory mucin glycoproteins through the up - regulation of mucin ( MUC ) genes by inflammatory mediators . Some pharmacological agents , including the glucocorticoid dexamethasone ( DB00514 ) , repress mucin concentrations in lung epithelial cancer cells . Here , we show that DB00514 reduces the expression of P98088 , a major airway mucin gene , in primary differentiated normal human bronchial epithelial ( NHBE ) cells in a dose - dependent and time - dependent manner , and that the DB00514 - induced repression is mediated by the glucocorticoid receptor ( GR ) and two glucocorticoid response elements ( GREs ) in the P98088 promoter . The pre - exposure of cells to ___MASK49___ , a GR antagonist , and mutations in either the GRE3 or GRE5 cis - sites abolished the DB00514 - induced repression . Chromatin immunoprecipitation ( ChIP ) assays showed a rapid temporal recruitment of GR to the GRE3 and GRE5 cis - elements in the P98088 promoter in NHBE and in A549 cells . Immunofluorescence showed nuclear colocalization of GR and histone deacetylase - 2 ( Q92769 ) in P98088 - expressing NHBE cells . ChIP also showed a rapid temporal recruitment of Q92769 to the GRE3 and GRE5 cis - elements in the P98088 promoter in both cell types . The knockdown of Q92769 by Q92769 - specific short interfering RNA prevented the DB00514 - induced repression of P98088 in NHBE and A549 cells . These data demonstrate that GR and Q92769 are recruited to the GRE3 and GRE5 cis - sites in the P98088 promoter and mediate the DB00514 - induced cis repression of P98088 gene expression . A better understanding of the mechanisms whereby glucocorticoids repress P98088 gene expression may be useful in formulating therapeutic interventions in chronic lung diseases .", "Molecular - based choice of cancer therapy : realities and expectations . Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success . Molecular research provides some opportunities to personalize antitumor treatment . For example , life - threatening toxic reactions can be avoided by the identification of subjects , who carry susceptible genotypes of drug - metabolizing genes ( e . g . P51580 , P22309 , P42898 , Q12882 ) . Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response . Tailoring of antiestrogen and trastuzumab therapy based on hormone and P04626 receptor status has already become a classical example of customized medicine . Other predictive markers have been identified both for cytotoxic and for targeted therapies , and include , for example , expression of TS , TP , Q12882 , OPRT , P07992 , P16455 , P11388 , class III beta - tubulin molecules as well as genomic alterations of P00533 , P10721 , P00519 oncogenes .", "___MASK15___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK15___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .", "Genetic variants associated with the risk of chronic obstructive pulmonary disease with and without lung cancer . Chronic obstructive pulmonary disease ( P48444 ) is a strong risk factor for lung cancer . Published studies about variations of genes encoding glutathione metabolism , DNA repair , and inflammatory response pathways in susceptibility to P48444 were inconclusive . We evaluated 470 single - nucleotide polymorphisms ( SNP ) from 56 genes of these three pathways in 620 cases and 893 controls to identify susceptibility markers for P48444 risk , using existing resources . We assessed SNP - and gene - level effects adjusting for sex , age , and smoking status . Differential genetic effects on disease risk with and without lung cancer were also assessed ; cumulative risk models were established . Twenty - one SNPs were found to be significantly associated with risk of P48444 ( P < 0 . 01 ) ; gene - based analyses confirmed two genes ( P48506 and P48637 ) and identified three additional genes ( Q9H4Y5 , P07992 , and P23921 ) . Carrying 12 high - risk alleles may increase risk by 2 . 7 - fold ; eight SNPs altered P48444 risk without lung cancer by 3 . 1 - fold and 4 SNPs altered the risk with lung cancer by 2 . 3 - fold . Our findings indicate that multiple genetic variations in the three selected pathways contribute to P48444 risk through P48506 , P48637 , Q9H4Y5 , P07992 , and P23921 genes . Functional studies are needed to elucidate the mechanisms of these genes in the development of P48444 , lung cancer , or both .", "Double - strand breaks induce homologous recombinational repair of interstrand cross - links via cooperation of P43246 , P07992 - Q92889 , O60673 , and the Fanconi anemia pathway . DNA interstrand cross - linking agents have been widely used in chemotherapeutic treatment of cancer . The majority of interstrand cross - links ( ICLs ) in mammalian cells are removed via a complex process that involves the formation of double - strand breaks at replication forks , incision of the ICL , and subsequent error - free repair by homologous recombination . How double - strand breaks effect the removal of ICLs and the downstream homologous recombination process is not clear . Here , we describe a plasmid - based recombination assay in which one copy of the P27918 gene is inactivated by a site - specific psoralen ICL and can be repaired by gene conversion with a mutated homologous donor sequence . We found that the homology - dependent recombination ( HDR ) is inhibited by the ICL . However , when we introduced a double - strand break adjacent to the site of the ICL , the removal of the ICL was enhanced and the substrate was funneled into a HDR repair pathway . This process was not dependent on the nucleotide excision repair pathway , but did require the P07992 - Q92889 endonuclease and O60673 . In addition , both the Fanconi anemia pathway and the mismatch repair protein P43246 were required for the recombinational repair processing of the ICL . These results suggest that the juxtaposition of an ICL and a DSB stimulates repair of ICLs through a process requiring components of mismatch repair , P07992 - Q92889 , O60673 , Fanconi anemia proteins , and homologous recombination repair factors .", "Structure of the C - terminal half of human P19447 helicase and the impact of the disease - causing mutation XP11BE . P19447 is a DNA - dependent helicase and a subunit of the TFIIH complex required for both transcription and DNA repair . P19447 contains four domains : an N - terminal domain , two conserved helicase domains ( HD1 and Q92769 ) and a C - terminal extension . The C - terminal extension is important for DNA repair since the phosphorylation of Ser751 inhibits 5 '- incision by P07992 - Q92889 endonuclease . A disease - causing frameshift mutation ( XP11BE ) that changes the last 42 amino acids of P19447 causes manifestations including impaired DNA repair and deficient transcription . Here , the crystal structure of the C - terminal half of P19447 ( residues 494 - 782 ) is reported at 1 . 8 Å resolution . The structure contained the conserved P19447 Q92769 and a C - terminal extension which shares structural similarity with O95786 , leading to a structural model of the Q92889 - P19447 - DNA complex for 5 ' incision during DNA repair . A mutation mimicking the XP11BE mutation produced the much less soluble mutant XPBm ( 494 - 781 ) . Western blotting results confirmed that the intracellular levels of P19447 and other TFIIH subunits in XP11BE patient cells were much lower than those from the healthy parents . Together , these results indicate that the XP11BE mutation not only divests the Q92889 - interaction motif , impairing DNA repair , but also reduces P19447 solubility , leading to a lower intracellular level of TFIIH and deficient transcription .", "___MASK3___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK3___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .", "FLEX data , P01116 and P07992 testing in oncology .", "Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .", "Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK77___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .", "Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance .", "Effects of lurasidone on executive function in common marmosets . Cognitive impairment is one of the major symptoms of schizophrenia , and is considered largely due to dysfunctions in the prefrontal cortex ( P27918 ) . ___MASK55___ , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 , 5 - Q13049 and P08908 receptors has been reported to have superior efficacy in rodents ' models of cognitive impairment . However , the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non - human primates . In this study , we investigated the effect of lurasidone on executive function , which is one of the cognitive domains , in common marmosets and compared the results to those of other antipsychotics . The effects of lurasidone , haloperidol , olanzapine , risperidone , quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours ( ORD ) task . Before drug treatment , marmosets ' success rates in the easy trial of the test were almost 90 % . However , maximum success in the difficult trial of the task reached only 50 % after 8 days of training . DB00502 , olanzapine and risperidone decreased correct performance even in the easy trial of the task . All drugs , except lurasidone , impaired success rate in the difficult trial . On the other hand , lurasidone dose - dependently increased marmosets ' success rates in the difficult trial with significant effect at 10mg / kg . In conclusion , we have shown in this study that lurasidone , unlike conventional antipsychotics , improves cognition associated with executive function in common marmosets . These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics .", "Characterization and analysis of Chinese hamster ovary cell P07992 mutant alleles . We isolated and characterized the P07992 coding sequence from three Chinese hamster ovary ( CHO ) parental ( CHO - AA8 , CHO - P01008 - 2 and CHO - 9 ) and 10 P07992 mutant cell lines . Two general classes of mutations were observed : two mutant cell lines exhibited nucleotide additions or deletions to produce frameshift mutations and seven mutant cell lines exhibited point mutations that resulted in transitions or transversions , including nonsense mutations and mutations that generated intron / exon splicing errors . One mutant ( UV201 ) which had been provisionally assigned to P07992 complementation group 1 ( CG1 ) had no detectable mutation in its coding sequence . Of the nine P07992 mutant alleles characterized two mutations were identified in the XpA binding region of the Ercc1 protein ; no mutations were found in the N - terminal portion of the Ercc1 protein . Results of Northern hybridization analysis showed that the relative levels of P07992 mRNA differed significantly both among the parental cell lines and among the mutant cell lines derived from each parental cell line . Western analysis with a CHO Ercc1 - specific antibody detected Ercc1 protein in each of the parental cell lines and also in UV201 . The marked reduction in Ercc1 protein levels observed in all the other mutants examined supports the hypothesis that P07992 mutations may destabilize this polypeptide .", "Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK24___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .", "Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK99___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .", "Phase II study of weekly intravenous oxaliplatin combined with oral daily capecitabine and radiotherapy with biologic correlates in neoadjuvant treatment of rectal adenocarcinoma . PURPOSE : To evaluate the efficacy of a combination of capecitabine , oxaliplatin , and radiotherapy ( RT ) in the neoadjuvant treatment of Stage II and III rectal cancers . METHODS : DB01101 was given at 725 mg / m ( 2 ) orally twice daily Monday through Friday concurrently with RT . DB00526 was given intravenously at 50 mg / m ( 2 ) once weekly five times starting the first day of RT . The radiation dose was 50 . 4 Gy in 28 fractions ( 1 . 8 Gy / fraction ) , five fractions weekly . Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase , thymidylate synthase , excision repair cross - complementing rodent repair deficiency complementation group 1 ( P07992 ) , and apoptosis . RESULTS : A total of 25 patients were enrolled in this study ; 6 patients ( 24 % ) had a complete pathologic response . T - downstaging occurred in 52 % of patients , and N - downstaging occurred in 53 % . Grade 3 diarrhea was the most common Grade 3 - 4 toxicity , occurring in 20 % of patients . Only 2 patients experienced disease recurrence , with a median of 20 months of follow - up . P04818 , thymidine phosphorylase , P07992 , and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies , nor did they predict for T - downstaging or a complete pathologic response . CONCLUSION : DB01101 at 725 mg / m ( 2 ) orally twice daily , oxaliplatin 50 mg / m ( 2 )/ wk , and RT at 50 . 4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls ." ]

[ "___MASK15___", "___MASK24___", "___MASK3___", "___MASK49___", "___MASK55___", "___MASK68___", "___MASK77___", "___MASK90___", "___MASK99___" ]

[ "A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK51___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .", "Impact of aromatic residues within transmembrane helix 6 of the human gonadotropin - releasing hormone receptor upon agonist and antagonist binding . To investigate the impact of aromatic residues within transmembrane helix 6 ( TMH6 ) of the human gonadotropin - releasing hormone receptor ( P30968 ) on agonist and antagonist binding , residues Y ( 283 ) , Y ( 284 ) , W ( 289 ) , Y ( 290 ) , W ( 291 ) , and F ( 292 ) were exchanged to alanine and analyzed comprehensively in functional reporter gene and ligand binding assays . Whereas receptor mutants Y ( 283 ) A , Y ( 284 ) A , and W ( 291 ) A were capable of neither ligand binding nor signal transduction , mutants W ( 289 ) A , Y ( 290 ) A , and F ( 292 ) A were functional : the F ( 292 ) A mutant behaved like wild - type receptor , while mutants W ( 289 ) A and Y ( 290 ) A differentiated between agonistic and antagonistic ligands . On the basis of the high - resolution X - ray structure of bovine rhodopsin as well as available data on P30968 mutants , models for ligand - receptor interactions are proposed . The model for D - DB00150 ( 6 )- DB00644 ( DB06825 ) binding , representing a superagonistic ligand , is in full accordance to available data . Furthermore , new interactions are proposed : pGlu ( 1 ) interacts with N ( 212 ) in transmembrane helix 5 , DB00135 ( 5 ) with Y ( 290 ) , and D - DB00150 ( 6 ) with W ( 289 ) . The binding behavior of mutants W ( 289 ) A and Y ( 290 ) A corresponds to the proposed binding model for the antagonist DB00050 . In summary , our data as presented indicate that Y ( 290 ) plays a key function in agonist but not antagonist binding .", "Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK91___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .", "Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK24___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .", "Characterization of the human gonadotropin - releasing hormone receptor heterologously produced using the baculovirus / insect cell and the Semliki Forest virus systems . 1 . Two eukaryotic viral systems , the baculovirus / insect cell and the Semliki Forest virus systems , were tested for heterologous expression of human gonadotropin - releasing hormone receptor ( GnRHR ) cDNA . 2 . An unmodified as well as a c - myc epitope - tagged human P30968 was produced in two insect cell lines ( Spodoptera frugiperda , Trichoplusia ni ) after infection with the respective recombinant baculoviruses . In both insect cell lines , the receptor was identified by immunoblot analysis as a triplet of bands between 35 and 40 kDa . After deglycosylation of the receptor the molecular mass decreased to 35 kDa . The P30968 was localized in membrane compartments within the infected insect cells . However , only in membranes of infected Trichoplusia ni insect cells could approximately 2000 receptors per cell be detected . 3 . Production of the P30968 in BHK cells using the Semliki Forest virus system resulted in approximately 50 , 000 receptors per cell . A maximal yield of 0 . 42 pmol / mg membrane protein was obtained 24 hr after electroporation of BHK cells with in vitro synthesized RNA . Binding of the antagonist [ 125I ] DB00050 was saturable with a KD of 1 . 3 nM . The receptor produced in the BHK cells was further characterized by ligand displacement studies . The rank order of agonist and antagonist affinities was DB00050 > DB06825 > Antide > DB00644 .", "Transcript and protein profiling identifies signaling , growth arrest , apoptosis , and NF - κB survival signatures following P01148 receptor activation . P01148 significantly inhibits proliferation of a proportion of cancer cell lines by activating P01148 receptor ( P30968 ) - G protein signaling . Therefore , manipulation of P30968 signaling may have an under - utilized role in treating certain breast and ovarian cancers . However , the precise signaling pathways necessary for the effect and the features of cellular responses remain poorly defined . We used transcriptomic and proteomic profiling approaches to characterize the effects of P30968 activation in sensitive cells ( HEK293 - P30968 , SCL60 ) in vitro and in vivo , compared to unresponsive HEK293 . Analyses of gene expression demonstrated a dynamic response to the P01148 superagonist DB06825 . Early and mid - phase changes ( 0 . 5 - 1 . 0 h ) comprised mainly transcription factors . Later changes ( 8 - 24 h ) included a P01148 target gene , P01215 , and up - or downregulation of transcripts encoding signaling and cell division machinery . Pathway analysis identified altered MAPK and cell cycle pathways , consistent with occurrence of G ( 2 )/ M arrest and apoptosis . Nuclear factor kappa B ( NF - κB ) pathway gene transcripts were differentially expressed between control and DB06825 - treated SCL60 cultures . Reverse - phase protein and phospho - proteomic array analyses profiled responses in cultured cells and SCL60 xenografts in vivo during DB06825 anti - proliferation . Increased phosphorylated NF - κB ( p65 ) occurred in SCL60 in vitro , and p - NF - κB and IκBε were higher in treated xenografts than controls after 4 days DB06825 . NF - κB inhibition enhanced the anti - proliferative effect of DB06825 in SCL60 cultures . This study reveals details of pathways interacting with intense P30968 signaling , identifies potential anti - proliferative target genes , and implicates the NF - κB survival pathway as a node for enhancing P01148 agonist - induced anti - proliferation .", "P30968 and peritoneal plasmin activity . Most surgical procedures performed by obstetrician - gynecologists are associated with pelvic adhesions that cause subsequent serious sequelae , including small bowel obstruction , infertility , chronic pelvic pain , and difficulty in postoperative treatment , including complexity during subsequent surgical procedures . This study was conducted to determine if gonadotropin - releasing hormone analogues ( GnRHa ) affect the expressing tissue - type plasminogen activator ( t - PA ) and its inhibitor - 1 ( P05121 ) in peritoneal cells in culture . Human peritoneal Met5A cells were used to examine the effects of GnRHa leuprolide , buserelin and goserelin on the levels of t - PA and PA - 1 . Antigen concentrations were measured in conditioned media and cell lysates by real - time PCR and ELISA . P30968 ( GnRHR ) mRNA was determined by RT - PCR . GnRHR mRNA was detected in Met5A cells . Exposure of Met5A cells to GnRHa induced a rapid decrease of P05121 level in cultured medium but not in cell lysate ( protein and mRNA ) . These effects of GnRHa on P05121 were not associated with any changes in t - PA level . These results suggest that GnRHa may be an effective stimulator of local peritoneal fibrinolytic activity , as it decreases P05121 secretion in peritoneal Met5A cells by a mechanism linked to GnRHR .", "[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK62___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .", "___MASK13___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK13___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .", "Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .", "Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .", "DB00644 induction of extracellular - signal regulated kinase is blocked by inhibition of calmodulin . Our previous studies demonstrate that DB00644 - induced P29323 activation required influx of extracellular Ca2 + in alphaT3 - 1 and rat pituitary cells . In the present studies , we examined the hypothesis that calmodulin ( Cam ) plays a fundamental role in mediating the effects of Ca2 + on P29323 activation . Cam inhibition using W7 was sufficient to block DB00644 - induced reporter gene activity for the c - Fos , murine glycoprotein hormone alpha - subunit , and MAPK phosphatase ( MKP ) - 2 promoters , all shown to require P29323 activation . Inhibition of Cam ( using a dominant negative ) was sufficient to block DB00644 - induced P29323 but not c - Jun N - terminal kinase activity activation . The Cam - dependent protein kinase ( CamK ) II inhibitor KN62 did not recapitulate these findings . DB00644 - induced phosphorylation of Q02750 and c - Raf kinase was blocked by Cam inhibition , whereas activity of phospholipase C was unaffected , suggesting that Ca2 +/ Cam modulation of the P29323 cascade potentially at the level of c - Raf kinase . Enrichment of Cam - interacting proteins using a Cam agarose column revealed that c - Raf kinase forms a complex with Cam . Reconstitution studies reveal that recombinant c - Raf kinase can associate directly with Cam in a Ca2 +- dependent manner and this interaction is reduced in vitro by addition of W7 . Cam was localized in lipid rafts consistent with the formation of a Ca2 +- sensitive signaling platform including the P30968 and c - Raf kinase . These data support the conclusion that Cam may have a critical role as a Ca2 + sensor in specifically linking Ca2 + flux with P29323 activation within the DB00644 signaling pathway .", "Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK16___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .", "Stimulation of luteinizing hormone secretion by N - methyl - D , L - aspartic acid in the adult male guinea - pig : incomplete blockade by gonadotropin - releasing hormone receptor antagonism . Stimulation of luteinizing hormone ( LH ) secretion by N - methyl - D , L - aspartic acid ( Q13145 ) , reported for several mammalian species , is generally accepted to be mediated through stimulation of hypothalamic gonadotropin - releasing hormone ( DB00644 ) release . In view of a previously reported unexpected inhibitory action of Q13145 on DB00644 release from hypothalamic explant of intact male guinea - pigs , the aim of the present study was to assess the in vivo effects of Q13145 in the adult male guinea - pig . In the gonadally intact male , Q13145 ( 5 mg / animal ) elicited a robust LH secretion , which was blocked by the N - methyl - D - asparte - receptor antagonist DL - 2 - amino - 5 - phosphonovaleric acid ( AP - 5 , 12 mg / animal ) . In the castrated male , Q13145 elicited only a marginal and inconsistent LH secretion . DB00050 ( DB00456 ) , a P30968 antagonist , administered intracardiacally 1 min or 45 min preceding bolus injection of Q13145 significantly reduced the LH response to Q13145 in the intact male . Surprisingly , following P30968 blockade with DB00456 , there still was a substantial residual serum LH response to Q13145 , while DB00456 completely abolished the serum LH response to high dose ( 1 microg or 10 microg ) guinea - pig DB00644 ( gpGnRH ) . These results indicate that Q13145 stimulates LH secretion in the gonadally intact male guinea - pig in vivo and that this effect is mediated in part through gpGnRH - independent mechanisms .", "A new compound heterozygous mutation of the gonadotropin - releasing hormone receptor ( L314X , Q106R ) in a woman with complete hypogonadotropic hypogonadism : chronic estrogen administration amplifies the gonadotropin defect . We describe a woman with complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the P30968 ( GnRHR ) gene . A null mutation L314X leading to a partial deletion of the seventh transmembrane domain of the GnRHR is associated with a Q106R mutation previously described . L314X mutant receptor shows neither measurable binding nor inositol phosphate production when transfected in CHO - P04264 cells compared to the wild - type receptor . The disease is transmitted as an autosomal recessive trait , as shown by pedigree analysis . Heterozygous patients with GnRHR mutations had normal pubertal development and fertility . The present study shows an absence of LH and DB00094 response to pulsatile DB00644 administration ( 20 microg / pulse , sc , every 90 min ) . However , DB00644 triggered free alpha - subunit ( FAS ) pulses of small amplitude , demonstrating partial resistance to pharmacological doses of DB00644 . DB00094 , LH , and FAS concentrations were evaluated under chronic estrogen treatment and repeat administration of DB00644 . Not only were plasma DB00094 , LH , and FAS concentrations decreased , but FAS responsiveness was reduced . This new case emphasizes the implication of the P30968 mutations in the etiology of idiopathic hypogonadotropic hypogonadism . We also have evidence for a direct negative estrogen effect on gonadotropin secretion at the pituitary level , dependent on the GnRHR signaling pathway .", "Effective treatment of experimental human endometrial cancers with targeted cytotoxic luteinizing hormone - releasing hormone analogues AN - 152 and AN - 207 . OBJECTIVE : To treat experimental human endometrial cancers based on targeted chemotherapy with the cytotoxic luteinizing hormone - releasing hormone ( P01148 ) analogues AN - 152 and AN - 207 . DESIGN : Experimental study using athymic nude mice bearing xenografts of O14777 - 1A and RL - 95 - 2 human endometrial cancers to assess the efficacy and toxicity of AN - 152 and AN - 207 . The expression of P01148 receptors in O14777 - 1A and RL - 95 - 2 cancers was determined by reverse transcription - polymerase chain reaction , Western blot analysis , and radioligand binding assays . SETTING : Experimental laboratory research . ANIMAL ( S ) : Female athymic nude mice ( Ncr , nu / nu ) . INTERVENTION ( S ) : Animals were treated with IV injections of the cytotoxic P01148 analogues AN - 152 and AN - 207 and their respective cytotoxic radicals doxorubicin ( DOX ) and AN - 201 ( 2 - pyrrolinodoxorubicin ) on a control vehicle solution . MAIN OUTCOME MEASURE ( S ) : Tumor volume , final tumor weight , tumor doubling time , body weight , white blood cell count , and P01148 receptor expression . RESULT ( S ) : AN - 152 significantly inhibited the growth of O14777 - 1A tumors . AN - 207 also significantly suppressed the proliferation in vivo of O14777 - 1A and RL - 95 - 2 cancers . The cytotoxic radicals DOX and AN - 201 had no effect . Furthermore , mRNA for P01148 receptors , P01148 receptor protein , and high - affinity binding sites for P01148 were demonstrated on tumors . CONCLUSION ( S ) : Targeted chemotherapy with AN - 152 and AN - 207 strongly inhibits the growth of human endometrial cancers , which express P01148 receptors , and could provide a new treatment modality for women with advanced endometrial carcinoma .", "DB00644 analogues reduce the proliferation of endometrial stromal cells but not endometriotic cells . AIMS : We investigated the potential of gonadotropin - releasing hormone ( DB00644 ) agonists and DB00644 antagonists to inhibit cell proliferation in endometriotic and endometrial stromal cells . METHODS : Twenty patients with ovarian endometriomas and 18 patients with uterine fibromas were recruited . Endometriotic and endometrial stromal cells were obtained from the ovarian chocolate cyst linings and the eutopic endometria of premenopausal women with uterine fibromas , respectively . RESULTS : DB00644 agonist or antagonist treatment attenuated tumor necrosis factor ( P01375 ) - α - induced cell proliferation in the endometrial stromal cells , whereas endometriotic stromal cells did not respond to treatment . The endometriotic stromal cells exhibited a decreased expression of the type I P30968 compared with the endometrial stromal cells . DB00644 agonists or antagonists did not repress P01375 - α - induced P10145 production in endometriotic stromal cells . CONCLUSION : DB00644 agonists and antagonists have similar effects in slowing the growth of endometrial stromal cells . Endometriotic stromal cells resist the antiproliferative effect of DB00644 agonists and antagonists .", "Agonist - promoted down - regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor . We recently reported two naturally occurring polymorphisms of the human serotonin1A ( P08908 ) receptor : glycine22 --> serine ( Ser22 ) and isoleucine28 --> valine ( Val28 ) in the putative aminoterminal domain of the receptor . To investigate the regulatory properties of these variants , the wild type ( WT ) and variant P08908 receptors were stably expressed in CHO - P04264 cells . WT , Ser22 , and Val28 displayed similar high - affinity binding to [ 3H ] - 8 - OH - DPAT . Competition experiments with P08908 agonists and antagonists demonstrated similar pharmacological profiles . Receptor agonist - promoted down - regulation was tested by exposure to 100 mumol / L 8 - OH - DPAT . After 24 - h exposure , WT and Val28 underwent 59 . 3 +/- 3 . 9 % and 59 . 5 +/- 1 . 4 % reduction in receptor density respectively , whereas the degree of down - regulation was significantly lower for Ser22 ( 21 . 4 +/- 4 . 2 % ) . Cell treatment for 24 h with 100 mumol / L 8 - OH - DPAT reduced the 5 - HT - induced inhibition of DB02527 accumulation by 24 . 9 +/- 5 . 1 % for WT and 16 . 4 +/- 0 . 8 % for Val28 , but only by 4 . 8 +/- 3 % for Ser22 . We conclude that the Ser22 variant is capable of attenuating agonist - mediated receptor down - regulation and desensitization .", "Longstanding survival without cancer progression in a patient affected by endometrial carcinoma treated primarily with leuprolide . We report here a case of a patient affected by endometrial cancer and treated primarily with leuprolide , the surgical approach being unfeasible due to her compromised conditions . The therapy was continued for more than 6 years , and no progression of the disease was observed . During this period , some histological and immunohistochemical evaluations of the tumour ( morphology , grading , proliferation and apoptotic index , P12830 expression ) were performed . Furthermore , the expression of m - RNA for luteinizing - hormone releasing hormone ( P01148 ) receptors was determined . The results showed a discrepancy between some biological parameters of the tumour and its clinical characteristics . In fact , despite features suggestive of a progression of the cancer ( such as the increase of both tumour grading and proliferating capacity ( MIB - 1 ) , and a fall in the reparative process ( appearance of mutated p53 , reduced expression of both bcl - 2 and c - erb - 2 ) being detected , neither local invasion nor metastatic lesions were clinically observed . This discrepancy might be due to the maintenance of high levels of E - cadhezin . Moreover , since this tumour was shown to express mRNA for P01148 receptors , new evidence is provided about the favourable impact of P01148 analogue treatment in patients affected by endometrial cancer .", "___MASK73___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK73___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .", "Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK84___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK84___ who were treated with a single dose of mifepristone .", "Agonists and antagonists of DB00644 and - II reduce metastasis formation by triple - negative human breast cancer cells in vivo . Metastasis to bone is a frequent problem of advanced breast cancer . Particularly breast cancers , which do not express estrogen and progesterone receptors and which have no overexpression / amplification of the P04626 - neu gene , so called triple - negative breast cancers , are considered as very aggressive and possess a bad prognosis . About 60 % of all human breast cancers and about 74 % of triple - negative breast cancers express receptors for gonadotropin - releasing hormone ( DB00644 ) , which might be used as a therapeutic target . Recently , we could show that bone - directed invasion of human breast cancer cells in vitro is time - and dose - dependently reduced by DB00644 analogs . In the present study , we have analyzed whether DB00644 analogs are able to reduce metastases of triple - negative breast cancers in vivo . In addition , we have evaluated the effects of DB00644 analogs on tumor growth . To quantify formation of metastasis by triple - negative MDA - MB - 435 and MDA - MB - 231 human breast cancers , we used a real - time PCR method based on detection of human - specific alu sequences measuring accurately the amount of human tumor DNA in athymic mouse organs . To analyze tumor growth , the volumes of breast cancer xenotransplants into nude mice were measured . We could demonstrate that DB00644 analogs significantly reduced metastasis formation by triple - negative breast cancer in vivo . In addition , we could show that DB00644 analogs significantly inhibited the growth of breast cancer into nude mice . Side effects were not detectable . In conclusion , DB00644 analogs seem to be suitable drugs for an efficacious therapy for triple - negative , P30968 - positive human breast cancers to prevent metastasis formation .", "A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK31___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow ." ]

[ "___MASK13___", "___MASK16___", "___MASK24___", "___MASK31___", "___MASK51___", "___MASK62___", "___MASK73___", "___MASK84___", "___MASK91___" ]

[ "Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .", "___MASK58___ activates P46937 through nAChRs mediated signaling in esophageal squamous cell cancer ( ESCC ) . Cigarette smoking is an established risk factor for esophageal cancers . P46937 ( P46937 ) , the key transcription factor of the mammalian Hippo pathway , has been reported to be an oncogenic factor for many cancers . In this study , we find nicotine administration can induce nuclear translocation and activation of P46937 in ESCC . Consistently , we observed nuclear translocation and activation of P46937 by knockdown of P32297 , which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells . ___MASK58___ administration or P32297 depletion substantially increased proliferation and migration in esophageal cancer cells . Interestingly , we find that P46937 physically interacts with nAChRs , and nAChRs - signaling dissociates P46937 from its negative regulatory complex composed with α - catenin , β - catenin and 14 - 3 - 3 in the cytoplasm , leading to upregulation and nuclear translocation of P46937 . This process likely requires PKC activation , as PKC specific inhibitor Enzastaurin can block nicotine induced P46937 activation . In addition , we find nicotine signaling also inhibits the interaction of P46937 with Q9H3D4 , which contributes to the inhibitory effect of nicotine on apoptosis . Using immunohistochemistry analysis we observed upregulation of P46937 in a significant portion of esophageal cancer samples . Consistently , we have found a significant association between P46937 upregulation and cigarette smoking in the clinical esophageal cancer samples . Together , these findings suggest that the nicotine activated nAChRs signaling pathway which further activates P46937 plays an important role in the development of esophageal cancer , and this mechanism may be of a general significance for the carcinogenesis of smoking related cancers .", "Multipotent cancer stem cells derived from human malignant peritoneal mesothelioma promote tumorigenesis . During the progression of malignant peritoneal mesothelioma ( MPeM ) , tumor nodules propagate diffusely within the abdomen and tumors are characterized by distinct phenotypic sub - types . Recent studies in solid organ cancers have shown that cancer stem cells ( CSCs ) play a pivotal role in the initiation and progression of tumors . However , it is not known whether tumorigenic stem cells exist and whether they promote tumor growth in MPeM . In this study , we developed and characterized a CSC model for MPeM using stably expandable tumorigenic stem cells derived from patient tumors . We found morphologically distinct populations of CSCs that divide asymmetrically or symmetrically in MPeM in vitro cell culture . The MPeM stem cells ( MPeMSCs ) express stem cell markers c - MYC , P48681 and P35968 and in the presence of matrix components cells form colony spheres . MPeMSCs are multipotent , differentiate into neuronal , vascular and adipose progeny upon defined induction and the differentiating cells express lineage - specific markers such as Q13509 , an early neuronal marker ; P04275 , P15692 , P49767 and P10145 , endothelial markers ; and PPARγ and P15090 , adipose markers . Xenotransplantation experiments using MPeMSCs demonstrated early tumor growth compared with parental cells . Limiting dilution experiments using MPeMSCs and endothelial lineage - induced cells derived from a single MPeMSC resulted in early tumor growth in the latter group indicating that endothelial differentiation of MPeMSCs is important for MPeM tumor initiation . Our observation that the MPeM tumors contain stem cells with tumorigenic potential has important implications for understanding the cells of origin and tumor progression in MPeM and hence targeting CSCs may be a useful strategy to inhibit malignant progression .", "An P12821 inhibitor reduces Th2 cytokines and TGF - beta1 and TGF - beta2 isoforms in murine lupus nephritis . BACKGROUND : P12821 ( P12821 ) inhibitors , such as captopril , are used to control hypertension . In patients and animals with primary nephropathies , these agents improve renal function more than that would be expected from their control of hypertension . Here , we examine the effects of treatment with captopril on lupus nephritis and discuss the potential mechanism ( s ) by which this agent exerts its renoprotective effects . METHODS : Lupus - prone , NZB / NZW F1 and MRL - lpr / lpr , mice were treated with captopril or with a control antihypertensive agent , verapamil . Mice were monitored for nephritis , and their sera and tissues analyzed for cytokine and transforming growth factor - beta ( TGF - beta ) expression . RESULTS : ___MASK89___ treatment delayed the onset of proteinuria when administered to prenephritic mice , whereas verapamil did not . ___MASK89___ treatment also retarded disease progression when given to lupus mice that had early disease , and even reversed severe proteinuria in at least some older animals with advanced disease . It reduced chronic renal lesions , but had no effect on autoantibody production . The improvement in renal disease correlated with reduced TGF - beta expression , particularly of the TGF - beta1 and TGF - beta2 isoforms , in the kidneys . Interestingly , in vivo or in vitro exposure to captopril reduced splenic levels of type 2 cytokines , interleukin ( IL ) - 4 and P22301 , suggesting a possible role of the immune system in captopril - mediated disease modulation . CONCLUSION : Since type 2 cytokines are known to promote lupus glomerulosclerosis , decreased P05112 and P22301 production in captopril - treated mice may be related to this agent ' s renoprotective effects . We argue here that P12821 inhibitors not only act as selective TGF - beta inhibitors , but also as selective immunomodulators , to improve lupus nephritis .", "Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance .", "Characterization of human dental pulp cells - derived spheroids in serum - free medium : stem cells in the core . Spheroid models have led to an increased understanding of differentiation , tissue organization and homeostasis . In the present study , we have observed that under a serum - free medium , human dental pulp cells ( DPCs ) spontaneously formed spheroids , and could survive over 15 weeks . To characterize these spheroids , we investigated their dynamics , microenvironment , cell distribution , molecular profiles , and neuronal / osteogenic potential . Cell tracking assay showed that cells inside the spheroids have very slow cycling . Although the spheroids had hypoxia microenvironments , there were not any massive cell die - offs even after long - term cultivation . Whole mount immunofluorescence staining and histological analysis showed a distribution of stem cells in the central / intermediate zones of spheroids . qRT - PCR analysis demonstrated that the expression of stemness markers Q9H9S0 , Q9H3D4 , and P16070 in the spheroids were much higher than within the monolayer cultures . Gene expression levels of neural markers P19022 , P07197 , Q13509 , and P25063 in the spheroids were much higher than the monolayer DPCs and increased in a culture time - dependent manner . Without any neural induction , spheroid - derived cells spontaneously converted into neuron - like cells with positive staining of neural markers Q14576 / D and P75 under the serum - free medium for about 2 weeks . When the spheroids were transferred into osteogenic medium , they rapidly differentiated into osteo / odontogenic cells , especially the central original cells . Compared to the monolayer DPCs , mineralization in spheroids were significantly increased . This spheroid model offers a study tool to explore the molecular bases of stem cell homeostasis and tissue organization , and can be wildly used for nerve tissue and bone regeneration .", "Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK2___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .", "Antiinflammatory steroid action in human ovarian surface epithelial cells . The human ovarian surface epithelium ( OSE ) is subject to serial injury and repair during ovulation , which is a natural inflammatory event . We asked whether there is a compensatory antiinflammatory component to this process , involving steroid hormones produced locally at the time of ovulation . Quantitative RT - PCR analysis of total RNA from cultured human OSE cell monolayers showed that exposure to proinflammatory IL1alpha ( 500 pg / ml ) increased mRNA levels of cyclooxygenase - 2 ( P35354 ) ( P < 0 . 01 ) at 48 h . The P35354 mRNA response to IL1alpha was associated with an approximate 18 - fold ( P < 0 . 01 ) increase in mRNA levels of 11beta - hydroxysteroid dehydrogenase type 1 ( 11betaHSD1 ) , encoding the steroid dehydrogenase that reversibly reduces cortisone to antiinflammatory cortisol . Addition of cortisol to OSE cell culture medium dose - dependently suppressed the P35354 mRNA response to IL1alpha ( P < 0 . 01 ) but reciprocally enhanced the 11betaHSD1 mRNA response ( P < 0 . 05 ) , with both effects strongest at 1 microm cortisol . Presence of glucocorticoid receptor - alpha mRNA and protein was established in OSE cell monolayers and treatment with IL1alpha shown to significantly up - regulate the glucocorticoid receptor - alpha mRNA level ( P < 0 . 05 ) . P04150 antagonist ( ___MASK86___ , 10 microm ) fully reversed the inhibitory effect of 1 microm cortisol on IL1alpha - stimulated P35354 mRNA expression . Progesterone also suppressed IL1alpha - induced P35354 mRNA expression but had no significant effect on IL1alpha - stimulated 11betaHSD1 expression . These data provide direct evidence for antiinflammatory actions of cortisol and progesterone in human OSE cells .", "The effects of P04035 inhibitor on vascular progenitor cells . Circulating bone marrow - derived vascular progenitor cells contribute to angiogenesis , atherosclerosis , and the response to vascular injury . These vascular progenitor cells consist of two cell groups , endothelial progenitor cells ( EPCs ) and smooth muscle progenitor cells ( SMPCs ) . Although P04035 inhibitors ( statins ) have been reported to inhibit atherosclerosis partially by increased EPCs , the effects of statins on SMPCs are unclear . Therefore , we investigated the relationship between EPCs and SMPCs and whether pravastatin has atheroprotective effects on SMPCs . Peripheral mononuclear cells ( MNCs ) were isolated and cultured on fibronectin - coated dishes in SMPC medium . MNCs were stained with acetylated low density lipoprotein and lectin , or alpha - smooth muscle actin , and cell numbers were counted . mRNA expression and vascular endothelial growth factor ( P15692 ) protein synthesis of MNCs were evaluated . ___MASK28___ significantly increased the number of EPC and decreased the number of SMPC . mRNA expression of P15692 , endothelial nitric oxide synthase , P15692 receptor - 2 ( P35968 ) , and Akt were up - regulated , and P15692 secretion was increased by pravastatin . The present study demonstrated that pravastatin has promotive effects on the differentiation from MNCs to EPC cells , while inhibitory effects to SMPC cells . Our findings suggest a previously unreported mechanism of the effect of statin therapy on vascular progenitor cells .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK70___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .", "Analysis of stemness gene expression and CD133 abnormal methylation in neuroblastoma cell lines . Neuroblastoma is the most common extracranial solid tumor in children , accounting for up to 10 % of all childhood malignancies . Cellular heterogeneity is a hallmark of this embryonal cancer , as distinct neural crest lineages can be found within the same tumor sample . The aim of our study was to investigate the presence of a subpopulation of immature cells with features of cancer - like stem cells in 10 neuroblastoma cell lines . RT - PCR and flow cytometry were performed in order to analyze different kinds of ' stemness genes ' such as : NESTIN ( P48681 ) , CD133 , SOX - 2 , P35226 , c - P10721 , MELK1 , MUSASHI - 1 ( O43347 ) , FAS , P16070 and VIMENTIN ( P08670 ) . In addition , glial and neuronal markers such as P13591 , P14136 and B - TUBULIN III ( Q13509 ) were analyzed . Epigenetic changes within the CD133 ( O43490 ) gene promoter were also analyzed . Neuroblastoma cell lines showed a particular pattern of expression , suggesting the presence of an immature cancer stem cell - like subpopulation . The CD133 protein , commonly used to enrich putative cancer propagating stem cell - like populations in different kinds of solid tumors , presented a half - methylated DNA state in 7 of the 12 neuroblastoma cell lines analyzed . An increase in RNA and protein levels of CD133 was achieved following demethylation by assays using DB01262 ( 5 - Aza - dC ) . Since cancer stem cells are believed to be responsible for tumor metastasis , escape from anticancer therapies and disease relapse , their therapeutic targeting and analysis is crucial in neuroblastoma . Moreover , the regulation of CD133 by epigenetic changes may provide an innovative mechanism of CD133 expression as its regulation still remains unclear .", "Enriched P13591 - positive cells form functional dopaminergic neurons in the rat model of Parkinson ' s disease . We describe a method of generating an enriched population of P13591 - positive cells from a human teratocarcinoma cell line ( NTera2 / D1 ) and their differentiation into midbrain dopaminergic neurons in the absence of the caudalizing factor retinoic acid ( RA ) . NTera2 cells were induced to form embryoid bodies and then to generate nestin - positive cells on treatment with serum - free defined medium supplemented with neurotrophic factors . We enriched the neuroprogenitor population by magnetic sorting of the nestin - positive cells using the antibody to neural cell adhesion molecule ( P13591 ) . These cells were expanded by exposing them to the signaling molecule sonic hedgehog ( SHH ) in conjunction with fibroblast growth factor - 8 ( P55075 ) . The predifferentiated cells when analyzed by RT - PCR showed expression of dopaminergic markers such as Nurr1 , Engrailed - 1 , aromatic amino decarboxylase ( P20711 ) , Q05940 , tyrosine hydroxylase ( TH ) , and dopamine transporter ( Q01959 ) . These cells also stained positively for protein markers such as nestin , P13591 , P11137 , and TH . We further demonstrated that when transplanted into the brain of Parkinsonian rats , these neuroprogenitor cells did not form tumors but differentiated into dopaminergic neurons , as revealed by TH immunolabeling . The origin of transplanted cells were further confirmed by positive immunolabeling with anti - human nuclei . Our results suggest that enriching the neuroprogenitor population by magnetic sorting prevents tumor formation and is a prerequisite before cell replacement therapy for Parkinson ' s disease .", "Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK23___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .", "Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK62___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK62___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .", "Tubulin , P38398 , P07992 , Abraxas , Q96RL1 mRNA expression , p53 / P38936 immunohistochemistry and clinical outcome in patients with advanced non small - cell lung cancer receiving first - line platinum - gemcitabine chemotherapy . BACKGROUND : The aim of this study was to assess the predictive value of tumor expression of nine genes on clinical outcome in patients with advanced NSCLC receiving platinum - gemcitabine chemotherapy . METHODS : Quantitative PCR or immunohistochemistry were used to analyze the expression of β - tubuline IIA ( Q13885 ) , β - tubuline III ( Q13509 ) , P38398 , P07992 , Abraxas ( ABRX ) and Q96RL1 in mRNA isolated from paraffin - embedded tumor biopsies of 45 NSCLC patients treated as part of a larger observational trial . All patients received first - line platinum - gemcitabine chemotherapy for stage IIIB or IV NSCLC . RESULTS : Median progression - free survival ( PFS ) was 7 months , overall survival ( OS ) 12 months . A partial treatment response was found in 14 patients ( 33 % ) . Patients with low P07992 or ABRX expression had a significantly better response to chemotherapy ( R =- 0 . 45 , p < 0 . 01 for P07992 ; R =- 0 . 40 , p = 0 . 016 for ABRX ) . A significant correlation was found between the individual time for PFS and the expression of both P07992 ( R =- 0 . 36 , p = 0 . 015 ) and ABRX ( R =- 0 . 46 , p = 0 . 001 ) . Patients with low P07992 expression had a longer OS as compared to patients with high P07992 expression ( HR = 0 . 26 , log - rank p = 0 . 02 ) . CONCLUSIONS : The study confirms tumor expression of P07992 as a predictor for clinical outcome in patients with advanced NSCLC receiving platinum - based chemotherapy , and found ABRX expression to be similarly predictive of clinical outcome . Prospective validation is warranted and - if confirmed - non platinum - containing chemotherapy should be explored as the preferred treatment in patients with high P07992 or ABRX expression and no activating mutations of P00533 .", "P22301 regulates progenitor differentiation and modulates neurogenesis in adult brain . The adult subventricular zone ( SVZ ) is the main neurogenic niche in the adult brain of mice and rats . The adult SVZ contains neural stem cells ( NSCs ) that primarily differentiate into committed neuroblasts . The newly generated neuroblasts accumulate in dorsal SVZ where they further differentiate and initiate a long migration pathway to their final destination , the olfactory bulb ( OB ) . Here , we report a new role for Interleukin 10 ( P22301 ) that is different to its well - known anti - inflammatory properties . We show that the P22301 receptor is expressed in P48681 - positive progenitors restricted to the dorsal SVZ in adult brain . Using P22301 gain models , we observed that P22301 maintains neural progenitors in an undifferentiated state by keeping progenitors in an active cycle where pro - neural gene markers ( P48681 , Sox1 , Sox2 , Musashi , Mash1 ) are upregulated and neuronal gene expression ( Numb , O43602 , Q13509 ) is downregulated . In addition , P22301 reduces neuronal differentiation and ultimately impairs endogenous neurogenesis . Consistently , in the absence of P22301 , in vivo neuronal differentiation of SVZ progenitors is enhanced and the incorporation of new neurons in the adult OB is increased . Thus , our results provide the first evidence that P22301 acts as a growth factor on SVZ progenitors and regulates neurogenesis in normal adult brain .", "Oral soft tissue alterations in patients with neurofibromatosis . Our aim was to characterize the type and frequency of oral soft tissue alterations in neurofibromatosis . A total of 103 patients with neurofibromatosis 1 ( P21359 ) and three patients with neurofibromatosis 2 ( P35240 ) were clinically evaluated for their oral soft tissue alterations . Disturbing growths were removed from nine patients with P21359 and from one patient with P35240 . The specimens were analyzed using routine histological methods and with immunohistochemistry using antibodies to S100 , type IV collagen , P28906 , neurofilament , and neuron - specific tubulin ( Q13509 ) . Alterations including oral tumors , overgrowths of gingival soft tissue , and enlarged papillae of the tongue were discovered in 74 % of P21359 patients . The results showed that three tumors clinically classified as plexiform neurofibromas and five out of six discrete mucosal tumors displayed histology and immunohistology consistent with that of neurofibroma . The histology of one palatal lesion resembled that of a scar , and the lesion removed from the patient with P35240 was classified as an amyloid tumor . To conclude , oral soft tissue growths are common findings in P21359 , but most lesions do not require treatment and the patients may even not be aware of these alterations . Collagen IV , S100 , and P28906 are useful biomarkers in the analysis of P21359 - related oral soft tissue tumors . The clinicians should recognize that oral soft tissue alterations are relatively common in P21359 . Some of the growths are disturbing , and plexiform neurofibromas may bear a risk of malignant transformation .", "The P04035 inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1 . Neurofibromatosis Type 1 ( P21359 ) is a common neurological disorder caused by mutations in the gene encoding P21359 , a p21Ras GTPase Activating Protein ( P20936 ) . Importantly , P21359 causes learning disabilities and attention deficits . A previous study showed that the learning and memory deficits of a mouse model of P21359 ( nf1 +/- ) appear to be caused by excessive p21Ras activity leading to impairments in long - term potentiation ( LTP ) , a cellular mechanism of learning and memory . Here , we identify lovastatin as a potent inhibitor of p21Ras / Mitogen Activated Protein Kinase ( MAPK ) activity in the brain . ___MASK16___ is a specific inhibitor of three - hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase , used commonly for the treatment of hypercholesterolemia . We report that lovastatin decreased the enhanced brain p21Ras - MAPK activity of the nf1 +/- mice , rescued their LTP deficits , and reversed their spatial learning and attention impairments . Therefore , these results demonstrate that lovastatin may prove useful in the treatment of Neurofibromatosis Type 1 .", "Microdeletions involving chromosomes 12 and 22 associated with syndromic Duane retraction syndrome . BACKGROUND : Duane retraction syndrome ( Q9H307 ) is the most common of the congenital cranial dysinnervation disorders ( CCDDs ) . CCDDs can be monogenic or chromosomal in origin . Identification of the genetic cause ( s ) in patients and families with Q9H307 facilitates definitive diagnosis and provides insights into these developmental errors . MATERIALS AND METHODS : This study described a young girl with Q9H307 on the left and several additional developmental abnormalities . Clinical examination including neuroimaging , sequencing of candidate genes associated with Q9H307 , and array comparative genomic hybridization ( array CGH ) were performed . RESULTS : The proband had unilateral Q9H307 type 3 on the left with somewhat low - set ears , mild motor delay with normal intelligence , and an asymmetric neck without a palpable right sternocleidomastoid muscle . Spine X - rays revealed a Klippel - Feil syndrome ( KFS ) and an Q9BWK5 showed a webbed neck . She also had spina bifida at Q99618 - T1 and a submucosal cleft palate . The parents of the proband were related with no other family member affected similarly . Sequencing of Q9UJQ4 , P15882 , P49639 , and Q13509 did not show any mutation . Array CGH revealed de novo deletions of 21 Kb on chromosome 12q24 . 31 and 11 Kb on chromosome 22q13 . 31 , each encompassing only one gene , ring finger protein 34 , E3 ubiquitin protein ligase ( Q969K3 ) and peroxisome proliferator - activated receptor alpha ( Q07869 ) respectively . CONCLUSIONS : This patient presents an unusual phenotype associated with a unique combination of two chromosomal microdeletions .", "Genetic polymorphisms in diabetes : influence on therapy with oral antidiabetics . Due to new genetic insights , etiologic classification of diabetes is under constant scrutiny . Hundreds , or even thousands , of genes are linked with type 2 diabetes . Three common variants ( Lys23 of Q14654 , Pro12 of P37231 , and the T allele at rs7903146 of Q9NQB0 ) have been shown to be predisposed to type 2 diabetes mellitus across many large studies . Individually , each of these polymorphisms is only moderately predisposed to type 2 diabetes . On the other hand , monogenic forms of diabetes such as MODY and neonatal diabetes are characterized by unique clinical features and the possibility of applying a tailored treatment . Genetic polymorphisms in drug - metabolizing enzymes , transporters , receptors , and other drug targets have been linked to interindividual differences in the efficacy and toxicity of a number of medications . Mutations in genes important in drug absorption , distribution , metabolism and excretion ( ADME ) play a critical role in pharmacogenetics of diabetes . There are currently five major classes of oral pharmacological agents available to treat type 2 diabetes : sulfonylureas , meglitinides , metformin ( a biguanide ) , thiazolidinediones , and α - glucosidase inhibitors . Other classes are also mentioned in literature . In this work , different types of genetic mutations ( mutations of the gene for glucokinase , HNF 1α , HNF1β and Kir6 . 2 and Q09428 subunit of KATP channel , Q07869 - γ , OCT1 and OCT2 , cytochromes , direct drug - receptor ( Q14654 ) , as well as the factors that influence the development of the disease ( Q9NQB0 ) and variants of genes that lead to hepatosteatosis caused by thiazolidinediones ) and their influence on the response to therapy with oral antidiabetics will be reviewed .", "Biomarker analysis of neoadjuvant doxorubicin / cyclophosphamide followed by ixabepilone or Paclitaxel in early - stage breast cancer . PURPOSE : Predictive biomarkers offer the potential to improve the benefit : risk ratio of a therapeutic agent . DB04845 achieves comparable pathologic complete response ( pCR ) rates to other active drugs in the neoadjuvant setting . This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent . EXPERIMENTAL DESIGN : Women with untreated , histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin / cyclophosphamide , followed by 1 : 1 randomization to ixabepilone ( n = 148 ) or paclitaxel ( n = 147 ) . Rates of pCR were compared between treatment arms based on predefined biomarker sets : Q13509 , Q9Y6A5 , and CAPG gene expression , a 20 - and 26 - gene expression model , P08183 protein expression , and other potential markers of sensitivity . βIII - tubulin protein expression is reported separately but is referred to here for completeness . All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy . Gene expression profiling data were used for molecular subtyping . RESULTS : There was no significant difference in the rate of pCR in both treatment arms in βIII - tubulin - positive patients . Higher pCR rates were observed among βIII - tubulin - positive patients than in βIII - tubulin - negative patients . Furthermore , no correlation was evident between Q13509 , Q9Y6A5 , and CAPG gene expression , P08183 protein expression , multi - gene expression models , and the efficacy of ixabepilone or paclitaxel , even within the estrogen receptor - negative subset . CONCLUSION : These results indicate that βIII - tubulin protein and mRNA expression , P08183 protein expression , Q9Y6A5 and CAPG gene expression , and multigene expression models ( 20 - and 26 - gene ) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early - stage breast cancer ." ]

[ "___MASK16___", "___MASK23___", "___MASK28___", "___MASK2___", "___MASK58___", "___MASK62___", "___MASK70___", "___MASK86___", "___MASK89___" ]

[ "DB00112 ( avastin ) in ocular processes other than choroidal neovascularization . DB00112 is a full - length humanized murine monoclonal anti - P15692 ( vascular endothelial growth factor ) IgG1 antibody that was approved by the U . S . Food and Drug Administration in 2004 for the treatment of metastatic colorectal cancer . The intravenous formulation of bevacizumab was first injected intravitreally in 2005 and has proven to be a relatively safe and extremely effective off - label treatment for neovascular ocular disease and diseases associated with macular edema . This paper is a review of the ophthalmic uses of bevacizumab in processes other than choroidal neovascularization .", "[ Renal cell carcinoma and antiangiogenic therapies ] . Until 2006 , immunotherapy ( interferon - alpha or interleukin 2 ) was the standard medical treatment for metastatic renal cell carcinoma ( RCC ) , and its results were disappointing : despite a few cases of complete response with prolonged survival , median survival was one year . Better understanding of the molecular mechanisms of tumor angiogenesis , especially in clear cell carcinoma , has led to the development of multiple targeted therapies to inhibit key effectors : vascular endothelial growth factor ( P15692 ) , P15692 receptor , and P42345 ( target of rapamycin ) . Two inhibitors targeting several protein kinases , including the P15692 receptor , have increased progression - free survival in patients with metastatic RCC and are now commercially available : sunitinib ( Sutent ) as first - line treatment and sorafenib ( Nexavar ) as second - line treatment . These targeted therapies will certainly affect overall survival , but it is too early for any firm conclusions . Their side - effects , usually low or moderate , include asthenia , anorexia , diarrhea , hand - and - foot syndrome and hypertension . Optimal management is required to ensure prolonged exposure . Other drugs have been effective : bevacizumab ( DB00112 ) , a monoclonal antibody inhibiting P15692 , increases progression - free survival as second - line treatment , and temsirolimus ( ___MASK28___ ) , an P42345 protein kinase inhibitor , increases overall survival in the population of patients with poor prognosis . These targeted drugs will serve as the basis for development of future therapeutic strategies .", "The Chinese medicine formula HB01 reduces choroidal neovascularization by regulating the expression of vascular endothelial growth factor . BACKGROUND : Choroidal neovascularization ( CNV ) remains the leading cause of newly acquired blindness in the developed world . Currently anti - vascular endothelial growth factor ( P15692 ) therapies are broadly used to treat neovascular ocular disorders . Here we demonstrate the effect of a traditional Chinese medicine formula , HB01 , on CNV . METHODS : A rat model of laser - induced CNV was used to investigate the effect of HB01 in vivo . The CNV lesions in the eye were evaluated using fundus fluorescein angiography and visualized / quantified using confocal microscopy . Expression of P15692 in the choroidal and retinal tissues was measured using quantitative real - time PCR and immunohistochemistry . RESULTS : We demonstrated that a traditional Chinese Medicine formula , named HB01 , significantly reduced neovascularization in a rat CNV model . The effect of HB01 on CNV was comparable to the intravitreal injection of bevacizumab ( DB00112 ) . Our results also suggested that HB01 may reduce CNV partially through inhibiting the expression of P15692 . CONCLUSIONS : These data support HB01 as an alternative therapy for ocular neovascular disorders .", "Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis . BACKGROUND : Cerebral radiation necrosis is a serious complication of radiation treatment for brain tumors . Therapeutic options include corticosteroids , anticoagulation and hyperbaric oxygen with limited efficacy . DB00112 , an antibody against P15692 had been reported to reduce edema in patients with suspected radiation necrosis . We retrospectively reviewed 6 patients with biopsy proven cerebral radiation necrosis treated with bevacizumab between 2006 and 2008 . RESULTS : Interval Q9BWK5 follow - up demonstrated radiographic response in all patients with an average reduction of 79 % for the post gadolinium studies and 49 % for the FLAIR images . The initial partial radiographic response was noted for up to a mean follow - up time of 5 . 9 months ( 6 weeks to 18 months ) . CONCLUSION : DB00112 appears to produce radiographic response and clinical benefits in the treatment of patients with cerebral radionecrosis .", "The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK15___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .", "Spotlight on bevacizumab in advanced colorectal cancer , breast cancer , and non - small cell lung cancer . DB00112 ( DB00112 ) is a humanized recombinant antibody that prevents vascular endothelial growth factor ( P15692 ) receptor binding , and inhibits angiogenesis and tumor growth . In patients receiving an irinotecan plus fluorouracil / leucovorin ( IFL ) regimen for first - line treatment of metastatic colorectal cancer , the addition of bevacizumab significantly increased overall survival by 4 . 7 months relative to IFL plus placebo . In the second - line treatment of advanced colorectal cancer , patients who received bevacizumab in combination with a fluorouracil / leucovorin plus oxaliplatin ( FOLFOX4 ) regimen had an overall survival time that was 2 months longer than that in patients receiving FOLFOX4 . Preliminary results indicated that bevacizumab significantly extended progression - free survival by 4 . 9 months in patients receiving paclitaxel for the first - line treatment of locally recurrent or metastatic breast cancer . The addition of bevacizumab to paclitaxel plus carboplatin in the first - line treatment of advanced non - small cell lung cancer ( NSCLC ) significantly prolonged overall survival by > 2 months . DB00112 has acceptable tolerability in patients with advanced colorectal cancer , breast cancer , or NSCLC , with the majority of adverse events being generally mild and clinically manageable . Thus , bevacizumab provides a highly effective addition to standard chemotherapeutic regimens for advanced colorectal cancer , breast cancer , and NSCLC .", "Current status of anti - angiogenic agents in the treatment of ovarian carcinoma . During the last decade we have assisted in the development of new therapeutic strategies for the treatment of ovarian cancer , based on the best knowledge of molecular biology . One of the most promising strategies under investigation is antiangiogenic therapy . DB00112 is a monoclonal humanised antibody targeting vascular endothelial growth factor ( P15692 ) , which has shown antitumour activity in ovarian cancer in preclinical models as well as in clinical trials , both in monotherapy and in combination with other therapies . Currently , ongoing phase III trials are testing bevacizumab as a front - line therapy with carboplatin and paclitaxel . DB00112 has been generally well tolerated with mild frequent toxicities ( proteinuria , hypertension and bleeding ) . However , the drug may result in other uncommon , but potentially life - threatening side effects , such as arterial thromboembolism , wound healing complications , and gastrointestinal perforation or fistulae , which should be considered when the drug is administered . Other new therapeutic antiangiogenic strategies that include small - molecule tyrosine kinase inhibitors , antibodies neutralising the P15692 receptor ( VEGFR ) and soluble VEGFR hybrids ( DB08885 ) are being investigated with promising early results .", "DB00112 and chemotherapy for recurrent glioblastoma : a single - institution experience . OBJECTIVE : DB00112 has been shown to be effective in the treatment of recurrent glioblastoma in combination with chemotherapy compared with historic controls but not in randomized trials . METHODS : We conducted a retrospective analysis of patients treated for recurrent glioblastoma with bevacizumab vs a control group of patients , comparing progression - free survival ( PFS ) and overall survival ( OS ) between the two groups , and performed subgroup analysis based on age and performance status . Expression of vascular endothelial growth factor ( P15692 ) based on age was examined using DNA microarray analysis . We also evaluated the impact of bevacizumab on quality of life . RESULTS : We identified 44 patients who received bevacizumab and 79 patients who had not been treated with bevacizumab . There was a significant improvement in PFS and OS in the bevacizumab - treated group . Patients of older age ( > or = 55 years ) and poor performance status ( Karnofsky Performance Status < or = 80 ) had significantly better PFS when treated with bevacizumab , and bevacizumab - treated older patients had significantly increased OS . P15692 expression was significantly higher in older glioblastoma patients ( aged > or = 55 years ) . Patients treated with bevacizumab also required less dexamethasone use and maintained their functional status longer than the control group . CONCLUSIONS : DB00112 in combination with chemotherapy may be a more effective treatment for recurrent glioblastoma and warrants further randomized prospective studies to determine its effect on survival . DB00112 also has more effect in those with older age and might reflect biologic differences in glioblastoma in different age groups as seen with the expression of vascular endothelial growth factor .", "Anti - vascular endothelial growth factor antibody bevacizumab reduced the risk of anemia associated with chemotherapy - A meta - analysis . INTRODUCTION : Vascular endothelial growth factor ( P15692 ) may play a role in erythropoiesis . We performed a meta - analysis of randomized controlled trials ( RCT ) to determine the effect of the anti - P15692 antibody bevacizumab on anemia in cancer patients treated with chemotherapy . METHODS : Databases from PUBMED , the Web of Science , Embase , the Cochrane Library , and abstracts presented at the American Society of Clinical Oncology ( ASCO ) conferences until May 2010 were searched to identify relevant studies . Eligible studies included prospective RCTs in which the combination of bevacizumab and chemotherapy was compared with chemotherapy alone . Summary incidence rate , relative risk ( RR ) , and 95 % confidence interval ( CI ) were calculated . RESULTS : A total of 6439 patients with a variety of solid tumors were included for analysis from 11 RCTs . Among those patients receiving bevacizumab and chemotherapy , the incidences of all - grade and high - grade ( grade 3 and above ) anemia were 17 . 8 % ( 95 % CI : 11 . 1 - 27 . 1 % ) and 2 . 8 % ( 95 % CI : 1 . 6 - 5 . 0 % ) respectively . In comparison with chemotherapy alone , bevacizumab significantly reduced all - grade ( RR , 0 . 79 ; 95 % CI : 0 . 66 - 1 . 0 , p = 0 . 007 ) and high - grade anemia ( RR , 0 . 72 ; 95 % CI : 0 . 57 - 0 . 90 , p = 0 . 005 ) . The effect did not vary significantly among bevacizumab doses ( p = 0 . 88 ) , tumor types ( p = 0 . 75 ) or chemotherapy regimens ( p = 0 . 98 ) . DISCUSSION : DB00112 may significantly reduce the risk of anemia with chemotherapy in cancer patients .", "Cancer and Leukemia Group B 90206 : A randomized phase III trial of interferon - alpha or interferon - alpha plus anti - vascular endothelial growth factor antibody ( bevacizumab ) in metastatic renal cell carcinoma . The majority of sporadic clear cell renal cell carcinoma ( RCC ) is characterized by loss of heterozygosity of the von Hippel - Lindau ( P40337 ) tumor suppressor gene and somatic inactivation of the remaining P40337 allele . The resulting P40337 gene silencing leads to induction of hypoxia - regulated genes including vascular endothelial growth factor ( P15692 ) . Thus , therapeutic inhibition of P15692 holds promise for treatment of this historically refractory malignancy . An antibody to P15692 ( bevacizumab , DB00112 ) has demonstrated a significant prolongation of time to disease progression compared with placebo in patients with metastatic RCC . Interferon - alpha ( IFN - alpha ) is a standard initial cytokine therapy in RCC with a modest response rate and a survival advantage demonstrated in randomized trials . We hypothesized that the addition of anti - P15692 therapy to IFN - alpha would prolong survival in untreated metastatic RCC patients . A Phase III trial is now being conducted randomizing untreated , metastatic clear cell RCC patients to IFN - alpha alone or IFN - alpha plus DB00112 .", "Antivascular endothelial growth factor monoclonal antibody therapy : a promising paradigm in colorectal cancer . Angiogenesis plays an important role in tumor growth and development . Vascular endothelial growth factor ( P15692 ) is one of the most potent proangiogenic factors and therefore is an ideal target in colorectal cancer therapy . DB00112 ( DB00112 , Genentech , Inc . , South San Francisco , CA ) is a humanized monoclonal antibody , designed to directly target P15692 . The agent has shown promising activity in preclinical and phase I and II studies and is well tolerated compared with conventional cytotoxic chemotherapy . The U . S . Food and Drug Administration recently approved bevacizumab in combination with 5 - fluorouracil - based chemotherapy as first - line therapy for patients with metastatic colorectal cancer . The approval was based on phase III data demonstrating that patients treated with bevacizumab plus chemotherapy survived approximately five months longer compared with patients treated with chemotherapy alone . This article will focus on the role of P15692 in tumorigenesis and summarize the available data on the use of bevacizumab in the treatment of metastatic colorectal cancer .", "Tumoral angiogenesis : review of the literature . Tumoral angiogenesis is necessary for the growth of neoplasms and the production of metastasis . The vascular endothelial growth factor ( P15692 ) is a homodimeric heparin - binding glycoprotein that binds to P15692 - receptors and can induce endothelial cell mitosis , invasion , and eventually capillary tube formation . DB00112 , a humanized monoclonal antibody against P15692 , inhibits tumoral angiogenesis and may also improve the delivery of chemotherapy to the tumor mass . Some new antiangiogenic agents , called multi - kinase inhibitors ( sorafenib and sunitinib ) , have also activity against other receptors , such as epidermal growth factor - receptor or platelet - derived growth factor - receptor . A new schedule of treatment ( metronomic chemotherapy ) also has antiangiogenic activity .", "___MASK37___ : kinetic and dynamic profile in the treatment of pain . ___MASK37___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK37___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK37___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK37___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .", "Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .", "Persistent elevation of intraocular pressure following intravitreal injection of bevacizumab . BACKGROUND : The number of patients treated with intravitreal injections has increased significantly over the past few years , mainly following the introduction of anti - vascular endothelial growth factor antibody intraocular drugs . DB00112 is mostly used in this group of medications . OBJECTIVES : To describe persistent elevation of intraocular pressure ( IOP ) following intravitreal injection of bevacizumab . METHODS : We reviewed consecutive cases of persistent IOP elevation after intravitreal bevacizumab injection for exudative age - related macular degeneration ( AMD ) . A total of 424 patients ( 528 eyes ) met the inclusion criteria and received 1796 intravitreal injections of bevacizumab . Persistent IOP elevation was found in 19 eyes ( 3 . 6 % , 19 / 528 ) of 18 patients ( 4 . 2 % , 18 / 424 ) with IOP elevated 30 - 70 mmHg 3 - 30 days after injection . RESULTS : Mean IOP was 42 . 6 mmHg ( range 30 - 70 ) ; IOP elevations occurred after an average of 7 . 8 injections of bevacizumab ( range 3 - 13 ) . Injected eyes ( 19 / 528 ) had a significantly higher incidence of elevated IOP than uninjected eyes ( fellow eyes ) , 1 / 328 , P < 0 . 001 . CONCLUSIONS : Like other anti - vascular endothelial growth factor ( P15692 ) substances reported in a few recent studies , intravitreal injection of bevacizumab for neovascular AMD may be associated with persistent IOP elevation . Providers should be aware that significant IOP elevation might occur after repeated treatments .", "DB00741 response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . DB00741 is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post - stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress - coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro - hypertrophic nuclear factor of activated T - cell ( NFAT ) signaling ] and increased P15692 gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild - type European brown trout , Salmo trutta . A positive correlation between post - stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post - stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well - known from mammalian cardiology .", "[ Present status of studies on the treatment of choroidal neovascularization by Anecortave acetate ] . Choroidal neovascularization ( CNV ) is a major cause of vision loss in various ocular fundus diseases . The purpose of traditional therapies was to treat established CNV , but they only have limited effects . Drug treatment targeting the pathogenesis of CNV has become a hot research topic recently . Anecortave acetate is an angiostatic steroid which shows distinct mechanism of action in inhibiting neovascularization , making it different from the anti - P15692 agents ( DB04895 , DB01270 and DB00112 ) . As the studies on the mechanism of CNV going more deeply , effective treatment targeting the pathogenesis of CNV will bring hope for these patients .", "DB00112 in the treatment of metastatic breast cancer : friend or foe ? Metastatic breast cancer ( MBC ) is a major cause of death among women worldwide . Progress has been made in treating MBC with the advent of anti - estrogen therapies , potent cytotoxic agents , and monoclonal antibodies . DB00112 is a monoclonal antibody against circulating vascular endothelial growth factor ( P15692 ) , which was approved in 2008 by the US Food and Drug Administration ( FDA ) , for first - line treatment of HER - 2 negative MBC in combination with paclitaxel . The FDA then reversed this decision in December 2010 by recommending removal of the MBC indication from bevacizumab , citing primarily safety concerns , and that these risks did not outweigh the ability of bevacizumab to significantly prolong progression - free survival . This decision was unexpected in the oncology community and remains controversial . This review looks at all available phase 3 data with bevacizumab in the MBC setting to determine whether the data support this decision by the FDA , and discusses the future of bevacizumab in breast cancer .", "Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK23___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .", "The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK40___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .", "No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK16___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK16___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK16___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK16___ among adults with ADHD .", "Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .", "DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .", "Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .", "Hypericin - mediated photodynamic therapy in combination with DB00112 ( bevacizumab ) improves tumor response by downregulating angiogenic proteins . Photodynamic therapy ( PDT ) is a therapeutic modality in which a photosensitizer is locally or systemically administered followed by light irradiation of suitable wavelength to achieve selective tissue damage . In addition , PDT is an oxygen - consuming reaction , that causes hypoxia mediated destruction of tumor vasculature that results in effective treatment . However , the hypoxic condition within tumors can cause stress - related release of angiogenic growth factors and cytokines and this inflammatory response could possibly diminish the efficacy of PDT by promoting tumor regrowth . In such circumstances , PDT effectiveness can be enhanced by combining angiogenesis inhibitors into the treatment regimen . DB00112 ( bevacizumab ) , a vascular endothelial growth factor ( P15692 ) specific monoclonal antibody in combination with chemotherapy is offering hope to patients with metastatic colorectal cancer . In this study we evaluated the combination of hypericin - mediated PDT and DB00112 on P15692 levels as well as its effect on overall tumor response . Experiments were conducted on bladder carcinoma xenografts established subcutaneously in Balb / c nude mice . Antibody array , enzyme - linked immunosorbent assay ( ELISA ) and immunohistochemistry ( IHC ) were performed to assess P15692 concentrations in the various treatment groups . Our results demonstrated that the targeted therapy by DB00112 along with PDT can improve tumor responsiveness in bladder tumor xenografts . Immunostaining showed minimal expression of P15692 in tumors treated with combination therapy of PDT and DB00112 . Angiogenic proteins e . g . , angiogenin , basic fibroblast growth factor ( P09038 ) , epidermal growth factor ( P01133 ) and interleukins ( P05231 and P10145 ) were also found to be downregulated in groups treated with combination therapy .", "Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK52___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK52___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .", "Feasibility of rapid infusion of the initial dose of bevacizumab in patients with cancer . PURPOSE : DB00112 is a monoclonal antibody against vascular endothelial growth factor ( P15692 ) widely used in clinical oncology . DB00112 is commonly co - adminis - tered with chemotherapy . It is recommended that the first infusion of the antibody last 90 min , the second 60 and all subsequent 30 min . Since there is no clear rationale for the proposed schedule of administration , our study assessed the feasibility of a 30 min initial infusion . METHODS : Cancer patients eligible for de novo bevacizumab treatment were enrolled . All patients received standard bevacizumab dose of 5 , 7 . 5 or 10 mg / kg according to the indication , diluted in 250 ml normal saline , as a 30 - min intravenous infusion . RESULTS : Thirty two patients were enrolled : male 18 , female 14 , median age 58 years , range 42 - 78 . Oncologic diagnosis : lung cancer 16 , colorectal 4 , breast 3 , ovarian 7 , renal 2 . All patients tolerated the infusion well . No hypersensitivity reactions were noted . Mean systolic and diastolic blood pressures were 122 and 73 mm / Hg respectively prior to the infusion and 125 and 75 mm / Hg 15 min after the infusion ( p = 0 . 3 ) . During the observation period of 1 hour , blood pressure did not change . Transient grade 3 systolic hypertension was noted in 1 patient , with spontaneous regression in 45 min . CONCLUSION : Rapid administration of bevacizumab in 30 min , rather than the recommended in the package insert 90 min is feasible and safe . Such a practice limits the time of confinement in the treatment area to patients ' satisfaction and would result in cost savings by reducing health resource utilization .", "B cell activating factor - dependent expression of vascular endothelial growth factor in MH7A human synoviocytes stimulated with tumor necrosis factor - α . Angiogenesis in rheumatoid arthritis ( RA ) is one of the histological hallmarks , which is mediated by expression of vascular endothelial growth factor ( P15692 ) in RA synovium . P15692 expression is enhanced by P01375 - α , the main pro - inflammatory cytokine in RA . B cell activating factor ( Q9Y275 ) which plays a role in maturation and maintenance of B cells is also associated with autoimmune RA . Here , we investigated whether Q9Y275 could regulate P15692 expression in P01375 - α - stimulated synovium using MH7A synovial cells that are established by transfection with the SV40 T antigen . Changes in hBAFF and hVEGF were measured by western blotting , RT - PCR and luciferase promoter assay . When MH7A cells were treated with P01375 - α , we observed that P01375 - α increased the expression of hBAFF and hVEGF . P01375 - α also increased transcriptional activity of hBAFF and hVEGF as judged by luciferase promoter assay . Inhibition of hBAFF expression with Q9Y275 - siRNA decreased transcriptional level and activity of hVEGF . In addition , when c - fos expression was inhibited by the transfection of MH7A cells with c - fos - siRNA , data showed that transcriptional level and activity of both hBAFF and hVEGF were attenuated by the activation with P01375 - α . Our results demonstrate for the first time that P15692 - mediated angiogenesis in RA could be controlled by P01375 - α - induced Q9Y275 expression through c - Fos . Data suggest that P01375 - α - induced Q9Y275 expression and Q9Y275 - mediated P15692 expression in synovium may cooperate to maintain the capacity of such cells to protect B cells from apoptosis and the supply of nutrients and oxygen in inflammatory microenvironments .", "DB00112 in the treatment of breast cancer . The monoclonal antibody bevacizumab , targeted against the angiogenesis factor P15692 has clinical activity against several common cancers . In metastatic breast cancer it improves response rate and time to progression in combination with paclitaxel / docetaxel compared with paclitaxel / docetaxel alone ; the drug is currently being investigated in other combination regimens and as adjuvant and neoadjuvant therapy in early breast cancer . It is generally well tolerated . Side effects , including hypertension , proteinuria , thrombosis and bleeding , are uncommon and usually managed easily . Based on the clinical efficacy of bevacizumab , other small - molecule oral antiangiogenesis agents are now also under development .", "[ The treatment of the rubeosis of the iris and the neovascular glaucoma in proliferative diabetic retinopathy by means of anti - P15692 ] . The rubeosis of the iris is a serious complication especially in diabetic retinopathy and retinal veins occlusion . Cytokines , especially the vascular growing factor ( P15692 ) , are responsible for the forming of new vessels . The treatment that inhibits the effect of the P15692 presents new possibilities in the neovascular diseases treatment . DB00112 ( DB00112 ) is an anti - P15692 antibody that blocks all forms of P15692 . In three eyes with proliferative diabetic retinopathy and neovascularization of the iris and the anterior chamber angle , the dose of 1 . 25 mg of DB00112 was applied intravitrealy . Just one week after the application of the drug , the decrease of the leakage on the iris , and the total disappearance of the neovascularization in three weeks were visible on the fluorescein angiogram . The recurrence of the neovascularization was found in one eye after three months and the treatment had to be repeated . Nine months after the second application , the disease is stabilized without the neovascularization . The intraocular pressure was elevated in two eyes before the application of DB00112 , and was refractive to the treatment . After the disappearance of the neovascularization , the intraocular pressure was normalized and it was possible to terminate the antiglaucomatous therapy . The bevacizumab intravitreal treatment of the neovascularization of the iris and the anterior chamber angle was proved to be efficient , the neovascularization disappeared and the intraocular pressure was normalized . There were no side effects after the bevacizumab applications in any of our patients .", "Effect of endothelin receptor antagonist ___MASK52___ on chronic hypoxia - induced inflammation and chemoafferent neuron adaptation in rat carotid body . Chronic hypoxia ( CH ) induces an inflammatory response in rat carotid body that is characterized by immune cell invasion and the expression of pro - inflammatory cytokines . In the present study , we have investigated the role of type - A endothelin ( P25101 ) receptors in the development of CH - induced inflammation . After 7 days of CH ( 380 Torr ) , double - label immunofluorescence studies demonstrated elevated levels of P25101 receptor and tyrosine hydroxylase ( TH ) in O ( 2 )- sensitive type I cells . Following CH , P25101 receptors were also expressed on resident and invasive P08575 + immune cells distributed in tissue surrounding chemosensory cell lobules . Immnofluorescence and quantitative PCR studies showed that concurrent treatment with the P25101 / B receptor antagonist , ___MASK52___ ( 200 mg / kg / day ) , blocked CH - induced ED - 1 + macrophage invasion and the upregulation of cytokines , including interleukin - 1β ( IL - 1β ) , interleukin - 6 ( P05231 ) , tumor necrosis factor α ( TNFα ) , and monocyte chemoattractant protein - 1 ( P13500 ) . Moreover , ___MASK52___ treatment blocked the CH - induced increases in expression of acid - sensitive ion channels ( ASICs ) in chemoafferent neurons in the petrosal ganglion ( PG ) . Our findings are consistent with the hypothesis that CH - induced inflammation involves the upregulation and release of ET - 1 from type I cells . ET - 1 may act in an autocrine / paracrine mechanism via P25101 receptors on chemosensory type I cells and immune cells to promote an inflammatory response .", "The vascular disrupting agent BNC105 potentiates the efficacy of P15692 and P42345 inhibitors in renal and breast cancer . BNC105 is a tubulin targeting compound that selectively disrupts vasculature within solid tumors . The severe tumor hypoxia and necrosis that ensues translates to short term tumor growth inhibition . We sought to identify the molecular and cellular events activated following BNC105 treatment that drives tumor recovery . We investigated tumor adaptation to BNC105 - induced hypoxia in animal models of breast and renal cancer . HIF - 1α and P11166 were found to be strongly upregulated by BNC105 as was the P15692 signaling axis . Phosphorylation of P42345 , 4E - BP - 1 and elF2α were upregulated , consistent with increased protein synthesis and increased expression of P15692 . We sought to investigate the potential therapeutic utility of combining BNC105 with agents targeting P15692 and P42345 signaling . DB00112 and pazopanib target the P15692 axis and have been approved for first line use in renal cancer . DB01590 targets P42345 and is currently approved in second line therapy of renal and particular breast cancers . We combined these agents with BNC105 to explore the effects on tumor vasculature , tumor growth inhibition and animal survival . DB00112 hindered tumor vascular recovery following BNC105 treatment leading to greater tumor growth inhibition in a breast cancer model . Consistent with this , addition of BNC105 to pazopanib treatment resulted in a significant increase in survival in an orthotopic renal cancer model . Combination treatment of BNC105 with everolimus also increased tumor growth inhibition . BNC105 is currently being evaluated in a randomized phase II clinical trial in combination with everolimus in renal cancer .", "Activity of bevacizumab ( rhuMAB P15692 ) in advanced refractory epithelial ovarian cancer . BACKGROUND : Angiogenesis is pivotal in the development and progression of ovarian cancer and is an ideal candidate for novel treatment approaches . CASE : A case of advanced , recurrent and refractory serous carcinoma is presented that responded to bevacizumab 15 mg / m2 intravenously every 3 weeks after failing eleventh line cytotoxic chemotherapy and radiation . An objective durable response lasting at least 5 months was documented . CONCLUSION : DB00112 has activity in epithelial ovarian carcinoma and larger scale trials are indicated .", "DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .", "Macular infarction following intravitreal bevacizumab for treatment of central retinal vein occlusion . DB00112 , a monoclonal antibody against vascular endothelial growth factor ( P15692 ) , is widely used for the treatment of macular edema associated with central retinal vein occlusion ( CRVO ) . The authors present a series of three patients with CRVO who suffered apparent macular infarction within weeks of intravitreal administration of bevacizumab . Of the nearly 200 patients undergoing intravitreal injections of bevacizumab for this indication over a surveillance period of 3 years , this event occurred in three patients . This has not been described in the natural history of the disease and is associated with poor visual outcomes .", "[ Acceptable safety of bevacizumab therapy in combination with chemotherapy in patients with advanced lung cancer . ] . BACKGROUND : DB00112 is a recombinant humanized monoclonal IgG1 antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor ( P15692 ) . DB00112 was approved by the U . S . Food and Drug Administration ( FDA ) in October 2006 for use in combination with carboplatin and paclitaxel for the initial treatment of patients with unresectable , locally advanced , recurrent , or metastatic , nonsquamous , non - small cell lung cancer ( NSCLC ) . The aim of this study is to observe the safety of bevacizumab therapy in combination with chemotherapy in Chinese patients with NSCLC . METHODS : Patients with advanced non - squamous NSCLC were treated with DB00112 15 mg / kg , d1 , repeated every 21 days until PD ; Plus paclitaxel 175 mg / m ( 2 ) , on dl and carboplatin AUC = 6 on dl . The cycle was repeated every 21 days . RESULTS : One grade 3 epistaxis was observed in one patient . One grade 4 thrombosis was observed in one patient . 3 / 4 - grade epistaxis and thrombosis was the most significant adverse events . Other adverse effects , such as hemoptysis , hypertension and proteinuria , were not severe and could be well tolerated . CONCLUSIONS : Most chemotherapy - naive patients with advanced non - squamous NSCLC treated with bevacizumab in combination with paclitaxel and carboplatin have little adverse effects that can be well tolerated .", "Anti - angiogenesis therapy in pancreatic carcinoma . Pancreatic adenocarcinoma is a leading cause of cancer death in the United States and represents a challenging chemotherapeutic problem . The treatment of advanced pancreatic cancer with gemcitabine has only modest activity with a small survival benefit , and toxicity continues to be a major obstacle . New therapeutic strategies that notably lack cross resistance with established treatment regimens are much needed in pancreatic cancer . One such approach is the pharmacological control of angiogenesis that represents a novel approach to the management of pancreas cancer , since the pathological development of vascular supply is a critical step for tumor growth and may affect its prognosis . Since pancreatic carcinoma show strong tumor neoangiogenesis , overexpression of vascular endothelial growth factor ( P15692 ) , a key mediator of angiogenesis , in pancreatic cancer and consequently are highly vascularized , the role of anti - angiogenic therapies is under exploration at present . Hence , this review covers the summary of the development of anti - angiogenesis as anti - antitumor therapy in pancreatic carcinoma , including matrix - metalloproteinase inhibitors ( MMPIs ) , such as marimastat and BAY 12 - 9566 , anti - P15692 agent , bevacizumab ( DB00112 , Genentech , South San Francisco , CA , USA ) , celecoxib ( a cyclooxygenase - 2 inhibitor ) , thalidomide and others . Role of markers of angiogenesis in predicting response to therapy is also discussed .", "DB00112 exhibits therapeutic effects on collagen - induced arthritis in rat model . DB00112 is the monoclonal antibody for vascular endothelial growth factor ( P15692 ) . This study aimed to investigate therapeutic effect of DB00112 on type II collagen - induced arthritis . Type II chicken collagen was injected into the tails of Wistar rats , and 60 modeled female rats were randomly divided into three groups ( n = 20 ) : DB00112 group , DB00005 group , and control group . Arthritis index and joint pad thickness were scored , and the pathology of back metapedes was analyzed . The results showed that compared to control group , the arthritis index , target - to - non - target ratio , synovial pathological injury index , serum levels of P15692 and tumor necrosis factor alpha , and P15692 staining were decreased significantly 14 days after DB00112 or DB00005 treatment , but there were no significant differences between DB00112 group and DB00005 group . These data provide evidence that DB00112 exhibits similar effects to DB00005 to relieve rheumatoid arthritis in rat model and suggest that DB00112 is a promising therapeutic agent for rheumatoid arthritis .", "Emerging treatments for castrate - resistant prostate cancer . Castrate - resistant prostate cancer ( CRPC ) is a challenging aspect in the treatment of prostate cancer . Research has identified several pathways in the pathogenesis of CRPC . Several new agents targeting some of these pathways have shown promising data during clinical trials . In the area of androgen depletion , abiraterone acetate and MDV100 have been studied and have shown to decrease prostate - specific antigen ( PSA ) levels in phase I and II studies . DB00112 is a monoclonal antibody antiangiogenesis agent that targets vascular endothelial growth factor ( P15692 ) and has shown to decrease PSA levels in combination with other cytotoxic agents . Three agents , ixabepilone , patupilone , and sagopilone , in the class of epothilones ( tubulin polymerizing antitumor agents ) , have shown moderate reductions in PSA levels and moderate adverse effects . The results of ongoing studies with these new treatment agents may offer viable alternatives to the traditional treatment of CRPC to decrease disease progression and improve overall survival .", "Quantifying the increasing use of anti - vascular endothelial growth factor therapy in ophthalmology . INTRODUCTION : DB00112 ( DB00112 ; Genetech Inc . , South San Francisco , CA ) and ranibizumab ( Lucentis , Genetech Inc . ) are two anti - Vascular Endothelial Growth Factor ( P15692 ) agents used in increasing amounts off - label to treat ocular conditions . To date , no study has quantified how far reaching these therapies have been in treating eye disease and compared their off - label use to the number of clinical trials performed . METHOD : A systematic search of Ovid MEDLINE using the keywords bevacizumab and ranibizumab limited to \" Case Reports \" was used as an index of the number of diseases treated . Each keyword was also limited to \" Clinical Trials , All \" and \" Phase III Clinical Trials \" to discern the quality of evidence for these uses . RESULTS : DB00112 has been utilized for the treatment of 58 different ocular conditions , but only 14 conditions were studied in a trial , and none were part of a phase III clinical trial . DB01270 has been used for 17 different eye conditions , with only 6 studied in a trial and only 1 disease , \" wet \" age - related macular degeneration reported in 4 phase III trials . In the case reports , there were 21 different adverse events ascribed to bevacizumab and 2 to ranibizumab with retinal pigment epithelial tears being the most common . CONCLUSION : DB00112 is one of the most far reaching drugs in ophthalmology and even medicine , but it is not yet supported by high quality evidence . The much higher cost of ranibizumab may be responsible for bevacizumab ' s popularity among eye specialists . Patients should be fully informed about the off - label use of bevacizumab and the associated risks with its use .", "Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .", "Angiogenesis inhibitors and vascular disrupting agents in non - small cell lung cancer . Most patients diagnosed with non - small cell lung cancer ( NSCLC ) have advanced disease . Chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients . Considerable efforts have been initiated to identify novel targets for new biological agents which may be safely and effectively administered to NSCLC patients . New blood vessel formation , known as angiogenesis , is a fundamental event in the process of tumor growth and metastatic dissemination . The vascular endothelial growth factor ( P15692 ) and its receptors play an essential role in tumor proliferation . Approaches to limit P15692 activity include monoclonal antibodies ( mAbs ) and small molecules inhibiting the corresponding receptor - tyrosine kinase activity . DB00112 , an anti - P15692 recombinant humanized mAb , is the first targeted agent which , when combined with chemotherapy , has shown superior efficacy versus chemotherapy alone as first - line treatment of advanced NSCLC . Future clinical developments of bevacizumab in NSCLC treatment include the combination with other targeted therapies in advanced disease , and the integration into the combined modality approaches for the treatment of early and locally advanced disease stages . DB05294 , a small molecule targeting P15692 tyrosine - kinase activity , due to first indications of antitumor activity and the excellent toxicity profile seems to be a promising agent for the treatment of advanced NSCLC . Other antiangiogenic drugs , such as sorafenib , sunitinib , DB08885 and a new class named ' vascular disrupting agents ' , which includes ASA404 , are being tested in ongoing clinical trials which will further define their role in the management of NSCLC . This paper reviews the state of the art and the future developments of the main antiangiogenic agents in the treatment of NSCLC patients .", "Antagonism of endothelin action normalizes altered levels of P15692 and its signaling in the brain of stroke - prone spontaneously hypertensive rat . Stroke - prone spontaneously hypertensive rats ( SHRSP ) often suffer from spontaneous stroke , in part , due to abnormalities in the cerebrovasculature . Here , we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age - dependent stages of hypertension . The profile of P15692 and its receptor , Flk - 1 , was dependent on age and stage of hypertension ( i . e . , down regulated at pre - hypertensive and malignant hypertensive stages , but up regulated at typical hypertensive stage ) , while that of its downstream components , pAkt and P29474 , were down regulated in a time - dependent manner in the frontal cortex of SHRSP compared to age - matched genetic control , normotensive WKY rats . On the other hand , the expression of endothelin - 1 and its type A receptor ( endothelin P25101 receptor ) were up regulated , depending on age and stage of hypertension . In contrast , levels of endothelin type B receptor were down regulated . The regional cerebral blood flow decreased during the development of malignant hypertension . Thus , subsequent experiments were designed to investigate whether endothelin - 1 receptor antagonism , using endothelin - A /- B dual receptor antagonist SB209670 , could normalize the molecular profile of these factors in SHRSP brain . Interestingly , blockage of endothelin - 1 receptor restored to normal , levels of cerebral endothelin - 1 , endothelin P25101 receptor and endothelin ETB receptor ; P15692 and Flk - 1 ; endothelial nitric oxide synthase ( P29474 ) and pAkt , in SHRSP , compared to age - matched WKY . Endothelin receptor blocker might be important to prevent the progression in the defect in P15692 and its angiogenic signaling cascade in the pathogenesis of hypertension - induced vascular remodeling in frontal cortex of SHRSP rats .", "Advanced gynecologic malignancies treated with a combination of the P15692 inhibitor bevacizumab and the P42345 inhibitor temsirolimus . BACKGROUND : DB00112 and temsirolimus are active agents in gynecologic tumors . ___MASK28___ attenuates upregulation of HIF - 1α levels , a resistance mechanism for antiangiogenics , and targets the P19957 - kinase / AKT / P42345 axis , commonly aberrant in these tumors . PATIENTS AND METHODS : We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus . RESULTS : Median age of the 41 women was 60 years ( range , 33 - 80 years ) ; median number of prior systemic therapies was 4 ( 1 - 11 ) . Grade 3 or 4 treatment - related toxicities included : thrombocytopenia ( 10 % ) , mucositis ( 2 % ) , hypertension ( 2 % ) , hypercholesterolemia ( 2 % ) , fatigue ( 7 % ) , elevated aspartate aminotransferase ( 2 % ) , and neutropenia ( 2 % ) . Twenty - nine patients ( 71 % ) experienced no treatment - related toxicity greater than grade 2 . Q8N1N2 FDA - approved doses of both drugs ( bevacizumab 15mg / kg IV Q3weeks and temsirolimus 25mg IV weekly ) were administered without dose - limiting toxicity . Eight patients ( 20 % ) achieved stable disease ( SD ) > 6 months and 7 patients ( 17 % ) , a partial response ( PR ) [ total = 15 / 41 patients ( 37 % ) ] . Eight of 13 patients ( 62 % ) with high - grade serous histology ( ovarian or primary peritoneal ) achieved SD > 6 months / PR . CONCLUSION : DB00112 and temsirolimus was well tolerated . Thirty - seven percent of heavily - pretreated patients achieved SD > 6 months / PR , suggesting that this combination warrants further study .", "Antitumor effect and antiangiogenic potential of the P42345 inhibitor temsirolimus against malignant pleural mesothelioma . The P42345 inhibitor temsirolimus has antitumor and antiangiogenic activity against several carcinomas , yet few reports document the efficacy of temsirolimus against malignant pleural mesothelioma ( MPM ) . Therefore , we evaluated the efficacy of temsirolimus and the antiangiogenic effect of temsirolimus in the treatment of MPM . We examined the efficacy of temsirolimus alone and the efficacy of the combination of temsirolimus and cisplatin or pemetrexed against four MPM cell lines using the 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyl tetrazolium bromide ( MTT ) assay . The effect of temsirolimus on the production of proangiogenic cytokines by MPM cell lines was examined by enzyme - linked immunosorbent assay ( ELISA ) . Expression of P42345 and proangiogenic cytokines in clinical specimens from MPM patients was determined by immunohistochemistry . ___MASK28___ inhibited cell viability and suppressed cell proliferation of all MPM cell lines . Combined treatment with temsirolimus and cisplatin inhibited the viability of all MPM cell lines more effectively than temsirolimus alone . ___MASK28___ strongly inhibited the phosphorylation of p70s6k , a downstream molecule of P42345 , in all MPM cell lines and led to an increase in the levels of cleaved caspase - 3 in the H226 and Y - meso14 cells . ___MASK28___ also inhibited the production of vascular endothelial growth factor ( P15692 ) and platelet - derived growth factor - AA ( PDGF - AA ) . Phosphorylated P42345 and high expression of P15692 and PDGF were detected in 2 and 3 , respectively , out of the 5 MPM specimens . These results suggest that temsirolimus has activity against MPM cells by inhibition of cell proliferation and angiogenesis , and may be beneficial for a subset of MPM patients with high P42345 expression .", "Induction of high mobility group box 1 release from serotonin - stimulated human umbilical vein endothelial cells . High mobility group box 1 ( P09429 ) is a non - histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis . The P09429 functions as a potent proinflammatory cytokine in the extracellular spaces . Recently , P09429 has been implicated in the progression of atherosclerosis . However , the association between P09429 and the development of atherosclerosis is poorly understood . Therefore , we examined whether serotonin ( 5 - HT ) , a key factor involved in the development of atherosclerosis , induced P09429 release in human umbilical vein endothelial cells ( HUVECs ) . We found that 5 - HT induced the release of P09429 but not of P27361 / 2 and JNK from HUVECs via the 5 - HT receptor ( P28222 ) / p38 mitogen - activated protein kinase ( MAPK ) signaling pathway . The p38MAPK inhibitor SB203580 and the P28222 antagonist GR55526 markedly inhibited P09429 release from 5 - HT - stimulated HUVECs . The vascular endothelial growth factor ( P15692 ) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis . We found that P09429 induced P15692 production in macrophage - like RAW264 . 7 cells . P09429 induced the activation of p38MAPK , P27361 / 2 and Akt . The P19957 - kinase inhibitor LY294002 significantly inhibited P15692 production in P09429 - stimulated macrophages , while other kinase inhibitors did not . These results suggest that P09429 release may contribute as a risk factor in the development and progression of atherosclerosis .", "DB00112 as first - line treatment for advanced non - small cell lung cancer . DB00112 is a humanized monoclonal antibody ( mAb ) to vascular endothelial growth factor ( P15692 ) , a major proangiogenic factor in advanced solid tumors . Phase I and II trial results suggested that this agent was well tolerated and could be combined with standard regimens in various solid tumors . An initial randomized phase II trial in advanced non - small cell lung cancer ( NSCLC ) yielded positive results regarding the potential efficacy of this agent in combination with carboplatin and paclitaxel ( CbP ) . It also identified a safety signal in patients with squamous histology , who appear to have a higher rate of serious and potentially life - threatening pulmonary hemorrhage . Because of this observation , patients with predominantly squamous histology were excluded from the pivotal phase III trials , as were patients with brain metastases and a history of significant hemoptysis . Two phase III trials comparing a standard platinum - based doublet with or without bevacizumab have been reported in advanced NSCLC , both of which met their primary endpoints . The trial reported by the Eastern Cooperative Oncology Group ( ECOG 4599 ) was the first to show an overall survival benefit , as well as a benefit in response rates and progression - free survival resulting from the addition of bevacizumab to CbP . Certain toxicities were increased when bevacizumab was added to CbP , including neutropenia , febrile neutropenia , thrombocytopenia , bleeding ( including pulmonary hemorrhage ) , hypertension and proteinuria . DB00112 is the first targeted therapeutic agent to improve survival in advanced NSCLC when added to standard chemotherapeutic regimens .", "DB00112 immune complexes activate platelets and induce thrombosis in P12318 transgenic mice . BACKGROUND : Treatment with DB00112 has been associated with arterial thromboembolism in colorectal cancer patients . However , the mechanism of this remains poorly understood , and preclinical testing in mice failed to predict thrombosis . OBJECTIVE : We investigated whether thrombosis might be the result of platelet activation mediated via the FcgammaRIIa ( IgG ) receptor - which is not present on mouse platelets - and aimed to identify the functional roles of heparin and platelet surface localization in Bev - induced FcgammaRIIa activation . METHODS AND RESULTS : We found that Bev immune complexes ( IC ) activate platelets via FcgammaRIIa , and therefore attempted to reproduce this finding in vivo using FcgammaRIIa ( hFcR ) transgenic mice . Bev IC were shown to be thrombotic in hFcR mice in the presence of heparin . This activity required the heparin - binding domain of Bev ' s target , vascular endothelial growth factor ( P15692 ) . DB01109 promoted Bev IC deposition on to platelets in a mechanism similar to that observed with antibodies from patients with heparin - induced thrombocytopenia . When sub - active amounts of ADP or thrombin were used to prime platelets ( simulating hypercoagulability in patients ) , Bev IC - induced dense granule release was significantly potentiated , and much lower ( sub - therapeutic ) heparin concentrations were sufficient for Bev IC - induced platelet aggregation . CONCLUSIONS : The prevailing rationale for thrombosis in Bev therapy is that P15692 blockade leads to vascular inflammation and clotting . However , we conclude that Bev can induce platelet aggregation , degranulation and thrombosis through complex formation with P15692 and activation of the platelet FcgammaRIIa receptor , and that this provides a better explanation for the thrombotic events observed in vivo .", "Anti - vascular endothelial growth factor drugs safety and efficacy in ophthalmic diseases . Macular degeneration is the leading cause of blindness in developed countries . In the treatment of neovascular age - related macular degeneration , vascular endothelial growth factor ( P15692 ) has emerged as a key target for therapy . The intravitreal injection of anti - P15692 drugs has been widely employed to reduce the disease progression and improve the visual outcomes of the affected patients . However , each intravitreal inoculation poses a risk of several complications as infection , inflammation , endophthalmitis , intraocular inflammation , increase of intraocular pressure and vitreous hemorrhage . This short review evaluates the efficacy and the incidence of adverse drug reactions related to intravitreal administration of the main anti - P15692 drugs actually available : DB00112 , ranibizumab and aflibercept .", "___MASK50___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .", "Intravitreal bevacizumab for photodynamic therapy - induced massive macular detachment in acute central serous chorioretinopathy . We present a long followed up case of acute central serous chorioretinopathy ( CSC ) complicated by a severe visual loss due to massive pigment epithelium detachment of the macula after a full - dose photodynamic therapy ( PDT ) . Rapid anatomical and functional improvement was observed after a single intravitreal injection of bevacizumab . To our knowledge , we report the first case of PDT - treated CSC complicated by severe visual loss . We can only speculate that the serous detachment of the posterior pole might have been caused by PDT - induced P15692 overexpression , explaining such an impressive response to DB00112 treatment .", "The role of vascular endothelial growth factor in the pathogenesis , diagnosis and treatment of malignant pleural effusion . Malignant pleural effusions ( MPEs ) are a significant source of cancer - related morbidity . Over 150 , 000 patients in the United States suffer from breathlessness and diminished quality of life due to MPE each year . Current management strategies are of mostly palliative value and focus on symptom control ; they do not address the pathobiology of the effusion , nor do they improve survival . Further elucidation of the pathophysiological mechanisms , coupled with the development of novel treatments such as intrapleural chemotherapeutics targeting this process , has the potential to greatly improve the efficacy of our current management options . Vascular endothelial growth factor - A ( P15692 ) has been implicated as a critical cytokine in the formation of malignant pleural effusions . Elevated levels of P15692 produced by tumor cells , mesothelial cells , and infiltrating immune cells result in increased vascular permeability , cancer cell transmigration , and angiogenesis . Therefore antiangiogenic therapies such as DB00112 , a monoclonal antibody targeting P15692 , may have a potential role in the management of malignant pleural effusions . Herein we review the pathogenesis and potential treatment strategies of malignant pleural effusions , with a focus on angiogenesis and antiangiogenic therapeutics .", "DB00112 enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression . PURPOSE : In recent years , anti - angiogenesis drugs have shown promising clinical effects against many tumors , particularly in combination with chemotherapy . Although the combination has become a standard of care for many tumors , the mechanisms of the chemosensitizing activity of anti - angiogenic drugs are not fully understood . Here , we sought to determine if anti - angiogenesis drug bevacizumab could enhance the chemosensitivity of HCC by inhibition of survivin . METHODS : After treatment of human umbilical vein endothelial cells ( HUVECs ) and hepatocellular carcinoma ( HCC ) cell line P98160 / PRF / 5 ( P98160 ) with bevacizumab or / and adriamycin , the direct effects were examined by survival assays , and the expression of Akt , Phospho - Akt and survivin were evaluated by western blot . Tumor growth was observed in a human HCC xenograft nude mouse model treated with different drugs , and the expression of P12004 , CD31 and survivin in tumor tissues were evaluated by means of immunohistochemistry . RESULTS : DB00112 enhanced the chemosensitivity of HCC by inhibiting the P15692 - PI3 K / Akt - survivin signaling cascade in endothelial cells . The combination of bevacizumab with adriamycin therapy resulted in better outcomes compared with monotherapy in hepatocellular carcinoma xenografts ; bevacizumab significantly inhibited tumor angiogenesis and growth . In addition , bevacizumab reduced survivin expression in tumor tissues , including tumor vascular endothelial cells in vivo , although it did not inhibit survivin expression in tumor cells in vitro . CONCLUSION : These results implicate the bevacizumab - increased efficacy of adriamycin via an inhibition of survivin expression in malignant cells as well as tumor vasculature cells , which provides other insights into the mechanism of enhanced efficacy by combination of P15692 blocker and chemotherapeutic agents .", "The evolving role of P15692 - targeted therapies in the treatment of metastatic colorectal cancer . Therapies that target angiogenesis and the P15692 pathway are a component of treatment for patients with metastatic colorectal cancer ( mCRC ) . DB00112 is a humanized monoclonal antibody that binds to P15692 . Chemotherapy plus bevacizumab has led to improved outcomes for mCRC patients . Despite these benefits , progressive disease invariably ensues . Multiple members of the P15692 family can potentially contribute to tumor angiogenesis and / or evasion of antiangiogenic therapy if one pathway should be inhibited . DB08885 , a new biological agent , is a multiple angiogenic factor trap that prevents not only P15692 , but also P49765 and P49763 from activating their native receptors . Key clinical data for bevacizumab and aflibercept for treatment of mCRC , clinical evidence for use of these agents beyond progression , and the search for angiogenic biomarkers to better define patients most likely to benefit from these interventions will be reviewed .", "___MASK56___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .", "Optimizing the dose and schedule of anti - vascular endothelial growth factor antibodies in non - small - cell lung cancer . Lung cancer is the world ' s leading cause of cancer death . Most patients with non - small - cell lung cancer ( NSCLC ) present with advanced disease . Median survival is approximately 8 - 10 months for patients who receive standard platinum - based doublet therapy . In 2006 the FDA approved the anti - vascular endothelial growth factor ( P15692 ) antibody bevacizumab for patients with advanced , non - squamous , NSCLC based on the Eastern Cooperative Oncology Group E4599 trial . This trial demonstrated a 2 - month improvement in overall survival when bevacizumab was added to carboplatin / paclitaxel . European investigators presented further data supporting improvement in progression - free survival with the use of bevacizumab and a cisplatin doublet in the DB00112 in Lung Cancer ( AVAiL ) trial . DB00112 at doses of 7 . 5 mg / kg and 15 mg / kg are both effective and safe for patients with advanced NSCLC . Fatal hemorrhage has been reported for patients receiving the antiangiogenesis antibody . According to a retrospective study , the only significant clinical and radiographic variable associated with increased risk of pulmonary hemorrhage is the presence of cavitation . Common side effects include hypertension , proteinuria and minor mucosal bleeding . DB00112 monotherapy given every 21 days can be safely continued for patients without evidence of progression and for whom side effects of therapy are acceptable . Many questions remain , such as the role of the anti - P15692 antibody in early - stage disease , the safety of bevacizumab in patients with squamous histology NSCLC , and the benefit of combination therapy in elderly patients ." ]

[ "___MASK15___", "___MASK16___", "___MASK23___", "___MASK28___", "___MASK37___", "___MASK40___", "___MASK50___", "___MASK52___", "___MASK56___" ]

[ "Effects of DNA polymerase inhibitors on replicative and repair DNA synthesis in ultraviolet - irradiated HeLa cells . Aphidicolin specifically inhibits eukaryotic DNA polymerase alpha , while 2 ', 3 '- dideoxythymidine 5 '- triphosphate ( d2TTP ) inhibits P06746 and gamma but not alpha . DB00987 5 '- triphosphate ( araCTP ) inhibits both DNA polymerase alpha and beta although to a different extent . Here we measured the effects of these inhibitors on repair DNA synthesis of U . V .- irradiated HeLa cells by two different methods . Firstly , aphidicolin , 1 - beta - D - arabinofuranosylcytosine ( araC , a precursor of araCTP ) and 2 ', 3 '- dideoxythimidine ( d2Thd , a precursor of d2TTP ) were added directly to the culture medium . In this case , aphidicolin and araC strongly inhibited replicative DNA synthesis of HeLa cells , and they also inhibited repair synthesis after U . V .- irradiation but to a much lesser extent . In contrast , high concentrations of d2Thd inhibited repair DNA synthesis to a higher extent than replicative DNA synthesis . Secondly , the active form of inhibitor , d2TTP , was microinjection directly into cytoplasm or nuclei or U . V .- irradiated HeLa cells . Microinjection of d2TTP effectively inhibited repair synthesis . The microinjection of d2TTP , into either cytoplasm or nucleus , strongly inhibited replicative synthesis . These results might indicate that multiple DNA polymerases are involved in repair synthesis as well as in replicative synthesis .", "___MASK13___ block of cloned human T - type voltage - gated calcium channels . ___MASK13___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .", "Characterization of the region of the short arm of chromosome 8 amplified in breast carcinoma . Chromosomal region 8p11 . 2 - p12 is consistently amplified in human breast cancer . We have constructed a 2 . 8 Mb YAC contig of this region , centered on the human Fibroblast Growth Factor Receptor 1 ( P11362 ) locus and encompassing the Adrenergic beta 3 Receptor ( P13945 ) locus . A smaller centromeric YAC contig spanning 1 . 4 Mb was also assembled , and included the Ankyrin 1 ( P16157 ) and Tissue - type P00747 Activator ( P00750 ) genes . Results from mapping of the contigs showed physical linkage of the P13945 and P11362 genes , which were colocalized within the same YAC clone and separated by about 900 kb , P11362 being in centromeric position . It also showed physical linkage of P16157 and P00750 genes , which appear to be separated by a maximum of 700 kb . In parallel , several loci were mapped according to their amplification status in a large panel of breast tumor samples . The overall amplification pattern suggested a continuous amplicon with a core around P11362 . Data from both the detailed physical map and the amplification status allowed to establish the following gene order , from telomere to centromere : P13945 - D8S105 - P11362 - P16157 - P00750 - P06746 . The precise localization and YAC cloning of the core of the amplicon will allow to isolate a putative oncogene involved in mammary carcinogenesis .", "Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK64___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK20___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "Transient overexpression of mitochondrial transcription factor A ( Q00059 ) is sufficient to stimulate mitochondrial DNA transcription , but not sufficient to increase mtDNA copy number in cultured cells . Mitochondrial transcription factor A ( Q00059 ) stimulates transcription from mitochondrial DNA ( mtDNA ) promoters in vitro and in organello . To investigate whether changes of Q00059 levels also modulate transcription and replication in situ , the protein was transiently overexpressed in cultured cells . Mitochondrial mRNAs were significantly elevated at early time points , when no expansion of the Q00059 pool was yet observed , but were decreased when Q00059 levels had doubled , resemb - ling in vitro results . P29320 cells contain about 35 molecules of Q00059 per mtDNA . High levels of Q00059 were not associated with increases of full - length mtDNA , but nucleic acid species sensitive to RNAse H increased . Stimulation of transcription was more evident when Q00059 was transiently overexpressed in cells pre - treated with ethidium bromide ( EBr ) having lowered mtDNA , Q00059 and mitochondrial transcript levels . EBr rapidly inhibited mtDNA transcription , while decay of mtDNA was delayed and preferentially slowly migrating , relaxed mtDNA species were depleted . In conclusion , we show that transcription of mtDNA is submaximal in cultured cells and that a subtle increase of Q00059 within the matrix is sufficient to stimulate mitochondrial transcription . Thus , this protein meets all criteria for being a key factor regulating mitochondrial transcription in vivo , but other factors are necessary for increasing mtDNA copy number , at least in cultured cells .", "Involvement of the pathway phosphatidylinositol - 3 - kinase / AKT - 1 in the establishment of the survival response to ionizing radiation . Ionizing radiation is one of the agents inducing activation of DNA repair , cell cycle arrest , apoptosis and cell death . Here we report evidence for an enhanced activity of P06746 , one of the repair enzymes , concomitant to the activation of the pathway phosphatidylinositol - 3 - kinase / AKT - 1 ( P19957 - kinase / AKT - 1 ) , which delivers a survival signal in Friend erythroleukemia cells exposed to 15 Gy . Significantly , the preincubation of the cellls with P19957 - kinase inhibitors wortmannin and LY 294002 , disactivating this pathway , sensitizes the cells to ionizing radiation by further reducing the rate of proliferation without substantial variations of the number of dead cells . Thus , we suggest a role for these enzymes in maintaining survival programs upon exposure to ionizing radiation and in giving to these cells a chance to recover from this stress .", "Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is required in murine cell lines for base excision repair of oxidative DNA damage in the absence of P06746 . Oxidative DNA base damage is mainly corrected by the base excision repair ( BER ) pathway , which can be divided into two subpathways depending on the length of the resynthetized patch , either one nucleotide for short patch BER or several nucleotides for long patch BER . The role of proteins in the course of BER processes has been investigated in vitro using purified enzymes and cell - free extracts . In this study , we have investigated the repair of 8 - oxo - 7 , 8 - dihydroguanine ( 8 - oxoG ) in vivo using wild - type , polymerase beta (-/-) ( Polbeta (-/-) ) , poly ( ADP - ribose ) polymerase - 1 (-/-) ( P09874 (-/-) ) , and Polbeta (-/-) P09874 (-/-) 3T3 cell lines . We used non replicating plasmids containing a 8 - oxoG : C base pair to study the repair of the lesion located in a transcribed sequence ( TS ) or in a non - transcribed sequence ( P30990 ) . The results show that 8 - oxoG repair in TS is not significantly impaired in cells deficient in Polbeta or P09874 or both . Whereas 8 - oxoG repair in P30990 is normal in Polbeta - null cells , it is delayed in P09874 - null cells and greatly impaired in cells deficient in both Polbeta and P09874 . The removal of 8 - oxoG and presumably the cleavage at the resulting apurinic / apyrimidinic site are not affected in the P09874 (-/-) Polbeta (-/-) cell lines . However , 8 - oxoG repair is incomplete , yielding plasmid molecules with a nick at the site of the lesion . Therefore , P09874 (-/-) Polbeta (-/-) cell lines can not perform 5 '- dRP removal and / or DNA repair synthesis . Furthermore , the poly ( ADP - ribosyl ) ation activity of P09874 is essential for 8 - oxoG repair in a Polbeta (-/-) context , because expression of the catalytically inactive P09874 ( E988K ) mutant does not restore 8 - oxoG repair , whereas an wild type P09874 does .", "___MASK86___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK86___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .", "Inhibition of mammalian DNA polymerases by recombinant alpha - interferon and gamma - interferon . Interferons ( IFNs ) have been shown to suppress the growth of both normal and malignant cells . We examined the effect of gene - cloned IFN - alpha and P01579 on the in vitro activities of human , calf , or rat DNA polymerases . IFN - alpha strongly inhibited the reactions of DNA polymerase alpha and beta at apparent Ki values of 1 . 25 and 0 . 35 x 10 ( 5 ) antiviral units / ml , respectively , but inhibited DNA polymerase gamma only slightly . P01579 inhibited the reaction of DNA polymerase alpha more strongly ( Ki , 1 . 2 x 10 ( 4 ) units / ml ) than IFN - alpha , but not that of P06746 . On the other hand , neither IFN - alpha nor P01579 inhibited the reactions of DNA polymerase I from Escherichia coli , Klenow fragment , T - 4 DNA polymerase , and RNA polymerase . The fact that Ki values for IFN - alpha of DNA polymerase from calf thymus , human leukemic cells , and rat liver were similar suggests the absence of species specificity among animals with regard to the inhibition of DNA polymerases by IFNs . These results indicate that DNA polymerase may be one of the targets of the action of IFNs .", "Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK28___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .", "New features of mitochondrial DNA replication system in yeast and man . In this review , we sum up the research carried out over two decades on mitochondrial DNA ( mtDNA ) replication , primarily by comparing this system in Saccharomyces cerevisiae and Homo sapiens . Brief incursions into systems of other organisms have also been achieved when they provide new information . S . cerevisiae and H . sapiens mitochondrial DNA ( mtDNA ) have been thought for a long time to share closely related architecture and replication mechanisms . However , recent studies suggest that mitochondrial genome of S . cerevisiae may be formed , at least partially , from linear multimeric molecules , while human mtDNA is circular . Although several proteins involved in the replication of these two genomes are very similar , divergences are also now increasingly evident . As an example , the recently cloned human mitochondrial P06746 - subunit has no counterpart in yeast . Yet , yeast Abf2p and human Q00059 are probably not as closely functionally related as thought previously . Some mtDNA metabolism factors , like DNA ligases , were until recently largely uncharacterized , and have been found to be derived from alternative nuclear products . Many factors involved in the metabolism of mitochondrial DNA are linked through genetic or biochemical interconnections . These links are presented on a map . Finally , we discuss recent studies suggesting that the yeast mtDNA replication system diverges from that observed in man , and may involve recombination , possibly coupled to alternative replication mechanisms like rolling circle replication .", "Forced dimerization increases the activity of Δ P00533 / EGFRvIII and enhances its oncogenicity . Delta epidermal growth factor receptor ( Δ P00533 ) , an in - frame deletion mutant of the extracellular ligand - binding domain , which occurs in about 30 % of glioblastoma , is a potent oncogene that promotes tumor growth and progression . The signaling of Δ P00533 is ligand - independent and low intensity , allowing it to evade the normal mechanisms of internalization and degradation by the endocytic machinery and hence is persistent . The basis of the oncogenic potential of Δ P00533 remains incompletely understood , including whether dimerization plays an important role in its signal and whether its oncogenic potential is dependent on its relatively low intensity , when compared with the acutely activated wild - type receptor . To examine these two important questions , we have generated a chimeric Δ P00533 that allows forced dimerization via domains derived from variants of the P62942 protein that are brought together by FK506 derivatives . Forced dimerization of chimeric Δ P00533 significantly increased the intensity of its signal , as measured by receptor phosphorylation levels , suggesting that the naturally occurring Δ P00533 does not form strong or stable dimers as part of its low level signal . Interestingly , the increased activity of dimerized , chimeric Δ P00533 did not promote receptor internalization , implying that reduced rate of endocytic downregulation of Δ P00533 is an inherent characteristic . Significantly , forced dimerization enhanced the oncogenic signal of the receptor , implying that the Δ P00533 is a potent oncogene despite , not because of its low intensity .", "Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine - treated schizophrenic patients . RATIONALE : ___MASK69___ , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 , P35462 , P28223 , and P28335 ) on short - term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty - seven Estonian inpatients were evaluated before and after 4 - 6 weeks of treatment by Simpson - Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 , P35462 , P28223 , and P28335 gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 and the - 697C and 23Ser alleles of P28335 were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0 . 02 , 0 . 01 , and 0 . 02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 and P35462 genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 and P28335 genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .", "aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK35___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .", "P49674 / P35222 are synthetic lethal to P04637 in colorectal cancer and are markers for prognosis . Two genes are called synthetic lethal ( SL ) if their simultaneous mutations lead to cell death , but each individual mutation does not . Targeting SL partners of mutated cancer genes can kill cancer cells specifically , but leave normal cells intact . We present an integrated approach to uncovering SL pairs in colorectal cancer ( CRC ) . Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues , we first identified potential functionally relevant ( simultaneously differentially expressed ) gene pairs . From the top - ranked pairs , ~ 20 genes were chosen for immunohistochemistry ( IHC ) staining in 171 CRC patients . To find novel SL pairs , all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features , e . g . overall survival . Of the 11 predicted SL pairs , P43246 - P06746 and P49674 - MYC were consistent with literature , and we validated the top two pairs , P49674 - P04637 and P35222 - P04637 using RNAi knockdown and small molecule inhibitors of P49674 in isogenic HCT - 116 and RKO cells . Furthermore , synthetic lethality of P49674 and P04637 was verified in mouse model . Importantly , multivariate analysis revealed that P49674 - P04637 , P35222 - P04637 , P43246 - P06400 , and P38398 - P41221 were independent prognosis markers from stage , with P49674 - P04637 applicable to early - stage and the remaining three throughout all stages . Our findings suggest that P49674 is a promising target for P04637 - mutant CRC patients which constitute ~ 40 % to 50 % of patients , while to date safety regarding inhibition of P04637 is controversial . Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics , and it is readily accessible and applicable to other cancers .", "___MASK26___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK26___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .", "Anti - clastogenic effect of beta - glucan extracted from barley towards chemically induced DNA damage in rodent cells . beta - Glucan ( BG ) was tested in vitro to determine its potential clastogenic and / or anti - clastogenic activity , and attempts were made to elucidate its possible mechanism of action by using combinations with an inhibitor of DNA polymerase . The study was carried out on cells deficient ( CHO - k1 ) and cells proficient ( HTC ) in phases I and II enzymes , and the DNA damage was assessed by the chromosomal aberration assay . BG did not show a clastogenic effect , but was anti - clastogenic in both cell lines used , and at all concentrations tested ( 2 . 5 , 5 and 10 microg / mL ) in combination with damage inducing agents ( methylmethane sulfonate in cell line CHO - k1 , and methylmethane sulfonate or 2 - aminoanthracene in cell line HTC ) . BG also showed a protective effect in the presence of a P06746 inhibitor ( cytosine arabinoside - 3 - phosphate , DB00987 ) , demonstrating that BG does not act through an anti - mutagenic mechanism of action involving P06746 .", "Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair . We present an oligonucleotide microarray ( \" MetaboChip \" ) based on the arrayed primer extension ( P27695 ) technique , allowing genotyping of single nucleotide polymorphisms ( SNPs ) in genes of interest for cancer susceptibility and pharmacogenetics . P27695 consists of a sequencing reaction primed by an oligonucleotide anchored with its 5 ' end to a glass slide and terminating one nucleotide before the polymorphic site . The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism . Ninety - three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project , using a set of 102 reference DNA samples from the Coriell Biorepository . Selected SNPs belong to the following genes : P00325 , P05091 , P27695 , CDKN2A , P21964 , P04798 , P05177 , Q16678 , P11509 , P33261 , P11712 , P05181 , P08684 , P14416 , P21917 , P07099 , P07992 , P18074 , Q92889 , P28715 , P30550 , O15217 , P21266 , P09211 , GSTT2 , LIG3 , Q00987 , P16455 , P05164 , NAT1 , NAT2 , P15559 , O15527 , P12004 , P06746 , Q01959 , P04179 , P04637 , P18887 , O43543 , O43542 , and O15287 . We assessed the performance of P27695 by comparing the results obtained with MetaboChip against those reported by the SNP500 . Among 88 SNPs that yielded signals , 6 showed less than 99 % of concordance , whereas 82 performed accurately , showing that P27695 is a reliable and sensitive genotyping method .", "Cloning , mutagenesis , and structural analysis of human pancreatic alpha - amylase expressed in Pichia pastoris . Human pancreatic alpha - amylase ( Q9Y251 ) was expressed in the methylotrophic yeast Pichia pastoris and two mutants ( D197A and D197N ) of a completely conserved active site carboxylic acid were generated . All recombinant proteins were shown by electrospray ionization mass spectrometry ( P19957 - MS ) to be glycosylated and the site of attachment was shown to be Asn461 by peptide mapping in conjunction with P19957 - MS . Treatment of these proteins with endoglycosidase F demonstrated that they contained a single N - linked oligosaccharide and yielded a protein product with a single N - acetyl glucosamine ( GlcNAc ) , which could be crystallized . Solution of the crystal structure to a resolution of 2 . 0 A confirmed the location of the glycosyl group as Asn461 and showed that the recombinant protein had essentially the same conformation as the native enzyme . The kinetic parameters of the glycosylated and deglycosylated wild - type proteins were the same while the k ( cat )/ Km values for D197A and D197N were 10 ( 6 )- 10 ( 7 ) times lower than the wild - type enzyme . The decreased k ( cat )/ Km values for the mutants confirm that D197 plays a crucial role in the hydrolytic activity of Q9Y251 , presumably as the catalytic nucleophile .", "Modulation of arsenic - induced epidermal growth factor receptor pathway signalling by resveratrol . Arsenic ( As ) is both a human carcinogen and an effective anticancer drug . These aspects of arsenic toxicity develop as a consequence of arsenic - induced oxidative stress and modifications to signal pathway activity which alter gene expression . DB02709 ( RVL ) a food antioxidant found in grapes and other fruits , exhibits anti - carcinogenic properties by reducing oxidative stress and restoring signal pathway control . This study investigated the impact of RVL on arsenite [ As ( III ) ] - induced cell signalling in HaCaT keratinocytes by assaying phosphorylation status of epidermal growth factor receptor ( P00533 ) signalling intermediates and measuring changes in expression of Phase II and DNA repair biomarkers . As ( III ) exposure produced dose - dependent toxicity which was associated with increased activation of P00533 pathway intermediates , cSrc , Rac1 and extracellular signal - regulated kinases 1 and 2 ( P27361 / 2 ) . Arsenic - mediated P27361 / 2 activation negatively regulated P06746 expression and up regulated heme - oxygenase - 1 at toxic concentrations . RVL treatment modulated As ( III )- mediated P27361 / 2 activation by shifting the balance of cSrc regulatory domain phosphorylation . These effects significantly altered the response of the P00533 pathway to growth factor - induced stimulation . Our research provides evidence that treatment with pharmacologically relevant doses of RVL influences cellular responses to As ( III ) , largely due to RVL - mediated changes to Src and P27361 / 2 activation .", "Effects of 1 - beta - D - arabinofuranosylcytosine incorporation on elongation of specific DNA sequences by P06746 . DB00987 ( ara - C ) is an effective antileukemic agent which acts as an inhibitor of DNA synthesis . The precise mechanism responsible for this inhibitory effect , however , remains unclear . The present work has examined the effects of the triphosphate derivative , ara - P53007 , on purified P06746 . These studies were performed on M13 phage DNA templates of defined sequence . The results demonstrate that ara - C is incorporated into DNA by P06746 . The results also demonstrate that the incorporated ara - C residue acts as a relative chain terminator . Moreover , the relative chain terminating effects of ara - C are sequence specific . In this regard , DNA strand elongation was progressively slowed at sequences of two , three , and four contiguous sites for cytosine incorporation . We also demonstrate that the inhibitory effects of ara - C are reversed by competition with deoxycytidine - triphosphate for incorporation into the DNA strand . Taken together , these findings are consistent with structural differences of the incorporated arabinosyl moiety which alter reactivity of the 3 '- terminus and thereby inhibit chain elongation . These findings also provide new insights regarding the inhibitory effects of ara - C on elongation of specific DNA sequences .", "The Role of Different Supplements in Expression Level of Monoclonal Antibody against Human P11836 . BACKGROUND : Recombinant monoclonal antibodies have been marketed in last three decades as the major therapeutic proteins against different cancers . However choosing a proper medium and supplements to reach the high expression is a challenging step . Despite of commercial serum free and chemically defined media , there are still numerous researches seeking the optimum media to gain higher expression titer . Selecting the best basal media followed by proper supplementation to increase the cell density and expression titer needs proper and accurate investigation . METHODS : In this study , we have determined the expression titer of monoclonal antibody against human P11836 using soy extract , Essential Amino Acid , Non - Essential Amino Acid , Panexin P30990 , Peptone , Yeast extract , P01308 - transferrin selenite , DB00062 , Bovine Serum Albumin , Lipid , and two commercially available supplements , Power and Xtreme feed . In each experiment , the expression level was compared with a well defined media , ProCHO5 , RPMI 1640 and DMEM - P00748 . RESULTS : It has been shown that supplementing the ProCHO5 basal medium with 10 % power feed or combination of 5 % PanexinNTS , 1 . 5 g / L yeast and 1 . 5g / L peptone results in the best production levels with 450 and 425 mg / L of anti P11836 mAb expression level , respectively . CONCLUSION : Panexin P30990 , yeast and peptone cane be proper supplement for fed - batch cell culture instead of commercial Power feed supplement which is a cost effective way to increase expression level . And thereby ProCHO5 may be replaced with common media such as RPMI 1640 and DMEM - P00748 .", "The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .", "Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK8___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility ." ]

[ "___MASK13___", "___MASK20___", "___MASK26___", "___MASK28___", "___MASK35___", "___MASK64___", "___MASK69___", "___MASK86___", "___MASK8___" ]

[ "Regulation of 5 - HT receptors and the hypothalamic - pituitary - adrenal axis . Implications for the neurobiology of suicide . Disturbances in the serotonin ( 5 - HT ) system is the neurobiological abnormality most consistently associated with suicide . Hyperactivity of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis is also described in suicide victims . The Q9Y251 axis is the classical neuroendocrine system that responds to stress and whose final product , corticosteroids , targets components of the limbic system , particularly the hippocampus . We will review results from animal studies that point to the possibility that many of the 5 - HT receptor changes observed in suicide brains may be a result of , or may be worsened by , the Q9Y251 overactivity that may be present in some suicide victims . The results of these studies can be summarized as follows : ( 1 ) chronic unpredictable stress produces high corticosteroid levels in rats ; ( 2 ) chronic stress also results in changes in specific 5 - HT receptors ( increases in cortical 5 - Q13049 and decreases in hipocampal P08908 and P28222 ) ; ( 3 ) chronic antidepressant administration prevents many of the 5 - HT receptor changes observed after stress ; and ( 4 ) chronic antidepressant administration reverses the overactivity of the Q9Y251 axis . If indeed 5 - HT receptors have a partial role in controlling affective states , then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood . These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance .", "Clinical pharmacology of serotonin - altering medications for decreasing alcohol consumption . Variations in serotonin neurotransmission influence alcohol consumption ( AC ) . Levels of 5 - HT and metabolites are low in some brain regions of alcohol preferring rats and in P04141 of alcoholics . Pharmacological treatments which enhance serotonergic neurotransmission ( uptake inhibitors , releasers , agonists ) consistently reduce AC in rats . Serotonin uptake inhibitors ( SUI ; e . g . , citalopram , fluoxetine ) have been studied extensively in humans . In several double - blind randomized , placebo - controlled clinical trials , SUI have consistently decreased AC by averages of 15 % to 20 % in nondepressed mildly / moderately dependent alcoholics who received no other treatment . Effects were dose - dependent and not related to side effects ( few and mild ) or changes in anxiety or depression ( not observed ) . SUI also decreased desire to drink and liking for alcohol , thus suggesting a mechanism for effects . Other drugs acting on the 5 - HT system have been tested in humans , but results are difficult to interpret . For example , buspirone , a P08908 receptor partial agonist , reduced anxiety and alcohol craving , but not AC ; a 5 - HT partial agonist , m - CPP , increased alcohol craving in abstinent alcoholics ; modest reductions in AC were observed with a 5 - Q9H205 antagonist , ondansetron ( 0 . 5 mg / day , but not 4 mg / day ) . The therapeutic potentials of these medications are being studied . For example , SUI effects on AC were enhanced by a brief psychosocial intervention . Since SUI decrease urge to drink , they may be suitable pharmacological adjuncts in relapse prevention strategies . SUI and other serotonin - altering medications are promising new neuropharmacological treatments for reducing AC .", "Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .", "The antimalarial drug mefloquine inhibits cardiac inward rectifier K + channels : evidence for interference in PIP2 - channel interaction . The antimalarial drug mefloquine was found to inhibit the KATP channel by an unknown mechanism . Because mefloquine is a Cationic amphiphilic drug and is known to insert into lipid bilayers , we postulate that mefloquine interferes with the interaction between PIP2 and Kir channels resulting in channel inhibition . We studied the inhibitory effects of mefloquine on Kir2 . 1 , Kir2 . 3 , Kir2 . 3 ( I213L ) , and Kir6 . 2 / SUR2A channels expressed in P29320 - 293 cells , and on IK1 and Q14654 from feline cardiac myocytes . The order of mefloquine inhibition was Kir6 . 2 / SUR2A ≈ Kir2 . 3 ( IC50 ≈ 2 μM ) > Kir2 . 1 ( IC50 > 30 μM ) . Similar results were obtained in cardiac myocytes . The Kir2 . 3 ( I213L ) mutant , which enhances the strength of interaction with PIP2 ( compared to WT ) , was significantly less sensitive ( IC50 = 9 μM ) . In inside - out patches , continuous application of PIP2 strikingly prevented the mefloquine inhibition . Our results support the idea that mefloquine interferes with PIP2 - Kir channels interactions .", "A 4 - week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys . ___MASK47___ is indicated for the treatment of patients with breast cancer overexpressing human epidermal growth factor 2 ( P04626 ) . Women with P04626 - positive tumors have an increased risk of brain metastases . The blood - brain barrier and blood - cerebrospinal fluid ( P04141 ) barrier may prevent trastuzumab from reaching appropriate concentrations in the brain and P04141 following standard intravenous administration . To evaluate the potential of effects on the central nervous system , a 4 - week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0 , 3 , or 15 mg . No trastuzumab - related effects on body weight , clinical signs , neurological function , clinical pathology , or anatomic pathology were noted . The applied doses and P04141 concentrations achieved in the current study exceeded those reported in patients after intrathecal administration . The results support future studies for further evaluation of intrathecal application of trastuzumab in patients with brain metastases in P04626 - positive breast cancer .", "___MASK87___ - induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . ___MASK87___ - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin - induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 function - blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin - induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin - enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 .", "Attenuated P08908 receptor signaling in brains of suicide victims : involvement of adenylyl cyclase , phosphatidylinositol 3 - kinase , Akt and mitogen - activated protein kinase . Positron emission tomography studies in major depression show reduced serotonin ( 5 - HT ) 1A receptor antagonist - binding potentials in many brain regions including occipital cortex . The functional meaning of this observation in terms of signal transduction is unknown . We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of P08908 receptor activation . The diagnosis was established by means of psychological autopsy using Diagnostic and Statistical Manual of Mental Disorders ( DSM ) III - R criteria . Measurements of [ 35S ] GTPgammaS binding to Galphai / o in the occipital cortex of suicide victims and matched controls revealed a blunted response in suicide subjects and a decrease in the coupling of P08908 receptor to adenylyl cyclase . No significant group differences were detected in the expression levels of Galphai / o , Galphaq / 11 or Galphas proteins , or in the activity of DB02527 - dependent protein kinase A . Studies of a parallel transduction pathway downstream from P08908 receptor activation demonstrated a decrease in the activity of phosphatidylinositol 3 - kinase and its downstream effector Akt , as well as an increase in P60484 ( phosphatase and tensin homolog deleted on chromosome 10 ) , the phosphatase that hydrolyzes phosphatidylinositol 3 , 4 , 5 - triphosphate . Finally , the activation of extracellular signal - regulated kinases 1 and 2 was attenuated in suicide victims . These data suggest that the alterations in agonist - stimulated P08908 receptor activation in depressed suicide victims are also manifest downstream from the associated G protein , affecting the activity of second messengers in two P08908 receptor transduction pathways that may have implications for cell survival .", "Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects . The capability of pravastatin and lovastatin , P04035 inhibitors likely to be taken chronically for hypercholesterolemia , to cross the blood - brain barrier was investigated in normal male volunteers . DB00227 , which is lipophilic , was detected in cerebrospinal fluid ( P04141 ) at concentrations that may have a pharmacologic effect . ___MASK87___ , which is hydrophilic , was not detected in P04141 . It is concluded that pravastatin may have less potential for causing CNS - related side effects than lovastatin .", "Serotonin via P34969 receptors activates p38 mitogen - activated protein kinase and protein kinase C epsilon resulting in interleukin - 6 synthesis in human U373 MG astrocytoma cells . Serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes . Previously , it has been demonstrated that 5 - HT may induce interleukin ( IL ) - 6 expression in primary rat hippocampal astrocytes . The present study was undertaken to investigate the molecular pathways underlying this induction of P05231 synthesis . As a model system , we used the human astrocytoma cell line U373 MG , which synthesizes P05231 upon stimulation with various inducers . 5 - HT dose - and time - dependently induced P05231 protein synthesis . We identified several 5 - HT receptors to be expressed on U373 MG cells , including the P28221 , 5 - Q13049 , 5 - Q9H205 and P34969 receptors . In this report , we show that the 5 - HT - induced P05231 release is mediated by the P34969 receptor based on several agonist / antagonists that were used . 5 - HT - induced P05231 synthesis is inhibited by the partially selective P34969 receptor antagonist , pimozide , and the selective antagonist SB269970 . Furthermore , P05231 synthesis was induced by the P34969 receptor agonist carboxamidotryptamin . In addition , we found p38 MAPKs and protein kinase C ( PKC ) epsilon to be involved in 5 - HT - induced P05231 synthesis as specific inhibitors of these enzymes ( SB202190 and RO - 31 - 8425 , respectively ) blocked 5 - HT - induced P05231 synthesis . Furthermore , 5 - HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform . The Q8NFH3 / 44 MAPKs , however , were not involved in 5 - HT - induced P05231 synthesis . This study shows , for the first time , a central role of P34969 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells .", "Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .", "Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .", "Human P30939 receptor - stimulated [ 35S ] GTPgammaS binding : correlation with inhibition of guinea pig dural plasma protein extravasation . To determine the potency and efficacy of P30939 receptor ligands , a [ 35S ] GTPgammaS binding assay was developed and optimized for the human P30939 receptor . Compounds which are known to be effective in the abortive treatment of migraine were tested for efficacy and potency in this assay . DB00952 , sumatriptan , zolmitriptan , and rizatriptan all had agonist activity . The P30939 receptor ligand LY334370 ( 4 - fluoro - N -[ 3 -( 1 - methyl - 4 - piperidinyl )- 1H - indol - 5 - yl ]- benzamide ) was the most potent compound tested with an EC50 of 2 . 13 +/- 0 . 15 nM . LY302148 ( 5 - fluoro - 3 -[ 1 -[ 2 -( 1 - methyl - 1H - pyrazol - 4 - yl ) ethyl ]- 4 - piperidinyl ]- 1H - ind ole ) , methysergide , LY306258 ( 3 - dimethylamino - 2 , 3 , 4 , 9 - tetrahydro - 1H - carbazol - 6 - ol ) , dihydroergotamine ( DHE ) , L - 694 , 247 and CP - 122 , 288 were also investigated for potency and efficacy . There was a statistically significant correlation between the pEC50 for the stimulation of [ 35S ] GTPgammaS binding and the pID50 for the inhibition of trigeminal nerve - stimulated dural plasma protein extravasation in the guinea pig . In the course of these studies , it was found that the purportedly selective P28221 receptor antagonist GR127935 inhibited P30939 receptor - stimulated [ 35S ] GTPgammaS binding with a Ki of 39 . 6 +/- 9 . 5 nM . These studies demonstrate that P30939 receptor - mediated stimulation of [ 35S ] GTPgammaS binding in a clonal cell system is a reproducible , high throughput assay that is predictive of an in vivo model of P30939 receptor activation .", "High - dose heparin suppresses platelet alpha granule secretion . Platelet degranulation has been implicated in the pathophysiology of acute arterial thrombosis , intimal hyperplasia , and atherogenesis . Most previous studies that examined the effect of heparin on platelet function have used platelet aggregometry . These studies have resulted in contradictory data and , by the nature of the assay , reveal no information with regard to platelet degranulation . In contrast , flow cytometry allows accurate quantification of the extent of platelet degranulation by measurement of the platelet surface binding of a P16109 specific monoclonal antibody ( P28222 ) . P16109 is only expressed on the platelet surface after platelet alpha granule release . In the present study increasing concentrations of heparin were added to whole blood anticoagulated with sodium citrate . Platelets were activated with a panel of agonists , and the extent of platelet degranulation was quantified by whole blood flow cytometry . ___MASK60___ concentrations as high as 100 units / ml were found to suppress platelet alpha granule release induced by either a thromboxane A2 analog ( U46619 ) or a combination of adenosine diphosphate and epinephrine . ___MASK60___ suppressed alpha granule release induced by thrombin both in whole blood and in washed platelets . The addition of heparin after platelet activation had no effect on P28222 binding . In summary , heparin in high concentrations is a potent inhibitor of platelet degranulation , an action that is unrelated to its effect on the coagulation cascade . Although the heparin concentrations used in this study exceed those used clinically by a factor of 10 or more , future studies of heparin fractions may allow the separation of the anticoagulant and antiplatelet properties of the molecule and allow the administration of an agent that selectively suppresses platelet degranulation without the humoral anticoagulant effect .", "Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK31___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .", "Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK92___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .", "Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .", "DB00952 has a selective inhibitory effect on trigeminovascular neurones at central P08908 and 5 - HT ( 1B / 1D ) receptors in the cat : implications for migraine therapy . The triptans are agonists at serotonin ( 5 - HT ) 1B / 1D receptors ; however , they are also active at P08908 and P30939 receptors . We conducted this series of experiments to further elucidate the site of action of naratriptan using a well - established animal model of trigeminovascular stimulation . Following electrical stimulation of the superior sagittal sinus of the cat , single cell responses ( n = 83 ) were recorded in the trigeminal nucleus caudalis . Most cells ( 91 % ) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields . The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation ( response suppressed by 47 +/- 4 % , P < 0 . 001 ) . The effect of naratriptan was significantly attenuated by application of either the 5 - HT ( 1B / 1D ) receptor antagonist GR - 127935 ( P < 0 . 001 ) or the P08908 antagonist WAY - 100635 ( P < 0 . 05 ) . The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan , but by only 20 +/- 3 % . Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs . receptive field responses in trigeminal neurones . These results indicate that naratriptan has a central effect in the trigeminovascular system , selectively inhibiting afferent activity in craniovascular neurones , via both 5 - HT ( 1B / 1D ) and P08908 receptors .", "DB00952 . The new P28222 / 1D agonist naratriptan , introduced in many countries in 1997 and 1998 for the acute treatment of migraine , was designed to complement the sumatriptan portfolio of offerings ( including the injection , the tablets , the nasal spray , and in some countries , the suppository ) by offering patients excellent tolerability and a sustained duration of action . Clinical studies on naratriptan , including more than 4000 patients treating more than 15 , 000 migraine attacks , show that naratriptan tablets 2 . 5 mg are distinguished from other P28222 / 1D agonists for migraine on the basis of their excellent tolerability profile , which does not differ from that of placebo . In addition to its tolerability , naratriptan tablets 2 . 5 mg possess a long duration of action with a low incidence of headache recurrence ( 17 - 28 % in phase II and III clinical trials ) . With its tolerability profile and long duration of action , naratriptan tablets 2 . 5 mg may be particularly appropriate as a single - dose alternative to NSAIDs and analgesics , which often are not effective in migraine but are used because of tolerability considerations .", "Post - DB00669 era for the treatment of acute migraine . There now is one realized and several attractive targets for the treatment of acute attacks of migraine that will follow and augment the use of serotonin P28222 / 1D receptor agonists , the triptans . P01258 gene - related peptide ( P80511 ) receptor blockade recently has been shown to be an effective acute antimigraine strategy ; therefore , blockade of P80511 release by inhibition of trigeminal nerves would seem a logical approach . A number of targets are reviewed in this article including serotonin P30939 and P28221 receptors , adenosine A1 receptors , nociceptin , vanilloid Q8NER1 receptors , and anandamide P21554 receptors . Development of one or more such compound offers the exciting prospect of new non - vasoconstrictor treatments for migraine and cluster headache .", "Role of serotonin in the regulation of interferon - gamma production by human natural killer cells . Monocytes , recovered directly from peripheral blood by counter - current centrifugal elutriation ( CCE ) , were shown to provide two regulatory signals for induction of interferon - gamma ( P01579 ) in natural killer ( NK ) cells in response to interleukin - 2 ( P60568 ) : an upregulating signal and an inhibitory signal . The inhibitory signal was time - dependent , irreversible , and operating on a pretranslational level , as indicated by the inability of enriched NK cells to accumulate P01579 mRNA in the presence of elutriated monocytes . Monocyte - induced inhibition of P01579 production was abrogated by the biogenic amine serotonin , acting via the 5 - hydroxytryptamine , or serotonin ( P08908 ) , subset of serotonin receptors ( 5 - HTR ) . Thereby , serotonin effectively promoted P01579 production in the presence of monocytes . We conclude that serotonergic P08908 receptors transduce signals that are required for NK cells to produce P01579 in response to P60568 .", "Indian red scorpion ( Buthus tamulus ) venom - induced augmentation of cardiac reflexes is mediated through the involvement of peripheral 5 - Q9H205 and central P08908 receptor subtypes . The present study was undertaken to identify 5 - HT receptor subtypes involved in Buthus tamulus ( BT ) venom - induced augmentation of cardiac reflexes elicited by phenyldiguanide ( PDG ) . Intravenous injection of PDG ( 10 microg / kg ) produced parallel decrease in mean arterial pressure ( Q96HU1 ) and heart rate ( HR ) in urethane anaesthetized rats ( r = 0 . 82 ; p < 0 . 001 ) . Injection of PDG ( 1 - 40 microg / kg , i . v . ) produced concentration - dependent decrease in time - response area of the HR . After BT venom ( 20 microg / kg ) the concentration - response curve was shifted to the left . Further , fall of Q96HU1 and HR in response to submaximal concentration of PDG ( 10 microg / kg ) were augmented significantly . Pretreatment with 5 - Q9H205 receptor antagonist ( ondansetron ; 10 microg / kg ) intravenously , blocked the BT venom - induced augmentation of PDG reflex but spiperone ( 100 microg / kg ; P08908 / 5 - HT2 antagonist ) or ketanserin ( 300 microg / kg ; 5 - HT2 antagonist ) failed to do so . Afferent discharges elicited by PDG ( 10 microg / kg ) in vagus nerve were doubled after exposure to BT venom . ___MASK92___ ( 100 microg / kg , i . v . ) totally abolished the discharges after exposure to BT venom but not by spiperone or ketanserin . Intracerebroventricular injection of spiperone ( 100 microg / kg ) but not ketanserin or ondansetron , blocked the BT venom - induced augmentation of PDG reflex . Results show that the BT venom - induced augmentation of reflex elicited by PDG is mediated through the involvement of 5 - Q9H205 receptors peripherally and P08908 type of receptors centrally .", "Molecular determinants of trastuzumab efficacy : What is their clinical relevance ? ___MASK47___ - containing therapy is a standard of care for human epidermal growth factor receptor - 2 ( P04626 ) - positive breast cancer . In pre - clinical models , a wide range of molecular mechanisms have been associated with reduced sensitivity to trastuzumab in vitro . These include expression of the truncated P04626 receptor fragment p95HER2 , activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3 - kinase ( P42336 ) , loss of phosphatase and tensin homolog ( P60484 ) , activation of other downstream signal transducers , prevention of cell cycle arrest , increased signaling through alternative ( HER or non - HER ) tyrosine kinase receptors , and resistance to antibody - dependent cellular cytotoxicity . However , the clinical significance of these mechanisms as determinants of trastuzumab efficacy in vivo has been unclear . Here , we review clinical studies of potential predictive biomarkers of trastuzumab efficacy in P04626 - positive breast cancer and consider whether evaluation of such markers might inform patient selection for therapy . We find that clinical evidence relating to potential predictive biomarkers is mostly limited to small , retrospective studies , many of which have yielded conflicting findings . Some trends are evident in the retrospective data and in biomarker analyses from randomized clinical trials , particularly relating to activation of the phosphatidylinositol 3 - kinase pathway , but none is sufficiently strong to form a basis for patient selection . This may be explained by the fact that multiple mechanisms of action determine the clinical efficacy of trastuzumab . In the absence of novel , validated biomarkers of efficacy , trastuzumab eligibility should continue to be based on evaluation of P04626 status according to standard methods .", "Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes . OBJECTIVE : Type 2 diabetes is a common complex disorder with environmental and genetic components . We used a candidate gene - based approach to identify single nucleotide polymorphism ( SNP ) variants in 222 candidate genes that influence susceptibility to type 2 diabetes . RESEARCH DESIGN AND METHODS : In a case - control study of 1 , 161 type 2 diabetic subjects and 1 , 174 control Finns who are normal glucose tolerant , we genotyped 3 , 531 tagSNPs and annotation - based SNPs and imputed an additional 7 , 498 SNPs , providing 99 . 9 % coverage of common HapMap variants in the 222 candidate genes . Selected SNPs were genotyped in an additional 1 , 211 type 2 diabetic case subjects and 1 , 259 control subjects who are normal glucose tolerant , also from Finland . RESULTS : Using SNP - and gene - based analysis methods , we replicated previously reported SNP - type 2 diabetes associations in P37231 , Q14654 , and P11168 ; identified significant SNPs in genes with previously reported associations ( P22413 [ rs2021966 , P = 0 . 00026 ] and NRF1 [ rs1882095 , P = 0 . 00096 ] ) ; and implicated novel genes , including Q13905 ( rs4740283 , P = 0 . 00013 ) and P04637 ( rs1042522 , Arg72Pro , P = 0 . 00086 ) , in type 2 diabetes susceptibility . CONCLUSIONS : Our study provides an effective gene - based approach to association study design and analysis . One or more of the newly implicated genes may contribute to type 2 diabetes pathogenesis . Analysis of additional samples will be necessary to determine their effect on susceptibility .", "Differential functional activity of 5 - hydroxytryptamine receptor ligands and beta adrenergic receptor antagonists at 5 - hydroxytryptamine1B receptor sites in Chinese hamster lung fibroblasts and opossum renal epithelial cells . Functional activity of 5 - hydroxytryptamine ( 5 - HT ) receptor ligands and beta adrenergic receptor antagonists was studied at P28222 receptor sites in Chinese hamster lung ( CHL ) fibroblasts by measuring two cellular responses : inhibition of forskolin - stimulated cyclic AMP formation and potentiation of basic fibroblast growth ( BFGF ) induced mitogenesis . A good correlation was found between the potency of agonists to inhibit forskolin - induced cyclic AMP formation and their potency to potentiate P09038 - induced thymidine incorporation in CHL fibroblasts . Potent agonist activity was measured with 5 - methoxy - 3 , 1 , 2 , 3 , 6 - tetrahydro - 4 - pyidinyl - 1H - indole ( RU 24 , 969 ) , 5 - carboxamidotryptamine ( 5 - CT ) , 3 -( 1 , 2 , 5 , 6 )- tetrahydro - 4 - pyridyl - 5 - pyrrolo ( 3 , 2 - b ) pyril - 5 - one ( CP 93 , 129 ) and 5 - HT , whereas sumatriptan displayed weak agonist activity at concentrations different from its binding affinity for P28222 binding sites . In contrast to the observed P28222 receptor - mediated agonist activity in opossum kidney cells for metergoline and the beta adrenergic receptor antagonists : cyanopindolol , 4 -( 3 - tert - butyl - amino - 2 - hydroxypropoxy )- indole - 2 carbonic acid isopropyl ester ( SDZ 21 , 009 ) , isamoltane , (-)- propranolol and (-)- pindolol , antagonist activity at P28222 receptor sites was yielded in CHL fibroblasts in accordance with the reported observations at rat brain P28222 receptors . Methiothepin was the only compound that antagonized both the opossum kidney cell and CHL fibroblast P28222 receptor - mediated responses although the antagonist effect was more pronounced in CHL fibroblasts . ( ABSTRACT TRUNCATED AT 250 WORDS )", "Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .", "DB00952 mitigates CGRP1 - associated motor neuron degeneration caused by an expanded polyglutamine repeat tract . Spinal and bulbar muscular atrophy ( SBMA ) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor ( AR ) gene . Here , we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene - related peptide α ( CGRP1 ) . In neuronal cells , overexpression of CGRP1 induced cellular damage via the activation of the c - Jun N - terminal kinase ( JNK ) pathway , whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR . The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA . DB00952 , a serotonin 1B / 1D ( 5 - hydroxytryptamine 1B / 1D , or P28222 / 1D ) receptor agonist , decreased CGRP1 expression via the induction of dual - specificity protein phosphatase 1 ( P28562 ) , attenuated JNK activity and mitigated pathogenic AR - mediated neuronal damage in cellular and mouse SBMA models . These observations suggest that pharmacological activation of the P28222 / 1D receptor may be used therapeutically to treat SBMA and other polyglutamine - related neurodegenerative diseases .", "Urgosedin inhibits hypotension , hypoglycemia , and pro - inflammatory mediators induced by lipopolysaccharide . Urgosedin is a newly synthesized compound especially with serotonergic and alpha - adrenergic blocking actions . In rat isolated thoracic aorta , urgosedin competitively antagonized norepinephrine - , clonidine - , and serotonin - induced vasocontractions in a concentration - dependent manner . In radioligand binding experiments , urgosedin had significant binding affinities on alpha1 / alpha2 , P08908 , P28222 and 5 - Q13049 receptors . Intravenous injection of lipopolysaccharide ( LPS ) produced a biphasic hypotension in normotensive rats . Although intravenous injection of urgosedin caused minor depressor actions in the normotensive Wistar rat , urgosedin significantly attenuated the secondary prolonged hypotension produced by LPS . The plasma levels of cytokines ( IL - 1beta , P05231 , P01375 , and P01579 ) and hypoglycemia induced by LPS were also reduced by urgosedin . Moreover , the acute survival rates ( 350 minutes ) of endotoxic shock increased from 0 % ( LPS group ) to 100 % in the groups pretreated with urgosedin . In RAW264 . 7 cells , urgosedin inhibited LPS - induced inducible nitric oxide synthase ( P35228 ) expression . In conclusion , our data suggest that urgosedin was a newly potent serotonergic and mild alpha - adrenergic blocking agent . Its prevention of LPS - induced hypotension and hypoglycemia might partially mediate through its inhibition activities on the P35228 expression and cytokines formation . Urgosedin might be an effective pharmacological agent against LPS - induced hypotension , hypoglycemia , and the formation of pro - inflammatory mediators .", "A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near - triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M - Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M - Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH @ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis .", "Structure functional expression and spatial distribution of a cloned cDNA encoding a rat P28221 - like receptor . Using polymerase chain reaction ( PCR ) a complementary DNA ( cDNA ) encoding a 5 - hydroxytryptamine ( 5 - HT ) receptor was isolated from rat forebrain . The amplified cDNA specifies an open reading frame of 374 amino acids comprising seven putative transmembrane regions . Expression of the cloned cDNA in human embryonic kidney cells ( P29320 293 ) was used to establish the pharmacological profile of the encoded receptor polypeptide . Membranes containing the cloned receptor showed high affinity binding of [ 3H ] - 5 - HT . Competition binding experiments with a variety of serotonin receptor ligands displayed a rank order of affinities corresponding to a P28221 subtype : 5 - CT > 5 - HT = metergoline > CGS 12066 > methysergide > sumatriptan > mianserin = (-) alpha - Me - 5 - HT = yohimbine > 8 - OH - DPAT > or = rauwolscine > spiperone > DOI > propranolol > or = 2 - Me - 5 - HT > or = ICS 205930 . Ketanserin and ritanserin displaced [ 3H ] - 5 - HT - binding in a biphasic manner . In situ hybridization revealed highest expression of the corresponding mRNA in the pyramidal layer of the olfactory tubercle and the nucleus caudatus and accumbens .", "AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK65___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .", "[ Pharmacy - clinic medication of the month . DB00952 ( naramig ) ] . DB00952 , launched by Glaxo Wellcome under the trade name Naramig , is a potent and selective agonist of P28222 and P28221 vascular receptors . Available as tablets of 2 . 5 mg , it is indicated in the acute treatment of migraine , with or without aura . A single oral dose of 2 . 5 mg naratriptan is characterized by a satisfactory clinical efficacy ( already significant after one hour , maximum after 4 hours and persisting during 24 hours ) , a reduction by half of the recurrence of the migraine crisis within the 24 hours and an excellent tolerance profile .", "___MASK60___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK60___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK60___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .", "P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .", "2 ( 3H )- benzoxazolone and bioisosters as \" privileged scaffold \" in the design of pharmacological probes . The 2 ( 3H )- benzoxazolone heterocycle and its bioisosteric surrogates ( such as 2 ( 3H )- benzothiazolinone , benzoxazinone , etc . ) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template . These heterocycles and pyrocatechol have indeed similar pKa ' s , electronic charge distribution , and chemical reactivity . Therapeutic applications of this template are very broad , and range from analgesic anti - inflammatory compounds ( including P37231 antagonists ) to antipsychotic and neuroprotective anticonvulsant compounds . High affinity ligands have been obtained also for dopaminergic ( D2 and D4 ) , serotoninergic ( P08908 and P28223 ) , sigma - 1 and sigma - 2 receptors . Owing to the high number of positive hits encountered with this heterocycle and its congeners , 2 ( 3H )- benzoxazolone template certainly deserves the title of \" privileged scaffold \" in medicinal chemistry .", "Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK16___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK16___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .", "Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK45___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .", "TATA - driven transcriptional initiation and regulation of the rat serotonin P08908 receptor gene . The transcriptional initiation and regulation of the rat serotonin P08908 receptor gene were characterized . By three types of analyses , a single brain - specific site of transcriptional initiation was localized to - 967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line . This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element , suggesting TATA - driven transcription of the rat P08908 receptor . To identify the promoter activity of the receptor gene , progressive 5 ' deletions of the - 2 , 719 /- 117 - bp fragment of the P08908 promoter linked to luciferase gene were transfected into P08908 - negative ( pituitary GH4C1 , Q9BTT4 myoblast , and P13671 glioma ) and P08908 - positive ( septal SN - 48 and raphe RN46A ) cell lines . Enhancer regions were identified within a fragment between nucleotides - 426 and - 117 that selectively enhanced transcription in P08908 - positive cells . A nonselective enhancer / promoter that mediated expression in all cell lines was located upstream between - 1 , 519 and - 426 bp in a DNA segment containing consensus TATA , CCAAT , SP - 1 , and AP - 1 elements as well as a poly - GT26 dinucleotide repeat . Strong repression of transcription in all cell lines was conferred by the region upstream of - 1 , 519 bp that contains a 152 - bp DNA segment with > 80 % identity to RANTES , tumor necrosis factor - beta , and other immune system genes . Our results indicate that TATA - driven expression of the P08908 receptor is regulated by a novel proximal tissue - specific enhancer region , a nonselective promoter , and an upstream repressor region that is distinct from previously identified neuron - specific repressors .", "[ The cluster headache : a clinical model of immunologic receptor pathology ? ] . It is well established that cluster headache shows impaired functions at their neuroimmunomodulatory system level . Defect in receptor expression for 5 - HT , IL - 1 and P60568 have been found in these patients . Sumatriptan , a molecule with agonistic activity for P28221 receptor , truncates cluster headache attacks in 74 % of patients . Flow cytometric analysis of monocytes expressing 5 - HT receptor in cluster headache patients showed different trends clearly correlated with the clinical response to sumatriptan . Our findings strongly support the concept that cluster headache patients who are non responders to sumatriptan could present a block in their 5 - HT receptor possibly due to specific autoantibodies for this receptor site .", "Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK47___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK47___ is also being investigated as part of triplet drug regimens . ___MASK47___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .", "P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .", "Arsenic decreases antinociceptive activity of paracetamol : possible involvement of serotonergic and endocannabinoid receptors . We assessed whether repeated arsenic exposure can decrease paracetamol - mediated antinociception by modulating serotonergic and endocannabinoid pathways . Rats were preexposed to elemental arsenic ( 4ppm ) as sodium arsenite through drinking water for 28 days . Next day paracetamol ' s ( 400mg / kg , oral ) antinociceptive activity was assessed through formalin - induced nociception . Serotonin content and gene expression of P08908 , 5 - Q13049 and P21554 receptors were evaluated in brainstem and frontal cortex . Arsenic decreased paracetamol - mediated analgesia . DB00316 , but not arsenic , increased serotonin content in these regions . Arsenic attenuated paracetamol - mediated increase in serotonin level . DB00316 did not alter P08908 expression , but caused down - regulation of 5 - Q13049 and up - regulation of P21554 receptors . Arsenic down - regulated these receptors . However , paracetamol - mediated down - regulation of 5 - Q13049 was more pronounced . Arsenic did not modify paracetamol ' s effect on P08908 expression , but reduced paracetamol - mediated down - regulation of 5 - Q13049 and reversed up - regulation of P21554 receptors . Results suggest arsenic reduced paracetamol - induced analgesia possibly by interfering with pronociceptive 5 - Q13049 and antinociceptive P21554 receptors .", "Evidence for a spinal serotonergic control of the peripheral inflammation in the rat . We investigated the effect of serotonergic agonists and antagonists injected intrathecally by direct punction of the spinal cord at the lumbar level ( between Q15004 - Q9BTT4 ) on peripheral inflammatory edema . Edema was induced by carrageenan injected subcutaneously in one hindpaw 30 min after spinal treatments . Serotonin ( 0 . 1 , 1 , 10 pmol ) caused a graded - inhibition of the inflammatory paw edema . The corticosteroid inhibitor aminoglutethimide ( 100 mg / kg , p . o . 1 . 5 h before spinal treatment ) did not modify this effect . The P08908 agonist buspirone and the P28222 / 1D agonist sumatriptan ( 0 . 1 , 1 . 0 and 10 nmol ) also inhibited paw edema . The 5 - HT1 , 2 antagonist methysergide ( 10 and 100 pmol ) enhanced edema , but higher doses ( 4 and 8 nmol ) diminished edema . NAN - 190 ( 5 - HT1 antagonist ; 1 and 10 nmol ) increased paw edema , while ritanserin ( 5 - HT2 antagonist ; 1 nmol ) inhibited paw edema . ___MASK92___ ( 5 - Q9H205 antagonist ; up to 10 nmol ) did not affect edema , but metoclopramide ( 5 - Q9H205 antagonist / Q13639 agonist ; 5 , 10 and 30 pmol ) inhibited edema . These data suggest that a tonic release of serotonin in the spinal cord may occurs during ongoing peripheral inflammation , modulating the neurogenic component of edema either by an inhibitory action on 5 - HT1 receptors or by a stimulatory action on 5 - HT2 receptors . A disfunction in such mechanism may be involved in the pathophysiology of certain types of headaches or migraine , which seem to depend on neurogenic vasodilation , and may also help to explain the therapeuthic effectiveness of some serotonergic agents in these conditions .", "Evidence for serotonin ( 5 - HT ) 1B , P28221 and P30939 receptor inhibitory effects on trigeminal neurons with craniovascular input . Development of serotonin ( 5HT ( 1B / 1D ) ) agonists for the acute attack of migraine resulted in considerable interest in their action . The superior sagittal sinus ( SSS ) was isolated in alpha - chloralose ( 60 mg / kg , i . p . and 20 mg / kg i . v . i . supplementary 2 hourly ) anaesthetised cats . The SSS was stimulated electrically ( 100 V , 250 micros duration , 0 . 3 Hz ) and neurons of the trigeminocervical complex monitored using electrophysiological methods . To test 5 - HT ( 1B ) receptor - mediated activity common carotid blood flow ( CCF ) was monitored with a transonic flow probe placed around the vessel . DB00952 ( 5 - HT ( 1B / 1D / 1F ) receptor agonist ) and alniditan ( 5 - HT ( 1B / 1D ) receptor agonist ) produced reductions in carotid blood flow of 38 +/- 5 % and 42 +/- 6 % , respectively . These effects were attenuated by the 5 - HT ( 1B ) receptor antagonist SB224289 ( P < 0 . 05 ) . LY344864 ( 5 - HT ( 1F ) receptor agonist ) had no effect on CCF . DB00952 inhibited SSS - evoked activity ( 61 +/- 7 % ) , an effect partially inhibited by the 5 - HT ( 1B ) receptor antagonist SB224289 ( 30 +/- 5 % ) , or by the 5 - HT ( 1D ) receptor antagonist O95696 - 15572 ( 37 +/- 6 % ) . There remained an inhibitory effect of naratriptan after both 5 - HT ( 1B ) and 5 - HT ( 1D ) receptor blockade ( 22 +/- 5 % ) . Alniditan inhibited SSS - evoked trigeminal activity ( 53 +/- 6 % ) , an effect abolished after 5 - HT ( 1B ) and 5 - HT ( 1D ) receptor blockade . LY344864 ( 5 - HT ( 1F ) receptor agonist ) inhibited SSS - evoked trigeminal activity ( 28 +/- 5 % ) , an effect unaltered by either SB224289 or O95696 - 15572 . It can be concluded that there are inhibitory 5 - HT ( 1B ) , 5 - HT ( 1D ) and 5 - HT ( 1F ) receptors in the trigeminocervical complex of the cat . 5 - HT ( 1B ) receptor - mediated inhibition is the most potent of the three in terms of inhibition of trigeminovascular nociceptive traffic .", "P08908 receptor responsivity in unipolar depression . Evaluation of ipsapirone - induced DB01285 and cortisol secretion in patients and controls . The selective P08908 receptor ligand ipsapirone ( IPS ) induces corticotropin ( DB01285 ) and cortisol secretion in humans . To explore P08908 receptor - mediated hypothalamic - pituitary - adrenal ( Q9Y251 ) system activation in depression , 24 subjects ( 12 patients with unipolar depression and 12 individually matched controls ) were given 0 . 3 mg / kg IPS or placebo in random order . Compared with controls , the depressed patients exhibited significantly decreased DB01285 and cortisol responses to IPS in association with increased basal cortisol secretion . The impaired Q9Y251 response following P08908 receptor challenge in unipolar depression could have resulted from glucocorticoid - dependent subsensitivity of the ( post - synaptic ) P08908 receptor itself and / or from a defective postreceptor signaling pathway [ inhibitory guanine nucleotide - binding protein ( Gi ) - adenylate cyclase complex function ] , thus supporting the hypothesis that a disintegrated 5 - HT and Q9Y251 system interaction may be present in depression . Future studies of the Q9Y251 response to direct - acting P08908 ligands , such as IPS , should facilitate the assessment of 5 - HT / Q9Y251 system integrity in various affective disorders and its involvement in psychotropic drug effects .", "A new clinical evidence - based gene - environment interaction model of depression . In our current understanding of mood disorders , the role of genes is diverse including the mediation of the effects of provoking and protective factors . Different or partially overlapping gene sets play a major role in the development of personality traits including also affective temperaments , in the mediation of the effects of environmental factors , and in the interaction of these elements in the development of depression . Certain genes are associated with personality traits and temperaments including e . g . , neuroticism , impulsivity , openness , rumination and extroversion . Environmental factors consist of external ( early and provoking life events , seasonal changes , social support etc . ) and internal factors ( hormones , biological rhythm generators , comorbid disorders etc ) . Some of these environmental factors , such as early life events and some prenatal events directly influence the development of personality traits and temperaments . In the NEWMOOD cohort polymorphisms of the genes of the serotonin transporter , P08908 , P28222 and 5 - Q13049 and endocannabinoid P21554 receptors , tryptophan hydroxylase , P16220 , P23560 and GIRK provide evidence for the involvement of these genes in the development of depression . Based on their role in this process they could be assigned to different gene sets . The role of certain genes , such as promoter polymorphisms of the serotonin transporter ( 5 - HTTLPR ) and P21554 receptor has been shown in more than one of the above factors . Furthermore , gene - gene interactions of these promoters associated with anxiety suggest the application of these polymorphisms in personalized medicine . In this review we introduce a new model including environmental factors , genes , trait and temperament markers based on human genetic studies .", "DB00952 : a review . Even though naratriptan and sumatriptan are both P28222 / P28221 receptor agonists , the biological and pharmacokinetic profile of naratriptan differs significantly from that of sumatriptan . With a plasma half - life of 6 h , very high oral bioavailability of 63 - 74 % and higher lipophilicity than sumatriptan , naratriptan exhibits a distinct clinical therapeutic profile . The similar tolerability to placebo , prolonged efficacy for 24 h or more and very low headache recurrence rate make naratriptan an attractive option in the treatment of acute migraine .", "Identification of a potential molecular link between the glucocorticoid and serotonergic signaling systems . P04150 ( GR ) and serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) signaling systems play a pivotal role in the regulation of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis , but the molecular nature of interactions between these two systems remain largely unidentified . We used computational and experimental approaches to evaluate if DNA - protein interactions would provide a molecular link for the interaction between 5 - HT and GR systems . Bioinformatic analysis identified nine binding sites in various serotonin receptors ( P28221 , P30939 , P28223 , P46098 , and P50406 ) for transcription factors in the GR family . Electrophoretic mobility shift assays ( EMSA ) using HeLa nuclear extract and purified full - length GR verified most of the predicted DNA - protein interactions . Six binding sites verified by EMSA results were evolutionarily conserved in multiple species . Multiple lines of evidence from computational and experimental analyses in this study support the potential of a molecular link between 5 - HT and GR signaling systems . This finding provides new approaches to studies directed at mechanisms for glucocorticoid negative feedback regulation of the Q9Y251 axis involving 5 - HT and interventional studies directed to neuropsychiatric diseases .", "Mapping of the serotonin P28221 beta autoreceptor gene on chromosome 6 and direct analysis for sequence variants . Abnormal brain serotonin function may be characteristic of several neuropsychiatric disorders . Thus , it is important to identify polymorphic genes and screen for functional variants at loci coding for genes that control normal serotonin functions . P28221 beta is a terminal serotonin autoreceptor which may play a role in regulating serotonin synthesis and release . Using an SSCP technique we screened for P28221 beta coding sequence variants in psychiatrically interviewed populations , which included controls , alcoholics , and alcoholic arsonists and alcoholic violent offenders with low P04141 concentrations of the main serotonin metabolite 5 - HIAA . A common polymorphism was identified in the P28221 beta gene with allele frequencies of 0 . 72 and 0 . 28 . The SSCP variant was caused by a silent G to C substitution at nucleotide 861 of the coding region . This polymorphism could also be detected as a HincII RFLP of amplified DNA . DNAs from informative CEPH families were typed for the HincII RFLP and analyzed with respect to 20 linked markers on chromosome 6 . Multipoint analysis placed the P28221 beta receptor gene between markers D6S286 and D6S275 . A maximum two - point lod score of 10 . 90 was obtained to D6S26 , which had been previously localized on 6q14 - 15 . Chromosomal aberrations involving this region have been previously shown to cause retinal anomalies , developmental delay , and abnormal brain development . This region also contains the gene for North Carolina - type macular dystrophy .", "A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK2___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK2___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .", "Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat ." ]

[ "___MASK16___", "___MASK2___", "___MASK31___", "___MASK45___", "___MASK47___", "___MASK60___", "___MASK65___", "___MASK87___", "___MASK92___" ]